Atlas of Parathyroid Imaging and Pathology 3030409589, 9783030409586

Citation preview

Alexander L. Shifrin L. Daniel Neistadt Pritinder K. Thind Editors

Atlas of Parathyroid Imaging and Pathology

123

Atlas of Parathyroid Imaging and Pathology

Alexander L. Shifrin  •  L. Daniel Neistadt Pritinder K. Thind Editors

Atlas of Parathyroid Imaging and Pathology

Editors Alexander L. Shifrin Department of Surgery Jersey Shore University Medical Center Neptune, NJ USA

L. Daniel Neistadt Lenox Hill Radiology New York, NY USA

Pritinder K. Thind Department of Radiology Jersey Shore University Medical Center Neptune, NJ USA

ISBN 978-3-030-40958-6    ISBN 978-3-030-40959-3 (eBook) https://doi.org/10.1007/978-3-030-40959-3 © Springer Nature Switzerland AG 2020 All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

In memory of my father, Leonid Shifrin, medical engineer, the inventor of thromboelastographs, and my uncle, pediatric surgeon, Vadim Shifrin, MD. To my mother, Margarita Shifrina, for her love and endless support. To my beloved children, Michael, Daniel, Benjamin, Julia, Christian, and Liam, who continue to provide perspective on what is truly important in life. To the love of my life, Svetlana L. Krasnova, for her love, patience, and encouragement. To my teachers, who dedicated their lives and efforts to the science of surgery. Those who made me into a surgeon and inspired me to produce this atlas: William Inabnet, MD; John Chabot, MD; Ali Bairov, MD; Steven Raper, MD; and Jerome Vernick, MD. Alexander L. Shifrin, MD In memory of my father, Inderjit S. Thind, MD, for his guidance. To my mother, Narinder K. Thind, MD, for her unwavering support. To my daughter, Alexandra K. Harrigan, the joy of my life. Pritinder K. Thind, MD In memory of my esteemed radiology colleague Elias Kazam, MD. He was a brilliant teacher and innovator in ultrasonography and CT. I was privileged to have him share his unique diagnostic approach to parathyroid disease. To my fellow physicians, for our discussions and feedback of parathyroid surgery findings. L. Daniel Neistadt, MD

Preface

To use the same words is not a sufficient guarantee of understanding; one must use the same words for the same genus of inward experience; ultimately one must have one’s experiences in common. –– Friedrich Nietzsche

We can rephrase this famous quotation by saying “To use the same radiological study by different radiologic interpreters, or have the same pathological slide evaluated by a different pathologist, is not a sufficient guarantee that the results will be the same regardless of the interpreter. It is the shared experiences of experts in the field that gives the interpreter the ability to be proficient in their field.” This book is designed to highlight this experience and teach the next generation of radiologists, pathologists, endocrinologists, and surgeons the invaluable knowledge of parathyroid imaging and pathology. Over the past 40 years, primary hyperparathyroidism (PHPT) has evolved in its clinical presentation from clinically symptomatic to mildly symptomatic or asymptomatic disease. Indications for the surgical treatment of PHPT were established by the 4th International Workshop for Management and Treatment of Asymptomatic PHPT. Parathyroidectomy is the only curative approach. PHPT is caused by a single parathyroid gland adenoma in 85% of patients and either by multiple adenomas or hyperplasia in all four parathyroid glands in 15% of patients. Preoperative imaging studies are essential, therefore, to localize the parathyroid adenoma and perform successful minimally invasive parathyroidectomy. Several imaging studies are currently used to localize a parathyroid adenoma such as a Sestamibi scan, parathyroid ultrasound, four-dimensional computed tomography (4D CT) scan, and the thin-cut CT scan. Identifying parathyroid adenoma on imaging studies in patients with PHPT is challenging even for experienced radiologists. While the sensitivity of the traditional Sestamibi scan in  localization of parathyroid adenoma was only 50%, newer studies such as the SPECT (single-photon emission computerized tomography)/CT Sestamibi scan has sensitivity of about 85–90%. Currently, in addition to the SPECT/CT Sestamibi scan, several newer imaging modalities have been developed, such as thin-cut CT, 4D CT scans, and parathyroid MRI. Newer ultrasound machines are more sensitive and allow for localization of parathyroid adenomas in up to 85% of the cases. Patients with primary hyperparathyroidism have approximately 10% chance of developing recurrent or persistent disease. This may happen due to inability of the surgeon to find a parathyroid adenoma during the first surgery, failure of the surgeon to recognize additional abnormal parathyroid glands, not completely removing the abnormal parathyroid gland by leaving a portion of the parathyroid gland behind, or recurrence of the disease in glands that were previously normal. The recent Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Fourth International Workshop and the American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism stated that all patients with PHPT would benefit from surgical treatment for PHPT if imaging studies are conclusive in localization of the parathyroid adenoma. Therefore, imaging studies are the standard of care in the treatment of patients with PHPT. They are also crucial for diagnosis and for the surgical recommendation.

vii

viii

Preface

This atlas is designed to provide a visual demonstration of normal and ectopic locations of parathyroid adenomas using different modalities in patients with PHPT and to describe ­parathyroid gland-related pathology. The challenge in localization of parathyroid adenoma is not only in finding the right test to perform but in the expertise of the radiologist or ultrasonographer who may not be sufficiently knowledgeable in identifying parathyroid adenoma on imaging studies. We have included several modern imaging modalities for localization of parathyroid glands and parathyroid adenomas, such as Sestamibi scan, SPECT/CT Sestamibi scan, neck ultrasound, MRI, thin-cut CT, and 4D CT scans. The atlas also includes pathology images corresponding to radiology imaging for some presented cases (gross and high-power view). We have included radiological images of difficult-to-localize parathyroid adenomas in ectopic (abnormal) locations. The atlas is structured by location of the adenomas, such as upper right, lower right, upper left, and lower left parathyroid adenomas. Ectopic presentation and abnormal location of parathyroid glands are also presented. Each case demonstrates dual or triple modalities such as US; Sestamibi scan, or SPECT/CT Sestamibi scan; thin-cut CT scan; or 4D CT performed on the same patient. A chapter on parathyroid pathology was also included to help the reader understand challenges in pathological interpretation. The target audience for the atlas includes radiologists, endocrine surgeons, head and neck surgeons, ENT surgeons, surgical oncologists, endocrinologists, pathologists, nephrologists, endocrine fellows, endocrine surgery fellows, surgical residents, medical residents, radiology residents and fellows, students, and all physicians and allied health practitioners involved in the treatment of patients with primary, secondary, and tertiary hyperparathyroidism. Neptune, NJ, USA New York, NY, USA Neptune, NJ, USA

Alexander L. Shifrin L. Daniel Neistadt Pritinder K. Thind

Acknowledgments

I am very grateful to work with two of my colleagues for more than a decade, coeditors of this atlas, whose expertise helped me become a successful parathyroid surgeon, Dr. L. Daniel Neistadt and Dr. Pritinder Thind. It took them years to become proficient in their fields of radiological imaging. Their experience is indispensable. Special thanks to my colleagues, pathologists Dr. Min Zheng and Dr. Virginia A. LiVolsi, for their fabulous chapter on parathyroid pathology; to my long-term supporter and friend, Dr. Nancy Perrier and Dr. Hubert Chuang, for their images of parathyroid carcinoma; Dr Richard Chang for his chapter on Invasive Techniques for Parathyroid Localization; and to Dr. Jennifer Becker, Dr. Puneet Pawha, and Dr. Kambiz Neal for their tremendous effort in completing the chapter on parathyroid glands MRI. Special thanks to my colleagues, who spent countless hours facilitating surgical procedures, collecting data, and putting the pieces of this book together, Svetlana L. Krasnova, Tara Corrigan, George Kunak, Pedro Garcia, and Gina Soler. Special thanks to the artists who worked on this atlas at Springer; to Executive Editor Richard Hruska, who believed in me, and Senior Editor Lee Klein of Springer for his hard work and dedication. Finally, I would like to thank the entire staff at Springer, who was very supportive from the first idea of this atlas and maintained their enthusiasm until the end. Alexander L. Shifrin, MD, FACS, FACE, ECNU, FEBS (Endocrine), FISS I would like to thank my coauthors, especially Alexander L. Shifrin, who have fostered my interest in parathyroid imaging. In addition, I would like to thank my partners at University Radiology Group for their continued support. Scott Kalick, Department of Radiology at Jersey Shore University Medical Center, was invaluable in procuring the images used in the atlas. Pritinder K. Thind, MD My developing interest and experience in interpreting parathyroid localization studies is due entirely to working with Dr. Elias Kazam over many years. His reputation for accuracy in finding enlarged and normal-sized parathyroid glands drew a wide referral of cases, and I gradually worked into reading the studies. He is a great teacher. Feedback of results is essential to learning the art, and I am grateful to the surgeons who have shared with me their operative findings, particularly inaccuracies in diagnoses. I have interacted with many surgeons in the New York area who have shared their experiences and given advice: Drs. John Carew, Jason P. Cohen, Orrin Davis, Thomas Fahey, William Kuhel, Daniel Kuriloff, James A.  Lee, Jennifer Marti, Jennifer Ogilvie, Kepal Patel, Mark Persky, Edward Rhee, Ashok Shaha, Alexander L. Shifrin, Jonathan Smith, Rakesh Shreedhar, Brian Untch, and Richard Wong. Dr. Daniel Kuriloff (Director, Center for Thyroid and Parathyroid Surgery, New York Head and Neck Institute, Lenox Hill Hospital, New  York) has regularly provided discussions, descriptions, and pictures of operative specimens in multiple cases, providing great correlations to the radiographic pictures and providing insight into surgical decisions. ix

x

Acknowledgments

Most radiology images were performed at the offices of Lenox Hill Radiology, a RadNet subsidiary. I am grateful to RadNet for continuing to keep me connected with radiology beyond the typical retirement age. I am grateful for discussions of difficult cases with my colleagues who read the parathyroid studies: Drs. Douglas Hertford, Shelley Wertheim, Daniel Yang, and Patrick Kang. These discussions clarify our thinking and sharpen our collective acumen, and we share the feedback from referring surgeons. L. Daniel Neistadt, MD

Contents

Part I Ultrasound, Sestamibi Scan, and Pathology of the Parathyroid Glands 1 Parathyroid Ultrasound���������������������������������������������������������������������������������������������   3 Alexander L. Shifrin and Pritinder K. Thind 2 Scintigraphic Parathyroid Imaging���������������������������������������������������������������������������  11 Pritinder K. Thind 3 Pathology of the Parathyroid Glands�����������������������������������������������������������������������  15 Min Zheng and Virginia A. LiVolsi Part II Normal Anatomical Location of the Parathyroid Gland Adenomas: Ultrasound, Sestamibi Scan, and Gross Pathology 4 Right Superior Parathyroid Adenoma���������������������������������������������������������������������  35 Alexander L. Shifrin and Pritinder K. Thind 5 Right Inferior Parathyroid Adenoma�����������������������������������������������������������������������  47 Alexander L. Shifrin and Pritinder K. Thind 6 Left Superior Parathyroid Adenoma �����������������������������������������������������������������������  71 Alexander L. Shifrin and Pritinder K. Thind 7 Left Inferior Parathyroid Adenoma �������������������������������������������������������������������������  83 Alexander L. Shifrin and Pritinder K. Thind Part III Intrathyroidal Parathyroid Adenoma, Cystic Parathyroid Adenoma, and Parathyroid Carcinoma 8 Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid Adenoma������������� 101 Alexander L. Shifrin and Pritinder K. Thind 9 Imaging of the Parathyroid Carcinoma������������������������������������������������������������������� 133 Alexander L. Shifrin, Pritinder K. Thind, Hubert H. Chuang, and Nancy D. Perrier Part IV CT Scan of the Neck in Evaluation of Parathyroid Glands 10 Motivation for Imaging Studies��������������������������������������������������������������������������������� 145 L. Daniel Neistadt 11 Contrast CT Approach����������������������������������������������������������������������������������������������� 149 L. Daniel Neistadt 12 The CT Technique������������������������������������������������������������������������������������������������������� 151 L. Daniel Neistadt 13 Individual CT Phases������������������������������������������������������������������������������������������������� 153 L. Daniel Neistadt xi

xii

14 Sources of False Positive and False Negative Enlarged Parathyroid Glands ������� 157 L. Daniel Neistadt 15 Correlative Ultrasound����������������������������������������������������������������������������������������������� 161 L. Daniel Neistadt 16 Shape, Number, and Size of Parathyroids ��������������������������������������������������������������� 163 L. Daniel Neistadt 17 Location of Parathyroid Glands ������������������������������������������������������������������������������� 165 L. Daniel Neistadt 18 Multigland Disease����������������������������������������������������������������������������������������������������� 169 L. Daniel Neistadt 19 Rare Parathyroid Presentations ������������������������������������������������������������������������������� 171 L. Daniel Neistadt 20 Illustrative Cases��������������������������������������������������������������������������������������������������������� 175 L. Daniel Neistadt 21 Summary: CT Scan of the Neck in the Evaluation of Parathyroid Glands����������� 253 L. Daniel Neistadt Part V Invasive Techniques for Parathyroid Localization 22 Invasive Techniques for Parathyroid Localization��������������������������������������������������� 257 Richard Chang Part VI MRI of the Parathyroid Glands 23 MRI for Imaging Parathyroid Disease��������������������������������������������������������������������� 273 Jennifer L. Becker, Puneet S. Pawha, and Kambiz Nael Index������������������������������������������������������������������������������������������������������������������������������������� 281

Contents

Contributors

Jennifer  L.  Becker, MD  Department of Medical Imaging, University of Arizona, Tucson, AZ, USA Richard  Chang, MD Senior Clinician, Chief, Endocrine and Venous Services Section, Interventional Radiology, Department of Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, MD, USA Hubert H. Chuang, MD, PhD  Department of Nuclear Medicine, University of Texas, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Virginia A. LiVolsi, MD  Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA Kambiz Nael, MD  Department of Radiological Sciences, David Geffen School of Medicine at University of California, Los Angeles, CA, USA L. Daniel Neistadt, MD  Lenox Hill Radiology, Manhattan Diagnostic Radiology, New York, NY, USA Puneet S. Pawha, MD  Department of Radiology at Icahn School of Medicine at Mount Sinai, New York, NY, USA Nancy D. Perrier, MD, FACS  Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Alexander L. Shifrin, MD, FACS, FACE, ECNU, FEBS (Endocrine), FISS  Department of Surgery, Jersey Shore University Medical Center, Neptune, NJ, USA Pritinder K. Thind, MD  University Radiology Group, New Brunswick, NJ, USA Jersey Shore University Medical Center, Department of Radiology, Neptune, NJ, USA Min Zheng, MD, PhD  Department of Pathology, Jersey Shore University Medical Center, Neptune, NJ, USA

xiii

Part I Ultrasound, Sestamibi Scan, and Pathology of the Parathyroid Glands

1

Parathyroid Ultrasound Alexander L. Shifrin and Pritinder K. Thind

Introduction: Diagnosis of Hyperparathyroidism Primary hyperparathyroidism (PHPT) develops as a result of hyperfunctioning parathyroid glands. Up to 85% of cases of primary hyperparathyroidism are due to parathyroid adenomas, while parathyroid glands hyperplasia accounts for about 10% to 15% and parathyroid carcinoma for less than 1% of cases. The prevalence of PHPT in the general population is approximately 0.1%, with a higher incidence in patients older than 60  years of age. Female patients are affected two to three times more often than male patients. Diagnosis of PHPT is established biochemically by findings of an elevated serum calcium level with concurrent elevation in serum parathyroid hormone (PTH) level, which is considered the classic form of PHPT.  An elevation of serum calcium with a serum PTH level in the high normal range is called normohormonal PHPT, and an elevation of the serum PTH level with a high normal level of serum calcium is called normocalcemic PHPT. Most, up to 80% of patients are asymptomatic, so the diagnosis is established by screening blood tests for calcium and PTH levels. Based on the Fourth International Workshop and the American Association of Endocrine Surgeons (AAES) Guidelines for Definitive Management of Asymptomatic PHPT, the following are indications for surgical treatment of PHPT [1–3]:

A. L. Shifrin (*) Department of Surgery, Jersey Shore University Medical Center, Neptune, NJ, USA P. K. Thind University Radiology Group, New Brunswick, NJ, USA Jersey Shore University Medical Center, Department of Radiology, Neptune, NJ, USA

• Serum calcium 1.0 mg/dL (0.25 mmol/L) above the upper limit of normal • Presence of osteoporosis, defined by DEXA scan as BMD with a T-score of less than −2.5 at lumbar spine, total hip, femoral neck, and especially the distal third of the radius. Z-scores should be used instead of T-scores in premenopausal women and men younger than 50 years of age. • Presence of vertebral fracture by imaging studies such as x-ray, CT scan, MRI, or Vertebral Fracture Assessment (VFA) by the DEXA scan. • 24-hour urine for calcium above 400 mg/d (10 mmol/d) and increased kidney stone risk by biochemical stone risk analysis • Creatinine clearance 3.5 mmol/L), and PTH levels are usually 4–10 times above the upper limit of normal [94, 95]. Thus, most patients present with symptoms of various metabolic complications of hypercalcemia. Occasionally, patients present with hypercalcemic crisis. It is of note that about 10% of cases are nonfunctional [96–98]. Parathyroid carcinoma involves one gland, and ectopic locations (for instance, intrathyroidal) are rare [99–101]. About half of patients with parathyroid carcinoma have a palpable neck mass [102]. Hoarseness secondary to recurrent laryngeal nerve injury is a manifestation of malignancy [90]. Rarely, patients may

present with evidence of lymph node or distant metastasis [102, 103].

Gross Findings The gross findings of parathyroid carcinoma can be indistinguishable from those of benign parathyroid disease. Parathyroid carcinomas are generally large, with an average diameter of 3  cm, compared with 1.5  cm for parathyroid adenomas [90, 102, 104]. They are firm on palpation, often described intraoperatively as stone-hard in consistency. They are poorly circumscribed and densely adherent to the surrounding tissue. The cut surface ranges from pinkish tan to greyish white. These gross findings are different from typical parathyroid adenomas, which are usually smaller, encapsulated, and reddish brown in color.

22

Microscopic Findings Most parathyroid carcinomas are composed of neoplastic chief cells with round to ovoid nuclei, a dense chromatin pattern, and inconspicuous nucleoli. Some tumors exhibit significant nuclear pleomorphism, with clumped chromatin and prominent nucleoli. Mitotic figures are present in most cases of parathyroid carcinoma, with occasional atypical mitoses. The cytoplasm varies from eosinophilic to clear. Variable numbers of oxyphil cells, transitional oxyphil cells, and spindle cells may be present. The predominant growth patterns are solid and trabecular. Broad, fibrous bands subdivide the tumor into variably sized nodules. The hallmark of parathyroid carcinoma is the presence of invasive growth, manifested as tumor infiltration into the adjacent tissue (soft tissue, thyroid gland, esophagus, or other structures in the neck), vascular invasion, tumor necrosis, and perineural invasion (Fig.  3.5) [72, 105, 106]. In some cases, the histologic diagnosis of parathyroid carcinoma is challenging. Immunohistochemistry (IHC) is a helpful diagnostic aid. Positive staining for cytokeratin, chromogranin, and PTH is common for all parathyroid neoplasms, but several markers exhibit stronger stain, a higher percentage of positive-staining cases, or a higher percentage of positive-staining cells in parathyroid carcinoma than in parathyroid adenoma. These include p53, cyclin D1/PRAD1, Ki-67, p27, bcl-2, and mdm2 [107, 108]. Nevertheless, none of these stains can consistently and reliably distinguish parathyroid carcinomas from adenomas. Because the most frequent genetic alteration in parathyroid carcinomas is a somatic loss-of-function mutation of the CDC73/HRPT2 gene encoding parafibromin, IHC staining for parafibromin

a

M. Zheng and V. A. LiVolsi

has been explored as a marker in the diagnosis of parathyroid carcinoma. Up to 70% of parathyroid carcinoma cases show loss of parafibromin expression [109–112]. The rate of loss of parafibromin IHC expression is significantly higher in parathyroid carcinoma than in benign parathyroid disease, so parafibromin stain can be a useful ancillary test for the diagnosis of parathyroid carcinoma [112, 113].

Prognosis Parathyroid carcinomas tend to recur if incompletely excised. About half recur following simple parathyroidectomy, but the recurrence rate is less than 10% following en bloc resection [114]. Recurrence occurs locally with involvement of ipsilateral neck structures [92, 114]. Metastatic spread can occur late in the course of disease. Reported 5-year overall survival rates range from 76% to 85%, and 10-year rates range from 49% to 77% [90, 92, 93, 104]. Negative prognostic factors include older patient age, larger tumor size, male sex, positive nodal status, and the limited extent of surgical resection [92, 103–115]. In addition, loss of parafibromin expression due to mutations in CDC73/HRPT2 gene are associated with adverse survival outcomes [116, 117]. The prognosis of non-functional parathyroid carcinoma appears to be worse because diagnosis often occurs at advanced stages, with the presence of local invasion and a higher proportion of cases having nodal and/or distant metastasis. Parathyroid carcinoma-related morbidity and mortality is directly related to complications of the persistent and severe hypercalcemia rather than to local tumor burden and infiltration.

b

Fig. 3.5  Parathyroid carcinoma. (a) Tumor tissue shows invasive growth into the surrounding adipose tissue (H&E, 100×). (b) Tumor tissue has invaded the perineural space (arrow) (H&E, 400×)

3  Pathology of the Parathyroid Glands

23

Familial Hyperparathyroidism Although most cases of PHP occur sporadically, about 5–10% are associated with familial disease [118]. There are six syndromes of familial hyperparathyroidism, as listed on Table 3.1: • Multiple endocrine neoplasia type 1 (MEN1, Wermer syndrome) • Multiple endocrine neoplasia type 2A (MEN2A, Sipple syndrome) • Familial hypocalciuric hypercalcemia (FHH) • Neonatal severe hyperparathyroidism (NSHPT) • Hyperparathyroidism–jaw tumor (HPT-JT) • Familial isolated hyperparathyroidism (FIHP) Multiple endocrine neoplasia type 1 (MEN1) is the most common familial cause of primary hyperparathyroidism. It is characterized by tumors of the parathyroid gland, anterior pituitary, and pancreatic islet cells [119]. Parathyroid disease occurs in 95% of MEN1 patients, manifested as multigland nodular hyperplasia. Familial MEN1 is inherited in an autosomal dominant fashion. Germline inactivation of one allele of the MEN1 gene on chromosome 11q13 confers the tumor susceptibility. A somatic mutation or deletion of the second wild-type MEN1 allele is demonstrable in the majority of tumors from MEN1 patients [119, 120]. The MEN1 gene encodes the protein menin, which is involved in the regulation of transcription, genome stability, cell division, and cell proliferation [121–124]. MEN2A presents with a combination of medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumor [120]. PHP develops in 20–30% of patients with MEN2A and is characteristically a multigland disease, although isolated one-gland disease may be noted at presentation [125]. MEN2A is transmitted in an autosomal dominant fashion. MEN2A is caused by germline gain-offunction mutation in the c-ret proto-oncogene (RET) located on chromosome 10q11.2. The RET gene encodes a

transmembrane receptor tyrosine kinase involved in mitogenic signal transduction [120]. Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder characterized by asymptomatic hypercalcemia, hypocalciuria, and normal PTH concentrations in most patients [126]. FHH is genetically heterogeneous, due to loss-of-function mutations of the calcium-sensing receptor (CaSR, encoded by the CASR gene), G-protein subunit α11 (Gα11, encoded by the GNA11 gene), or the adapter protein 2 (AP2) sigma subunit (AP2r, encoded by the AP2S1 gene) [127–129]. The homozygous or compound heterozygous inheritance of two inactive CASR alleles typically results in the phenotype of neonatal severe hyperparathyroidism (NSHPT). NSHPT shows symptomatic hypercalcemia with skeletal manifestations of hyperparathyroidism in the first 6 months of life [130, 131]. Hyperparathyroidism–jaw tumor (HPT-JT) is a rare autosomal dominant syndrome of variable penetrance. Hyperparathyroidism is usually the presenting manifestation, owing to the development of parathyroid adenomas. Parathyroid carcinoma frequently occurs in HPT-JT, affecting more than 20% of patients [132]. Other associated tumors include ossifying fibroma of the maxilla and mandible, uterine tumors, and renal tumors. HPT-JT is due to germline loss-of-function mutation of the CDC73/HRPT2 gene on chromosome 1q31.2. The CDC73/HRPT2 gene is a tumor suppressor and encodes the protein parafibromin, which is involved in the regulation of cell cycle, protein synthesis, and lipid and nucleic acid metabolism [133–135]. HPT-JT–associated tumors have loss of heterozygosity (LOH) involving the chromosome 1q21.32 region [133, 136]. It is of note that CDC73/HRPT2 mutations with consequent inactivation of the encoded protein parafibromin are present in 65–100% of sporadic parathyroid carcinomas [137]. Familial isolated hyperparathyroidism (FIHP) is defined as familial hyperparathyroidism without a characteristic extraparathyroidal feature of a more complex ­hyperparathyroid syndrome [44]. Common clinical features

Table 3.1  Syndromic and hereditary forms of primary hyperparathyroidism (PHP) Condition Inheritance Gene MEN1 AD MEN1

Gene product Menin

Parathyroid pathology Hyperplasia/adenoma

MEN2A FHH

AD AD AR, AD AD

c-RET CaSR, Gα11, AP2r CaSR Parafibromin

Hyperplasia/adenoma Hyperplasia

NSHPT HPT-JT

RET CASR, GNA11, AP2S1 CASR CDC73/HRPT2

FIHP

AD, AR

GCM2, others

GCMb, others

Hyperplasia Adenoma (cystic)/ carcinoma Hyperplasia/adenoma/ carcinoma

Associated conditions Enteropancreatic tumors, pituitary and adrenal hyperplasia or tumors Medullary thyroid carcinoma, pheochromocytoma None None Jaw, renal, and uterine tumors None

AD autosomal dominant, AR autosomal recessive, FHH familial hypocalciuric hypercalcemia, FIHP familial isolated primary hyperparathyroidism, HPT-JT hyperparathyroidism–jaw tumor, MEN multiple endocrine neoplasia, NSHPT neonatal severe hyperparathyroidism

24

of FIHP include adult age at diagnosis, modest degree of hypercalcemia, and multiple parathyroid tumors. The concept of FIHP has evolved over the years because a diagnosis of FIHP requires exclusion of other types of familial hyperparathyroidism. Many FIHP cases diagnosed in the past have been shown to represent incomplete expression of MEN1, FHH, or HPT-JT.  Identification of mutations in MEN1, CASR, or CDC73/HRPT2 genes in FIHP kindreds enables their reclassification as the corresponding more complex familial hyperparathyroidism syndromes [43]. More recently, germline mutation of the GCM2 transcription factor has been identified by whole-exome sequence in FIHP [45]. The frequency of germline GCM2 mutation in FIHP is 17%; no specific mutation has yet been found in a majority of FIHP cases [44].

I ntraoperative Assessment of Parathyroid Lesions Parathyroidectomy is the treatment of choice for PHP, relieving symptoms of hypercalcemia and preventing renal and skeletal complications. A majority of PHP cases (85%) are due to parathyroid adenoma (single gland disease, rarely double adenoma), whereas parathyroid hyperplasia (multigland disease) accounts for the remaining 15% [21, 26, 27]. As detailed in other chapters of this book, techniques for preoperative localization of abnormal parathyroid glands have relatively high sensitivity and specificity. Methods for intraoperative assessment of parathyroid glands include rapid PTH measurement and frozen section analysis. Because the half-life of the PTH is short (3–5 minutes), excision of the parathyroid gland is followed by a rapid fall in serum level of PTH, which can be measured by a rapid PTH assay (turnaround time 15–20  minutes). A 10-minute post-excision PTH level that decreases 50% from baseline and is normal or near normal is usually regarded as confirmation of the removal of a solitary parathyroid adenoma. Patients who do not have an adequate reduction in PTH levels usually undergo bilateral neck exploration with resection of additional hyperfunctional parathyroid glands [138, 139]. Intraoperative PTH assay appears to be particular helpful in patients whose abnormal parathyroid glands either were not localized preoperatively or were identified with only one positive imaging study result [140–143]. Intraoperative frozen section tissue analysis has been used to confirm the presence of parathyroid tissue and to evaluate whether the parathyroid tissue is normal or abnormal [144, 145]. The frozen section analysis is a highly reliable means of verifying parathyroid tissue during parathyroid exploration, as parathyroid lesions have a relatively narrow range of morphological variations and diagnostic possibilities. The accuracy rate of distinguishing parathyroid tissue

M. Zheng and V. A. LiVolsi

from non-parathyroid tissue is up to 99.2% [146]. On rare occasions, the tissue identification is deferred because of overlapping morphological features compounded by freezing artifact. Included are difficulties in differentiating nodular thyroid tissue from parathyroid tissue, intrathyroidal parathyroid gland showing conspicuous follicular structure containing colloid-like materials, parathyroid tissue composed exclusively of oxyphil cells, and thyroid nodules with fatty stroma [146, 147]. On the other hand, the ability to differentiate normal from abnormal parathyroid tissue and adenoma from hyperplasia by frozen section analysis is limited. The accuracy of differentiating normal and abnormal parathyroid gland is not 100%, and the accuracy of the specific interpretation of adenoma or hyperplasia is even lower [148– 150]. Although parathyroid adenoma typically has a thin rim of compressed normal glandular tissue retained at the periphery of the tumor, the relatively low frequency of such a finding (in less than 50% of cases) and its similarity to an uneven proliferative pattern and retained stromal fat in parathyroid hyperplasia render it a less-reliable discriminating finding. Evaluation of intracellular fat by fat stain has been explored to assist in the intraoperative analysis. Compared with normal glands, the intracytoplasmic fat droplets in adenomatous glands are usually diminished or absent; this finding can be assessed intraoperatively by Oil Red O or Sudan Black stains (Fig. 3.6), providing a functional level of distinction between abnormal and normal parathyroid tissue [15, 16, 151]. Fat stains show inconsistent results in some cases, however, particularly in multigland disease [17–20]. A normal pattern of fat stain in one examined gland does not preclude abnormalities in another gland. A report from frozen section is usually descriptive (normocellular versus hypercellular parathyroid tissue, retained versus diminished or absent intracellular fat/stromal fat) instead of diagnostic (normal versus abnormal, hyperplasia versus adenoma). Therefore, surgical management decisions should be based on integration of all relevant findings (histology and intraoperative laboratory data) and critical clinical judgment [152, 153].

Secondary Tumors Secondary tumor involvement of a parathyroid gland is uncommon. Most reports are from individual cases or small series. A systemic evaluation of autopsy cases indicates that the frequency of metastases to the parathyroid glands in cancer death patients is 11.9% [154]. Parathyroid gland involvement is usually part of widespread metastases. The most common primary site and type of malignancies are breast carcinoma (66.9%), skin melanoma (11.8%), and lung carcinoma (5.5%) [155, 156]. This pattern largely reflects the prevalence of different types of malignancies in the general

3  Pathology of the Parathyroid Glands

25

a

b

Fig. 3.6  Frozen section analysis. (a) Frozen section shows a lack of stainable fat in this parathyroid adenoma by Oil Red O stain. In comparison, a rim of normal parathyroid tissue on the left edge of the field

a

b

contains abundant intracytoplasmic lipid droplets (stained red) and occasional stromal fat vacuoles (empty spaces) (Oil Red O stain, 200×). (b) The corresponding H&E-stained section (H&E, 200×)

c

Fig. 3.7  Metastasis to parathyroid gland. (a) Metastatic neuroendocrine tumor (NET) to primary parathyroid hyperplasia in the clinical setting of MEN1. Note the subtle difference in parathyroid tissue (left half of the field) and more densely packed NET tissue (right half of the field; the boundary is marked by arrows) (H&E, 100×). (b)

Both parathyroid tissue and NET tissue show positive staining for chromogranin (Chromogranin stain, 100×). (c) Only the metastatic NET tissue shows positive staining for synaptophysin (Synaptophysin stain, 100×). PTH stain (not shown) shows the opposite staining pattern

population. In contrast, isolated metastatic disease to the parathyroid glands without disseminated systemic metastasis is very rare (Fig. 3.7). Tumor-to-tumor metastasis is also very rare. Less than a dozen such cases are reported in the literature, and all of them are to parathyroid adenomas [157– 159]. Most of the patients with metastases to the parathyroid gland experience deranged calcium homeostasis, either hypercalcemia or hypocalcemia [156].

are diagnosed at the age of 30–60 years [161]. Most patients present with a neck mass, with some cases initially attributed to thyroid nodules. Large parathyroid cysts also can cause compression symptoms. The most common locations are lateral to the thyroid gland in close proximity to the lower parathyroid glands, superior mediastinum, and midline [161]. A majority of parathyroid cysts are nonfunctioning, developed from remnants of the third and fourth branchial pouches. Less than half are functioning, with clinical or biochemical evidence of hyperparathyroidism; these probably represent cystic parathyroid adenomas. Neck ultrasound evaluation accompanied by fine needle aspiration (FNA) and fluid analysis (fluid PTH measurement) is an effective diagnostic paradigm. Grossly, these are thin-walled, unilocular cysts containing clear fluid. Microscopic evaluation reveals a cystic structure lined by cuboidal or columnar epithelial cells (Fig.  3.8).

Miscellaneous Parathyroid Lesions Parathyroid Cyst Parathyroid cysts account for 1–5% of neck masses and less than 0.5% of parathyroid lesions [160]. There is a female predominance (male-to-female ratio, 1:1.85), and most cases

26

a

M. Zheng and V. A. LiVolsi

b

Fig. 3.8  Parathyroid cyst. (a) The inner cyst wall is lined by multiple layers of chief cells. (The rest of the cyst is lined by a single layer of chief cells.) The outer surface of the cyst is inked by a blue dye. The

cyst lumen (lower half of the field) contains amorphous materials (H&E, 200×). (b) The cyst wall lining cells are positive for PTH stain, confirming that they are chief cells (H&E, 200×)

These cells stain positive for cytokeratin, PTH, and chromogranin. Surgical excision is curative [162].

most common cause of acquired hypoparathyroidism is anterior neck surgeries, accounting for 75–80% of cases. These cases of iatrogenic hypoparathyroidism occur following thyroidectomy, parathyroidectomy, or other neck surgeries that damage or remove the parathyroid glands. The prevalence of hypoparathyroidism is higher in women than in men because thyroid operations are more frequently performed in women [169]. In neonates and young children, the etiology is usually a genetic defect. Familial isolated hypoparathyroidism may show autosomal dominant, autosomal recessive, or X-linked inheritance, affecting PTH, SOX3, CASR, GNA11, and GCM2 genes. Developmental defects associated with malformation of the third and fourth branchial pouches result in hypoplasia or aplasia of the parathyroid glands. The most common syndromic hypoparathyroidism is DiGeorge syndrome 1, due to 22q11.2 microdeletions. One of the genes involved is TBX1, encoding a DNA-binding transcription factor of the T-box family known to have important roles in vertebrate and invertebrate organogenesis and pattern formation [170]. In older children and adults, autoimmune destruction of the parathyroid glands is the main cause of nonsurgical hypoparathyroidism. Antibodies directed against the parathyroid cell surface calcium-sensing receptor (CaSR) is associated with autoimmune polyglandular syndrome type 1 [171]. This condition is due to mutations of the AIRE gene [172, 173]. Lack of AIRE protein disrupts the central ­immunological tolerance process by preventing the negative selection of the thymic T cells bearing the autoantigens. As a consequence, multiorgan autoimmunity develops [174]. Other rare causes of hypoparathyroidism include infiltration and replacement of parathyroid tissue by iron

Parathyromatosis The term parathyromatosis refers to the presence of multiple nodules of hyperfunctioning parathyroid tissue scattered in the soft tissues of the neck and/or mediastinum [163]. This condition can represent hyperplasia of the developmental rests (primary or developmental parathyromatosis) or incomplete parathyroidectomy with disruption and seeding of hyperplastic or neoplastic parathyroid tissue (secondary or postsurgical parathyromatosis) [164, 165]. The latter type can be associated with dense postoperative fibrosis, making it difficult to distinguish from parathyroid carcinoma. The morphological features are similar to those of parathyroid transplants, with irregular nests of blandappearing parathyroid tissue surrounded by areas of fibrosis. Vascular invasion is absent. Parathyromatosis displays an immunohistochemical profile (retained parafibromin and Rb expressions, low frequency of Galectin-3 expression, and low Ki-67 proliferation index) more similar to that of parathyroid adenoma than parathyroid carcinoma [110]. Parathyromatosis can be a rare cause of recurrent or persistent hyperparathyroidism [166, 167].

Hypoparathyroidism Hypoparathyroidism is a rare disorder characterized by low or insufficient PTH concentrations leading to hypocalcemia, hyperphosphatemia, and reduced bone turnover [168]. The

3  Pathology of the Parathyroid Glands

(­hemochromatosis), copper (Wilson disease), amyloid (amyloidosis), secondary tumors (metastatic carcinoma), and radiation damage (radiation therapy to the neck region).

References 1. Gilmour JR, Martin WJ. The weight of the parathyroid glands. J Pathol Bacteriol. 1937;44:431–62. 2. Dekker A, Dunsford HA, Geyer SJ. The normal parathyroid gland at autopsy: the significance of stromal fat in adult patients. J Pathol. 1979;128:127–32. 3. Akerström G, Malmaeus J, Bergström R.  Surgical anatomy of human parathyroid glands. Surgery. 1984;95:14–21. 4. Gomes EM, Nunes RC, Lacativa PG, Almeida MH, Franco FM, Leal CT, et  al. Ectopic and extranumerary parathyroid glands location in patients with hyperparathyroidism secondary to end stage renal disease. Acta Cir Bras. 2007;22:105–9. 5. Grevellec A, Tucker AS.  The pharyngeal pouches and clefts: development, evolution, structure and derivatives. Semin Cell Dev Biol. 2010;21:325–32. 6. LoPinto M, Rubio GA, Khan ZF, Vaghaiwalla TM, Farra JC, Lew JI.  Location of abnormal parathyroid glands: lessons from 810 parathyroidectomies. J Surg Res. 2017;207:22–6. 7. Wang C.  The anatomic basis of parathyroid surgery. Ann Surg. 1976;183:271–5. 8. Nanka O, Sedý J, Vítková I, Libánský P, Adámek S. Surgical anatomy of parathyroid glands with emphasis on parathyroidectomy. Prague Med Rep. 2006;107:261–72. 9. Wong KS, Lewis JS Jr, Gottipati S, Chernock RD.  Utility of birefringent crystal identification by polarized light microscopy in distinguishing thyroid from parathyroid tissue on intraoperative frozen sections. Am J Surg Pathol. 2014; 38:1212–9. 10. Dufour DR, Wilkerson SY. The normal parathyroid revisited: percentage of stromal fat. Hum Pathol. 1982;13:717–21. 11. Obara T, Fujimoto Y, Aiba M. Stromal fat content of the parathyroid gland. Endocrinol Jpn. 1990;37:901–5. 12. Iwasaki A, Shan L, Kawano I, Nakamura M, Utsuno H, Kobayashi A, et  al. Quantitative analysis of stromal fat content of human parathyroid glands associated with thyroid diseases using computer image analysis. Pathol Int. 1995;45:483–6. 13. Roth SI, Munger BL. The cytology of the adenomatous, atrophic, and hyperplastic parathyroid glands of man. A light- and electron-­ microscopic study. Virchows Arch Pathol Anat Physiol Klin Med. 1962;335:389–410. 14. Thiele J, Kärner J, Fischer R.  Ultrastructural morphometry on human parathyroid tissue. Morphological and functional implications. J Submicrosc Cytol Pathol. 1988;20: 491–500. 15. Roth SI, Gallagher MJ. The rapid identification of “normal” parathyroid glands by the presence of intracellular fat. Am J Pathol. 1976;84:521–8. 16. Saffos RO, Rhatigan RM. Intracellular lipid in parathyroid glands. Hum Pathol. 1979;10:483–5. 17. King DT, Hirose FM. Chief cell intracytoplasmic fat used to evaluate parathyroid disease by frozen section. Arch Pathol Lab Med. 1979;103:609–12. 18. Kasdon EJ, Rosen S, Cohen RB, Silen W.  Surgical pathology of hyperparathyroidism. Usefulness of fat stain and problems in interpretation. Am J Surg Pathol. 1981;5:381–4. 19. Dufour DR, Durkowski C.  Sudan IV stain. Its limitations in evaluating parathyroid functional status. Arch Pathol Lab Med. 1982;106:224–7.

27 20. Farnebo LO, von Unge H. Peroperative evaluation of parathyroid glands using fat stain on frozen sections. Advantages and limitations. Acta Chir Scand Suppl. 1984;520:17–24. 21. DeLellis RA, Mazzaglia P, Mangray S.  Primary hyperparathyroidism: a current perspective. Arch Pathol Lab Med. 2008;132:1251–62. 22. Habib Z, Camacho P.  Primary hyperparathyroidism: an update. Curr Opin Endocrinol Diabetes Obes. 2010;17:554–60. 23. Mather HG. Hyperparathyroidism with normal serum calcium. Br Med J. 1953;2(4833):424–5. 24. McSwiney RR, Prunty FT.  The diagnosis of minimal hyperparathyroidism-­determination of theoretical renal phosphorus threshold. Proc R Soc Med. 1961;54:639–40. 25. Eastell R, Brandi ML, Costa AG, D’Amour P, Shoback DM, Thakker RV.  Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99:3570–9. 26. Carlson D. Parathyroid pathology: hyperparathyroidism and parathyroid tumors. Arch Pathol Lab Med. 2010;134:1639–44. 27. LiVolsi VA, Montone KT, Baloch ZN. Parathyroid: the pathology of hyperparathyroidism. Surg Pathol Clin. 2014;7:515–31. 28. Richert L, Trombetti A, Herrmann FR, Triponez F, Meier C, Robert JH, Rizzoli R.  Age and gender distribution of primary hyperparathyroidism and incidence of surgical treatment in a European country with a particularly high life expectancy. Swiss Med Wkly. 2009;139:400–4. 29. Adami S, Marcocci C, Gatti D. Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res. 2002;17(Suppl 2):N18–23. 30. Wermers RA, Khosla S, Atkinson EJ, Achenbach SJ, Oberg AL, Grant CS, Melton LJ 3rd. Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993–2001: an update on the changing epidemiology of the disease. J Bone Miner Res. 2006;21:171–7. 31. Yeh MW, Ituarte PH, Zhou HC, Nishimoto S, Liu IL, Harari A, et  al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab. 2013;98:1122–9. 32. Rao SD, Frame B, Miller MJ, Kleerekoper M, Block MA, Parfitt AM.  Hyperparathyroidism following head and neck irradiation. Arch Intern Med. 1980;140:205–7. 33. Bendz H, Sjödin I, Toss G, Berglund K. Hyperparathyroidism and long-term lithium therapy--a cross-sectional study and the effect of lithium withdrawal. J Intern Med. 1996;240:357–65. 34. Carling T, Correa P, Hessman O, Hedberg J, Skogseid B, Lindberg D, et al. Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. J Clin Endocrinol Metab. 1998;83:2960–3. 35. Farnebo F, Teh BT, Kytölä S, Svensson A, Phelan C, Sandelin K, et  al. Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab. 1998;83:2627–30. 36. Heppner C, Kester MB, Agarwal SK, Debelenko LV, Emmert-­ Buck MR, Guru SC, et al. Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Genet. 1997;16:375–8. 37. Uchino S, Noguchi S, Sato M, Yamashita H, Yamashita H, Watanabe S, et al. Screening of the Men1 gene and discovery of germ-line and somatic mutations in apparently sporadic parathyroid tumors. Cancer Res. 2000;60:5553–7. 38. Newey PJ, Nesbit MA, Rimmer AJ, Attar M, Head RT, Christie PT, et  al. Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. J Clin Endocrinol Metab. 2012;97:E1995–2005. 39. Cromer MK, Starker LF, Choi M, Udelsman R, Nelson-Williams C, Lifton RP, Carling T.  Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. J Clin Endocrinol Metab. 2012;97:E1774–81.

28 40. Hemmer S, Wasenius VM, Haglund C, Zhu Y, Knuutila S, Franssila K, Joensuu H. Deletion of 11q23 and cyclin D1 overexpression are frequent aberrations in parathyroid adenomas. Am J Pathol. 2001;158:1355–62. 41. Tominaga Y, Tsuzuki T, Uchida K, Haba T, Otsuka S, Ichimori T, et al. Expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in parathyroid hyperplasia caused by chronic renal failure versus primary adenoma. Kidney Int. 1999;55:1375–83. 42. Yi Y, Nowak NJ, Pacchia AL, Morrison C.  Chromosome 11 genomic changes in parathyroid adenoma and hyperplasia: array CGH, FISH, and tissue microarrays. Genes Chromosomes Cancer. 2008;47:639–48. 43. Cardoso L, Stevenson M, Thakker RV. Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma. Hum Mutat. 2017;38:1621–48. 44. Marx SJ. New concepts about familial isolated hyperparathyroidism. J Clin Endocrinol Metab. 2019;104:4058–66. 45. Guan B, Welch JM, Sapp JC, Ling H, Li Y, Johnston JJ, et  al. GCM2-activating mutations in familial isolated hyperparathyroidism. Am J Hum Genet. 2016;99:1034–44. 46. Cusano NE, Maalouf NM, Wang PY, Zhang C, Cremers SC, Haney EM, et al. Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J Clin Endocrinol Metab. 2013;98:2734–41. 47. Rejnmark L, Amstrup AK, Mollerup CL, Heickendorff L, Mosekilde L.  Further insights into the pathogenesis of primary hyperparathyroidism: a nested case-control study. J Clin Endocrinol Metab. 2013;98:87–96. 48. Portillo MR, Rodríguez-Ortiz ME. Secondary hyperparathyroidism: pathogenesis, diagnosis, preventive and therapeutic strategies. Rev Endocr Metab Disord. 2017;18:79–95. 49. Messa P, Alfieri CM. Secondary and tertiary hyperparathyroidism. Front Horm Res. 2019;51:91–108. 50. VanderWalde LH, Liu IL, Haigh PI. Effect of bone mineral density and parathyroidectomy on fracture risk in primary hyperparathyroidism. World J Surg. 2009;33:406–11. 51. Cipriani C, Biamonte F, Costa AG, Zhang C, Biondi P, Diacinti D, et  al. Prevalence of kidney stones and vertebral fractures in primary hyperparathyroidism using imaging technology. J Clin Endocrinol Metab. 2015;100:1309–15. 52. Zhang L, Liu X, Li H. Long-term skeletal outcomes of primary hyperparathyroidism patients after treatment with parathyroidectomy: a systematic review and meta-analysis. Horm Metab Res. 2018;50:242–9. 53. Scholz DA, Purnell DC. Asymptomatic primary hyperparathyroidism. 10-year prospective study. Mayo Clin Proc. 1981;56:473–8. 54. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP.  A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med. 1999;341:1249–55. 55. Castleman B, Mallory TB.  The pathology of the parathyroid gland in hyperparathyroidism: a study of 25 cases. Am J Pathol. 1935;11:1–72.17. 56. Phitayakorn R, McHenry CR. Incidence and location of ectopic abnormal parathyroid glands. Am J Surg. 2006;191:418–23. 57. Roy M, Mazeh H, Chen H, Sippel RS.  Incidence and localization of ectopic parathyroid adenomas in previously unexplored patients. World J Surg. 2013;37:102–6. 58. Albuja-Cruz MB, Allan BJ, Parikh PP, Lew JI. Efficacy of localization studies and intraoperative parathormone monitoring in the surgical management of hyperfunctioning ectopic parathyroid glands. Surgery. 2013;154:453–60. 59. Thompson NW, Eckhauser FE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery. 1982;92:814–21. 60. Baloch ZW, LiVolsi VA. Double adenoma of the parathyroid gland: does the entity exist? Arch Pathol Lab Med. 2001;125:178–9.

M. Zheng and V. A. LiVolsi 61. De Gregorio L, Lubitz CC, Hodin RA, Gaz RD, Parangi S, Phitayakorn R, Stephen AE.  The truth about double adenomas: incidence, localization, and intraoperative parathyroid hormone. J Am Coll Surg. 2016;222:1044–52. 62. Goasguen N, Chirica M, Roger N, Munoz-Bongrand N, Zohar S, Noullet S, et  al. Primary hyperparathyroidism from parathyroid microadenoma: specific features and implications for a surgical strategy in the era of minimally invasive parathyroidectomy. J Am Coll Surg. 2010;210:456–62. 63. Abbona GC, Papotti M, Gasparri G, Bussolati G.  Proliferative activity in parathyroid tumors as detected by Ki-67 immunostaining. Hum Pathol. 1995;26:135–8. 64. Baloch ZW, LiVolsi VA.  Pathology of the parathyroid glands in hyperparathyroidism. Semin Diagn Pathol. 2013;30:165–77. 65. Erovic BM, Harris L, Jamali M, Goldstein DP, Irish JC, Asa SL, Mete O.  Biomarkers of parathyroid carcinoma. Endocr Pathol. 2012;23:221–31. 66. Boquist L.  Follicles in human parathyroid glands. Lab Investig. 1973;28:313–20. 67. Isotalo PA, Lloyd RV. Presence of birefringent crystals is useful in distinguishing thyroid from parathyroid gland tissues. Am J Surg Pathol. 2002;26:813–4. 68. Bai S, LiVolsi VA, Fraker DL, Bing Z.  Water-clear parathyroid adenoma: report of two cases and literature review. Endocr Pathol. 2012;23:196–200. 69. Elgoweini M, Chetty R.  Hyalinizing parathyroid adenoma and hyperplasia: report of 3 cases of an unusual histologic variant. Ann Diagn Pathol. 2011;15:329–32. 70. van Hoeven KH, Brennan MF. Lipothymoadenoma of the parathyroid. Arch Pathol Lab Med. 1993;117:312–4. 71. Rosai J, DeLellis RA, Carcangiu ML, Frable WJ, Tallin G. Parathyroid adenoma and variants. In: Tumors of the thyroid and parathyroid glands. Armed Forces Institute of Pathology, Atlas of tumor pathology 4th series. Silver Spring, MD: American Registry of Pathology; 2014. p. 513–42. 72. DeLellis R, Franssila KO, Arnold A, Haigh PI, Eng C, Hendy GN, et al. Parathyroid adenoma. In: Lloyd RV, Osamura RY, Kloppel G, Rosai J, editors. WHO classification of tumours of endocrine organs, International Agency for Research on Cancer. 4th ed. Lyon, France; 2017. p. 153–8. 73. Schneider R, Bartsch-Herzog S, Ramaswamy A, Bartsch DK, Karakas E.  Immunohistochemical expression of E-cadherin in atypical parathyroid adenoma. World J Surg. 2015;39:2477–83. 74. Cetani F, Marcocci C, Torregrossa L, Pardi E. Atypical parathyroid adenomas: challenging lesions in the differential diagnosis of endocrine tumors. Endocr Relat Cancer. 2019;26:R441–64. 75. Fernandez-Ranvier GG, Khanafshar E, Jensen K, Zarnegar R, Lee J, Kebebew E, et al. Parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis? Cancer. 2007;110:255–64. 76. Kruijff S, Sidhu SB, Sywak MS, Gill AJ, Delbridge LW. Negative parafibromin staining predicts malignant behavior in atypical parathyroid adenomas. Ann Surg Oncol. 2014;21:426–33. 77. Guarnieri V, Battista C, Muscarella LA, Bisceglia M, de Martino D, Baorda F, et al. CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort. Cell Oncol (Dordr). 2012;35:411–22. 78. Agarwal A, Pradhan R, Kumari N, Krishnani N, Shukla P, Gupta SK, et  al. Molecular characteristics of large parathyroid adenomas. World J Surg. 2016;40:607–14. 79. Arnold A, Brown MF, Ureña P, Gaz RD, Sarfati E, Drüeke TB.  Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest. 1995;95:2047–53. 80. Tominaga Y, Kohara S, Namii Y, Nagasaka T, Haba T, Uchida K, et al. Clonal analysis of nodular parathyroid hyperplasia in renal

3  Pathology of the Parathyroid Glands hyperparathyroidism. World J Surg. 1996;20:744–50; discussion 750–2 81. Shan L, Nakamura Y, Murakami M, Nakamura M, Naito A, Kawahara K, et  al. Clonal emergence in uremic parathyroid hyperplasia is not related to MEN1 gene abnormality. Jpn J Cancer Res. 1999;90:965–9. 82. Vandenbulcke O, Delaere P, Vander Poorten V, Debruyne F. Incidence of multiglandular disease in sporadic primary hyperparathyroidism. B-ENT. 2014;10:1–6. 83. Berger AC, Libutti SK, Bartlett DL, Skarulis MG, Marx SJ, Spiegel AM, et al. Heterogeneous gland size in sporadic multiple gland parathyroid hyperplasia. J Am Coll Surg. 1999;188:382–9. 84. Ezzat T, Maclean GM, Parameswaran R, Phillips B, Komar V, Mihai R, et al. Primary hyperparathyroidism with water clear cell content: the impact of histological diagnosis on clinical management and outcome. Ann R Coll Surg Engl. 2013;95:e60–2. 85. Boutzios G, Sarlanis H, Kolindou A, Velidaki A, Karatzas T.  Primary hyperparathyroidism caused by enormous unilateral water-clear cell parathyroid hyperplasia. BMC Endocr Disord. 2017;17:57. 86. Straus FH 2nd, Kaplan EL, Nishiyama RH, Bigos ST. Five cases of parathyroid lipohyperplasia. Surgery. 1983;94:901–5. 87. Carter JM, Landry A, Hinni M. Lipohyperplasia of the parathyroid glands. Ear Nose Throat J. 2012;91:441–3. 88. Krause MW, Hedinger CE. Pathologic study of parathyroid glands in tertiary hyperparathyroidism. Hum Pathol. 1985;16:772–84. 89. Nasrallah MP, Fraker DL, LiVolsi VA. Parathyroid carcinoma in the setting of tertiary hyperparathyroidism after renal transplant. Endocr Pathol. 2014;25:433–5. 90. Hundahl SA, Fleming ID, Fremgen AM, Menck HR.  Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985–1995: a National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1999;86:538–44. 91. Wang CA, Gaz RD.  Natural history of parathyroid carcinoma. Diagnosis, treatment, and results. Am J Surg. 1985;149:522–7. 92. Harari A, Waring A, Fernandez-Ranvier G, Hwang J, Suh I, Mitmaker E, et al. Parathyroid carcinoma: a 43-year outcome and survival analysis. J Clin Endocrinol Metab. 2011;96:3679–86. 93. Asare EA, Sturgeon C, Winchester DJ, Liu L, Palis B, Perrier ND, et al. Parathyroid carcinoma: an update on treatment outcomes and prognostic factors from the National Cancer Data Base (NCDB). Ann Surg Oncol. 2015;22:3990–5. 94. Robert JH, Trombetti A, Garcia A, Pache JC, Herrmann F, Spiliopoulos A, Rizzoli R.  Primary hyperparathyroidism: can parathyroid carcinoma be anticipated on clinical and biochemical grounds? Report of nine cases and review of the literature. Ann Surg Oncol. 2005;12:526–32. 95. Talat N, Schulte KM.  Clinical presentation, staging and long-term evolution of parathyroid cancer. Ann Surg Oncol. 2010;17:2156–74. 96. Fernandez-Ranvier GG, Jensen K, Khanafshar E, Quivey JM, Glastonbury C, Kebebew E, et  al. Nonfunctioning parathyroid carcinoma: case report and review of literature. Endocr Pract. 2007;13:750–7. 97. Wilkins BJ, Lewis JS Jr. Non-functional parathyroid carcinoma: a review of the literature and report of a case requiring extensive surgery. Head Neck Pathol. 2009;3:140–9. 98. Cetani F, Frustaci G, Torregrossa L, Magno S, Basolo F, Campomori A, et  al. A nonfunctioning parathyroid carcinoma misdiagnosed as a follicular thyroid nodule. World J Surg Oncol. 2015;13:270. 99. Lee KM, Kim EJ, Choi WS, Park WS, Kim SW.  Intrathyroidal parathyroid carcinoma mimicking a thyroid nodule in a MEN type 1 patient. J Clin Ultrasound. 2014;42:212–4.

29 100. Vila Duckworth L, Winter WE, Vaysberg M, Moran CA, Al-Quran SZ. Intrathyroidal parathyroid carcinoma: report of an unusual case and review of the literature. Case Rep Pathol. 2013;2013:198643. 101. DeLellis RA.  Parathyroid carcinoma: an overview. Adv Anat Pathol. 2005;12:53–61. 102. Wynne AG, van Heerden J, Carney JA, Fitzpatrick LA. Parathyroid carcinoma: clinical and pathologic features in 43 patients. Medicine (Baltimore). 1992;71:197–205. 103. Busaidy NL, Jimenez C, Habra MA, Schultz PN, El-Naggar AK, Clayman GL, et al. Parathyroid carcinoma: a 22-year experience. Head Neck. 2004;26:716–26. 104. Lee PK, Jarosek SL, Virnig BA, Evasovich M, Tuttle TM. Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer. 2007;109:1736–41. 105. Schantz A, Castleman B.  Parathyroid carcinoma. A study of 70 cases. Cancer. 1973;31:600–5. 106. Tamler R, Lewis MS, LiVolsi VA, Genden EM.  Parathyroid carcinoma: ultrasonographic and histologic features. Thyroid. 2005;15:744–5. 107. Vasef MA, Brynes RK, Sturm M, Bromley C, Robinson RA. Expression of cyclin D1 in parathyroid carcinomas, adenomas, and hyperplasias: a paraffin immunohistochemical study. Mod Pathol. 1999;12:412–6. 108. Stojadinovic A, Hoos A, Nissan A, Dudas ME, Cordon-Cardo C, Shaha AR, et al. Parathyroid neoplasms: clinical, histopathological, and tissue microarray-based molecular analysis. Hum Pathol. 2003;34:54–64. 109. Kim HK, Oh YL, Kim SH, Lee DY, Kang HC, Lee JI, et  al. Parafibromin immunohistochemical staining to differentiate parathyroid carcinoma from parathyroid adenoma. Head Neck. 2012;34:201–6. 110. Fernandez-Ranvier GG, Khanafshar E, Tacha D, Wong M, Kebebew E, Duh QY, Clark OH.  Defining a molecular phenotype for benign and malignant parathyroid tumors. Cancer. 2009;115:334–44. 111. Bergero N, De Pompa R, Sacerdote C, Gasparri G, Volante M, Bussolati G, Papotti M. Galectin-3 expression in parathyroid carcinoma: immunohistochemical study of 26 cases. Hum Pathol. 2005;36:908–14. 112. Juhlin CC, Nilsson IL, Lagerstedt-Robinson K, Stenman A, Bränström R, Tham E, Höög A. Parafibromin immunostainings of parathyroid tumors in clinical routine: a near-decade experience from a tertiary center. Mod Pathol. 2019;32:1082–94. 113. Pyo JS, Cho WJ. Diagnostic and prognostic implications of parafibromin immunohistochemistry in parathyroid carcinoma. Biosci Rep. 2019;39(4). pii: BSR20181778. https://doi.org/10.1042/ BSR20181778. 114. Koea JB, Shaw JH. Parathyroid cancer: biology and management. Surg Oncol. 1999;8:155–65. 115. Sandelin K, Auer G, Bondeson L, Grimelius L, Farnebo LO. Prognostic factors in parathyroid cancer: a review of 95 cases. World J Surg. 1992;16:724–31. 116. Witteveen JE, Hamdy NA, Dekkers OM, Kievit J, van Wezel T, Teh BT, et al. Downregulation of CASR expression and global loss of parafibromin staining are strong negative determinants of prognosis in parathyroid carcinoma. Mod Pathol. 2011;24:688–97. 117. Cetani F, Banti C, Pardi E, Borsari S, Viacava P, Miccoli P, et al. CDC73 mutational status and loss of parafibromin in the outcome of parathyroid cancer. Endocr Connect. 2013;2:186–95. 118. Cetani F, Saponaro F, Borsari S, Marcocci C. Familial and hereditary forms of primary hyperparathyroidism. Front Horm Res. 2019;51:40–51. 119. Kamilaris CDC, Stratakis CA. Multiple endocrine neoplasia type 1 (MEN1): an update and the significance of early genetic and clinical diagnosis. Front Endocrinol (Lausanne). 2019;10:339.

30 120. Al-Salameh A, Baudry C, Cohen R. Update on multiple endocrine neoplasia Type 1 and 2. Presse Med. 2018;47:722–31. 121. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, et  al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276:404–7. 122. Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, et al. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Hum Mol Genet. 1997;6:1177–83. 123. Matkar S, Thiel A, Hua X.  Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013;38:394–402. 124. Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci U S A. 2005;102:749–54. 125. Alevizaki M, Saltiki K.  Primary hyperparathyroidism in MEN2 syndromes. Recent Results Cancer Res. 2015;204:179–86. 126. Vannucci L, Brandi ML.  Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Front Horm Res. 2019;51:52–62. 127. Hannan FM, Nesbit MA, Zhang C, Cranston T, Curley AJ, Harding B, et  al. Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites. Hum Mol Genet. 2012;21:2768–78. 128. Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, et  al. Mutations affecting G-protein subunit α11  in hypercalcemia and hypocalcemia. N Engl J Med. 2013;368:2476–86. 129. Nesbit MA, Hannan FM, Howles SA, Reed AA, Cranston T, Thakker CE, et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet. 2013;45:93–7. 130. Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, et  al. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993;75:1297–303. 131. Hendy GN, Cole DE. Genetic defects associated with familial and sporadic hyperparathyroidism. Front Horm Res. 2013;41:149–65. 132. Chen JD, Morrison C, Zhang C, Kahnoski K, Carpten JD, Teh BT.  Hyperparathyroidism-jaw tumour syndrome. J Intern Med. 2003;253:634–42. 133. Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, et  al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet. 2002;32:676–80. 134. Chang M, French-Cornay D, Fan HY, Klein H, Denis CL, Jaehning JA.  A complex containing RNA polymerase II, Paf1p, Cdc73p, Hpr1p, and Ccr4p plays a role in protein kinase C signaling. Mol Cell Biol. 1999;19:1056–67. 135. Betz JL, Chang M, Washburn TM, Porter SE, Mueller CL, Jaehning JA.  Phenotypic analysis of Paf1/RNA polymerase II complex mutations reveals connections to cell cycle regulation, protein synthesis, and lipid and nucleic acid metabolism. Mol Gen Genomics. 2002;268:272–85. 136. Newey PJ, Bowl MR, Cranston T, Thakker RV.  Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-­jaw tumor syndrome (HPT-JT) and parathyroid tumors. Hum Mutat. 2010;31:295–307. 137. Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med. 2003;349:1722–9. 138. Richards ML, Thompson GB, Farley DR, Grant CS. An optimal algorithm for intraoperative parathyroid hormone monitoring. Arch Surg. 2011;146:280–5.

M. Zheng and V. A. LiVolsi 139. Gioviale MC, Damiano G, Altomare R, Maione C, Buscemi S, Buscemi G, Lo Monte AI. Intraoperative measurement of parathyroid hormone: a Copernican revolution in the surgical treatment of hyperparathyroidism. Int J Surg. 2016;28(Suppl 1):S99–102. 140. Chen H, Pruhs Z, Starling JR, Mack E. Intraoperative parathyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy. Surgery. 2005;138:583–7. 141. Barczynski M, Konturek A, Cichon S, Hubalewska-Dydejczyk A, Golkowski F, Huszno B.  Intraoperative parathyroid hormone assay improves outcomes of minimally invasive parathyroidectomy mainly in patients with a presumed solitary parathyroid adenoma and missing concordance of preoperative imaging. Clin Endocrinol. 2007;66:878–85. 142. Siperstein A, Berber E, Barbosa GF, Tsinberg M, Greene AB, Mitchell J, Milas M. Predicting the success of limited exploration for primary hyperparathyroidism using ultrasound, sestamibi, and intraoperative parathyroid hormone: analysis of 1158 cases. Ann Surg. 2008;248:420–8. 143. Zawawi F, Mlynarek AM, Cantor A, Varshney R, Black MJ, Hier MP, et al. Intraoperative parathyroid hormone level in parathyroidectomy: which patients benefit from it? J Otolaryngol Head Neck Surg. 2013;42:56. 144. Baloch ZW, LiVolsi VA. Intraoperative assessment of thyroid and parathyroid lesions. Semin Diagn Pathol. 2002;19:219–26. 145. Anton RC, Wheeler TM. Frozen section of thyroid and parathyroid specimens. Arch Pathol Lab Med. 2005;129:1575–84. 146. Westra WH, Pritchett DD, Udelsman R. Intraoperative confirmation of parathyroid tissue during parathyroid exploration: a retrospective evaluation of the frozen section. Am J Surg Pathol. 1998;22:538–44. 147. LiVolsi VA, Hamilton R.  Intraoperative assessment of parathyroid gland pathology. A common view from the surgeon and the pathologist. Am J Clin Pathol. 1994;102:365–73. 148. Black WC 3rd, Utley JR.  The differential diagnosis of parathyroid adenoma and chief cell hyperplasia. Am J Clin Pathol. 1968;49:761–75. 149. Saxe AW, Baier R, Tesluk H, Toreson W. The role of the pathologist in the surgical treatment of hyperparathyroidism. Surg Gynecol Obstet. 1985;161:101–5. 150. Bornstein-Quevedo L, Gamboa-Domínguez A, Angeles-Angeles A, Reyes-Gutiérrez E, Vargas-Voráckova F, Gamino R, Herrera MF.  Histologic diagnosis of primary hyperparathyroidism: a concordance analysis between three pathologists. Endocr Pathol. 2001;12:49–54. 151. Bondeson AG, Bondeson L, Ljungberg O, Tibblin S. Fat staining in parathyroid disease--diagnostic value and impact on surgical strategy: clinicopathologic analysis of 191 cases. Hum Pathol. 1985;16:1255–63. 152. Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY, et al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016;151:959–68. 153. Jason DS, Balentine CJ. Intraoperative decision making in parathyroid surgery. Surg Clin North Am. 2019;99:681–91. 154. Horwitz CA, Myers WP, Foote FW Jr. Secondary malignant tumors of the parathyroid glands. Report of two cases with associated hypoparathyroidism. Am J Med. 1972;52:797–808. 155. Shifrin A, LiVolsi V, Shifrin-Douglas S, Zheng M, Erler B, Matulewicz T, Davis J.  Primary and metastatic parathyroid malignancies: a rare or underdiagnosed condition? J Clin ­ Endocrinol Metab. 2015;100:E478–81. 156. Bauer JL, Toluie S, Thompson LDR. Metastases to the parathyroid glands: a comprehensive literature review of 127 reported cases. Head Neck Pathol. 2018;12:534–41. 157. Shifrin AL, LiVolsi VA, Zheng M, Lann DE, Fomin S, Naylor EC, et  al. Neuroendocrine thymic carcinoma metastatic to the para-

3  Pathology of the Parathyroid Glands thyroid gland that was reimplanted into the forearm in patient with multiple endocrine neoplasia type 1 syndrome: a challenging management dilemma. Endocr Pract. 2013;19:e163–7. 158. Lee HE, Kim DH, Cho YH, Kim K, Chae SW, Sohn JH. Tumor-­ to-­tumor metastasis: Hepatocellular carcinoma metastatic to parathyroid adenoma. Pathol Int. 2011;61:593–7. 159. Lee SH, Kim BH, Bae MJ, Yi YS, Kim WJ, Jeon YK, et  al. Concurrence of primary hyperparathyroidism and metastatic breast carcinoma affected a parathyroid gland. J Clin Endocrinol Metab. 2013;98:3127–30. 160. Arduc A, Tutuncu YA, Dogan BA, Arikan Ileri AB, Tuna MM, Ozcan HN, et al. Parathyroid cysts. Am Surg. 2015;81:E163–5. 161. Papavramidis TS, Chorti A, Pliakos I, Panidis S, Michalopoulos A. Parathyroid cysts: a review of 359 patients reported in the international literature. Medicine (Baltimore). 2018;97:e11399. 162. Aydoğdu K, Şahin F, İncekara F, Fındık G, Kaya S, Ağaçkıran Y.  Diagnosis and management of parathyroid cysts: description with two cases. Turk Thorac J. 2015;16:201–3. 163. Palmer JA, Brown WA, Kerr WH, Rosen IB, Watters NA.  The surgical aspects of hyperparathyroidism. Arch Surg. 1975; 110:1004–7. 164. Reddick RL, Costa JC, Marx SJ.  Parathyroid hyperplasia and parathyromatosis. Lancet. 1977;1(8010):549. 165. Erickson LA. Parathyromatosis. In: Atlas of endocrine pathology. New York: Springer; 2014. p. 139–42.

31 166. Lee PC, Mateo RB, Clarke MR, Brown ML, Carty SE. Parathyromatosis: a cause for recurrent hyperparathyroidism. Endocr Pract. 2001;7:189–92. 167. Hage MP, Salti I, El-Hajj FG. Parathyromatosis: a rare yet problematic etiology of recurrent and persistent hyperparathyroidism. Metabolism. 2012;61:762–75. 168. Shoback DM, Bilezikian JP, Costa AG, Dempster D, Dralle H, Khan AA, et  al. Presentation of hypoparathyroidism: Etiologies and clinical features. J Clin Endocrinol Metab. 2016;101:2300–12. 169. Rao SD. Epidemiology of parathyroid disorders. Best Pract Res Clin Endocrinol Metab. 2018;32:773–80. 170. Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, et  al. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003;362:1366–73. 171. Brown EM.  Anti-parathyroid and anti-calcium sensing receptor antibodies in autoimmune hypoparathyroidism. Endocrinol Metab Clin N Am. 2009;38:437–45. 172. Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 1997;17:399–403. 173. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et  al. Positional cloning of the APECED gene. Nat Genet. 1997;17:393–8. 174. Bruserud Ø, Oftedal BE, Wolff AB, Husebye ES. AIRE-mutations and autoimmune disease. Curr Opin Immunol. 2016;43:8–15.

Part II Normal Anatomical Location of the Parathyroid Gland Adenomas: Ultrasound, Sestamibi Scan, and Gross Pathology

4

Right Superior Parathyroid Adenoma Alexander L. Shifrin and Pritinder K. Thind

A right superior parathyroid adenoma—a mass identified as adjoining the superior pole of the right thyroid lobe—can be identified through imaging with ultrasound and Tc 99  m

s­ estamibi SPECT/CT scans, as illustrated in the four cases seen in Figs. 4.1, 4.2, 4.3, and 4.4.

A. L. Shifrin (*) Department of Surgery, Jersey Shore University Medical Center, Neptune, NJ, USA P. K. Thind University Radiology Group, New Brunswick, NJ, USA Jersey Shore University Medical Center, Department of Radiology, Neptune, NJ, USA © Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_4

35

36

A. L. Shifrin and P. K. Thind

b

a

C

TN

TN

T

T Tr

d

c

C

T Tr

Fig. 4.1 (a–c) Parathyroid ultrasound shows a solid, hypoechoic mass located posteriorly and inferiorly to the superior pole of the right thyroid lobe at the mid level of the right thyroid lobe (T). (a) Transverse view; (b) longitudinal view; (c) Doppler flow study, transverse view. The appearance of this right superior parathyroid adenoma (arrow) could be similar to the appearance of the carotid artery (C) on ultrasound study. Doppler flow study can help to differentiate between the two structures by showing the flow within the carotid artery and the

absence of flow within the parathyroid adenoma. (d) A three-dimensional (3D) volumetric rendering from a Tc 99 m sestamibi SPECT/CT scan. The arrow points to the right-sided parathyroid adenoma. (e) In coronal SPECT images from the Tc 99 m sestamibi scan, the arrows localize the parathyroid adenoma at the level of the right mid to lower pole of the thyroid gland. (f) The arrows demonstrate the parathyroid adenoma on transaxial images. (g) The gross pathological appearance of the parathyroid adenoma. TN thyroid nodule, Tr trachea

4  Right Superior Parathyroid Adenoma

e

Fig. 4.1 (continued)

37

38

A. L. Shifrin and P. K. Thind

f

g

Fig. 4.1 (continued)

4  Right Superior Parathyroid Adenoma

39

a

b

C

T T Tr

c

C

T

Tr

Fig. 4.2 (a–c) Parathyroid ultrasound shows a right superior parathyroid adenoma (arrow). This large, well-defined, solid, hypoechoic mass is located posteriorly and laterally to the superior pole of the right thyroid lobe (T). (a) Transverse view; (b) longitudinal view; (c) Doppler flow study (transverse view) showing the absence of the blood flow in the parathyroid adenoma (arrow), compared with the presence of the flow in the carotid artery (C). (d, e) Planar images from a Tc 99 m ses-

tamibi scan. On the immediate image (d), there is uptake within the thyroid gland, with focal uptake at the level of the lower pole of the right lobe. On the 3-hour delayed image (e), appropriate tracer washout from the thyroid gland has occurred. There is persistent tracer uptake at the level of the lower pole of the right lobe of the thyroid gland (arrow), compatible with a parathyroid adenoma. Tr trachea

40

A. L. Shifrin and P. K. Thind

d

Fig. 4.2 (continued)

e

4  Right Superior Parathyroid Adenoma

41

a

b

T

T

TN

C Tr

c

T

Tr

C

Fig. 4.3  Parathyroid ultrasound shows a solid, hypoechoic mass (arrow) located posteriorly and inferiorly to the superior pole and at the mid level of the right thyroid lobe (T). (a) Transverse view; (b) longitudinal view; (c) Doppler flow study (transverse view) showing the absence of blood flow within the parathyroid adenoma (arrow). (d–g) Immediate images from a Tc 99 m sestamibi scan. (d) This static planar image centered on the neck and chest shows asymmetric uptake within the right lobe of the thyroid gland, with a subtle focus of focal uptake at the level of the middle of the right thyroid lobe. Physiologic activity is seen in the submandibular glands, myocardium, and liver. (e–g) The

pinhole images are centered on the neck in the anterior, right anterior oblique (RAO), and left anterior oblique (LAO) projections, respectively. On images e and g, there is a focus of uptake at the level of the right midpole. (h–k) 3-Hour delayed images from a Tc 99 m sestamibi scan. (h) This anterior static planar image centered on the neck and chest shows appropriate tracer washout from the thyroid gland. The pinhole images (i–k) also demonstrate appropriate tracer washout from the thyroid gland, but there is a persistent focus of uptake at the level of the right middle, compatible with a parathyroid adenoma (arrow). C carotid artery, TN thyroid nodule, Tr trachea

42

Fig. 4.3 (continued)

A. L. Shifrin and P. K. Thind

d

e

f

g

h

i

j

k

4  Right Superior Parathyroid Adenoma

43

a

b

T

T C

c

d

T C

Fig. 4.4  Right superior parathyroid adenoma (arrow) seen on transverse (a) and longitudinal (b) images from a parathyroid ultrasound. The arrows demonstrate a noncalcified, well-circumscribed extrathyroidal solid nodule compatible with a parathyroid gland adenoma. It is hypoechoic relative to the thyroid gland and located posteriorly and inferiorly to the superior pole at the mid level of the right thyroid lobe (T). The transverse view of a color Doppler image (c) demonstrates an extrathyroidal feeding vessel to the parathyroid adenoma (arrow). (d) The top row of images demonstrate immediate Tc 99 m sestamibi planar images centered on the neck. The arrows point at a focus of increased activity at the level of the lower pole of the right lobe of the thyroid gland. The bottom row depicts delayed images, which show appropriate tracer washout from each lobe of the thyroid gland. There is

persistent uptake at the level of the lower half of the right lobe of the thyroid gland, compatible with a parathyroid adenoma. Physiologic activity is visualized within the salivary glands. (e) Focal uptake is seen at the level of the lower half of the right lobe of the thyroid gland. (f) On axial SPECT images, the focal activity is confirmed (arrows). The scintigraphic appearance on the planar and SPECT images is compatible with a parathyroid adenoma. (g) Gross pathology. A solid, ovoid, tanbrown, lobular soft tissue tumor measured 3.2 cm × 2 cm × 1.5 cm; the weight was 3.9 grams. On a frozen section, it was described as a hypercellular parathyroid gland with fibrosis and myxoid changes. The final pathology was consistent with enlarged and hypercellular parathyroid gland with fibrosis, favoring an atypical parathyroid adenoma. C-carotid artery

44

A. L. Shifrin and P. K. Thind

e

f

g Fig. 4.4 (continued)

4  Right Superior Parathyroid Adenoma

Suggested Reading Eslamy HK, Ziessman HA.  Parathyroid scintigraphy in patients with primary hyperparathyroidism: 99mTc sestamibi SPECT and SPECT/CT. Radiographics. 2008;28(5):1461–76. Haber R. Parathyroid ultrasound imaging. In: Pertsemlidis D, Inabnet W, Gagner M, editors. Endocrine surgery. 2nd ed. Boca Raton, FL: CRC Press; 2017. Johnson N, Tublin M, Ogilvie J.  Parathyroid imaging: technique and role in the preoperative evaluation of primary hyperparathyroidism. Am J Roentgenol. 2007;188:1706–15. Kuzminski SJ, Sosa JA, Hoang JK.  Update in parathyroid imaging. Magn Reson Imaging Clin N Am. 2018;26(1):151–66. Lavely W, Goetze S, Friedman K, Leal J, Zhang Z, Garret-Mayer E, et al. Comparison of SPECT/CT, SPECT, and planar imaging with single- and dual-phase 99mTc-sestamibi parathyroid scintigraphy. J Nucl Med. 2007;48:1084–9.

45 Machac J.  Parathyroid radionuclide imaging. In: Pertsemlidis D, Inabnet W, Gagner M, editors. Endocrine surgery. 2nd ed. Boca Raton, FL: CRC Press; 2017. Mitmaker E, Grogan R, Duh Q-Y.  Guide to preoperative parathyroid localization testing. In: Gregory W, Randolph MD, editors. Surgery of the thyroid and parathyroid glands. 2nd ed. Philadelphia: Saunders; 2012. Scheri R, Sosa J.  Localization studies in primary hyperparathyroidism. In: Clark O, Duh Q-Y, Kebebew E, editors. Textbook of endocrine surgery. 3rd ed. New Delhi, India: Jaypee Brothers Medical Publisher; 2016. Shifrin A.  Advances in the diagnosis and surgical management of primary hyperparathyroidism. In: Shifrin A, editor. Advances in treatment and management in surgical endocrinology. Elsevier: Philadelphia; 2019. p. 71–83. Slough CM, Kamani D, Randolph GW.  In-office ultrasonographic evaluation of neck masses/thyroid nodules. Otolaryngol Clin N Am. 2019;52(3):559–75.

5

Right Inferior Parathyroid Adenoma Alexander L. Shifrin and Pritinder K. Thind

The four cases seen in Figs. 5.1, 5.2, 5.3, and 5.4 illustrate images showing right inferior parathyroid adenomas— masses that ultrasound shows to be located posteriorly and inferiorly to the inferior pole of the right thyroid lobe. When Tc99m sestamibi SPECT/CT scans are used, the scintigraphic findings are compatible with a parathyroid adenoma at the level of the lower pole of the right lobe of the thyroid gland. On immediate images, a focus of increased tracer activity can be seen at the level of the lower pole of the right lobe. Elsewhere, tracer activity is uniform within each lobe, and no foci of ectopic tracer activity are identified. On 1-hour

delayed images, there is slight tracer washout from each lobe of the thyroid gland, with a persistent focus of increased tracer activity at the level of the lower pole of the right lobe, and no foci of ectopic tracer activity. The results of 2-hour SPECT/CT examination are similar, with further tracer washout from each lobe of the thyroid gland, and a persistent focus of increased tracer activity at the level of the lower pole of the right lobe. The 3-hour delayed images show a persistent focus of increased tracer activity at the lower pole of the right lobe, which is compatible with a parathyroid adenoma.

A. L. Shifrin (*) Department of Surgery, Jersey Shore University Medical Center, Neptune, NJ, USA P. K. Thind University Radiology Group, New Brunswick, NJ, USA Jersey Shore University Medical Center, Department of Radiology, Neptune, NJ, USA © Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_5

47

48

A. L. Shifrin and P. K. Thind

a

b

C

T

T Tr

Fig. 5.1 (a, b) Parathyroid ultrasound showing a right inferior parathyroid adenoma (arrow) in transverse view (a) and longitudinal view (b). The solid, hypoechoic mass is located posteriorly and inferiorly to the inferior pole of the right thyroid lobe (T). (c–e) Parathyroid scan with SPECT/CT (SPECT CT sestamibi). (c) Left to right: Static planar images of the neck and chest, left anterior oblique (LAO) pinhole, anterior pinhole, and right anterior oblique (RAO) pinhole images. The immediate images (top row) show a focus of increased activity at the level of the lower pole of the right lobe of the thyroid gland (arrow). On the 1-hour images (middle row), there is slight tracer washout from the thyroid gland, with a persistent focus of activity at the level of the right

lower pole (arrow). The 3-hour delayed images (bottom row) show adequate tracer washout from the thyroid gland; the persistent focus of increased activity at the level of the right lower thyroid pole (arrow) is compatible with a parathyroid adenoma. (d) Two-hour transaxial SPECT images show a discrete focus of increased activity at the level of the lower pole of the right lobe of the thyroid gland (arrow). (e) On the 2-hour coronal SPECT images, partial tracer washout from each lobe of the thyroid gland is apparent, but there is persistent focal uptake at the level of the right lower pole (arrows). Physiologic activity is seen within the salivary glands, myocardium, and liver. C-carotid artery, Tr-trachea

5  Right Inferior Parathyroid Adenoma

c

Fig. 5.1 (continued)

49

50

d

Fig. 5.1 (continued)

A. L. Shifrin and P. K. Thind

5  Right Inferior Parathyroid Adenoma

e

Fig. 5.1 (continued)

51

52

A. L. Shifrin and P. K. Thind

a

b

C

T

T Tr

Fig. 5.2 (a–c) Parathyroid ultrasound showing a solid, hypoechoic mass (arrows) located posteriorly and inferiorly to the inferior pole of the right thyroid lobe (T), seen in transverse view (a) and longitudinal view (b). Tr-trachea. A transverse Doppler flow study (c) shows the absence of blood flow in the right inferior parathyroid adenoma (arrow); flow is present in the carotid artery (C). (d) Tc 99 m sestamibi scan with planar imaging. This study was performed earlier in this patient. The top row demonstrates that the right lobe of the thyroid gland is larger than the left. There is asymmetrical increased activity within the right lobe. On the immediate zoom images, there is a focus of uptake subjacent to the lower pole of the right lobe (top arrow). On the delayed images, there is mildly impaired tracer washout from the thyroid gland, particularly the right lobe. The delayed zoom image shows a subtle focus of persistent uptake subjacent to the lower pole of the right lobe of the thyroid gland (lower arrow), compatible with a parathyroid adenoma. The top arrow depicts a focus of increased activity at the level of the lower lobe of the right lobe of the thyroid gland. The lower arrow depicts a persistent focus of uptake subjacent to the lower pole of the right thyroid lobe, compatible with a parathyroid adenoma. (e–i) Parathyroid scan with SPECT/CT (SPECT CT sestamibi). This study was performed later. The SPECT CT sestamibi scan is clearly

superior to the regular sestamibi scan (d). The addition of SPECT/CT increases the conspicuity of the parathyroid adenoma. (e) Static planar images of the neck and chest, left anterior oblique (LAO) pinhole, anterior pinhole, and right anterior oblique (RAO) pinhole images. On the immediate images (top row), activity is asymmetrically increased throughout the right lobe of the thyroid gland, compared with the left lobe. The 1-hour delayed images (middle row) show slight tracer washout from each lobe of the thyroid gland. There is persistent asymmetrically increased activity within the right lobe (arrows), compared with the left. On the anterior and RAO views, a subtle focus of increased tracer activity is seen subjacent to the lower pole of the right lobe. On the 3-hour delayed image (bottom row), retained tracer activity within each lobe of the thyroid gland markedly limits evaluation for a parathyroid adenoma. A subtle focus of increased tracer activity subjacent to the lower pole of the right lobe is best appreciated on the anterior view (arrow). (f–i) The 2-hour SPECT-CT examination shows minimal further tracer washout from each lobe of the thyroid gland. There is an extremely subtle focus of increased tracer activity subjacent to the lower pole of the right lobe, posteriorly (arrows). No foci of ectopic tracer activity are identified. (f) SPECT CT with fused imaging. (g) Axial SPECT. (h) Coronal SPECT. (i) Sagittal SPECT

5  Right Inferior Parathyroid Adenoma

53

c

C

T Tr

Fig. 5.2 (continued)

54

A. L. Shifrin and P. K. Thind

d

Fig. 5.2 (continued)

5  Right Inferior Parathyroid Adenoma

e

Fig. 5.2 (continued)

55

56

A. L. Shifrin and P. K. Thind

f

Fig. 5.2 (continued)

5  Right Inferior Parathyroid Adenoma

g

Fig. 5.2 (continued)

57

58

h

Fig. 5.2 (continued)

A. L. Shifrin and P. K. Thind

5  Right Inferior Parathyroid Adenoma

59

a

b

C

T

Tr

T SA

Fig. 5.3 (a–c) Parathyroid ultrasound shows a solid, hypoechoic mass located posteriorly and inferiorly to the inferior pole of the right thyroid lobe (T) at the level above the right subclavian artery (SA), seen in transverse view (a) and longitudinal view (b). A Doppler flow study in transverse view (c) shows the absence of blood flow in the right inferior parathyroid adenoma (arrow), compared with the flow present in the carotid artery (C) and subclavian artery (SA). (d) The right column shows Tc 99 m sestamibi static planar images centered on the neck and thorax. The remaining images demonstrate pinhole static images centered on the neck. The immediate images (top row) show uniform tracer activity within each lobe of the thyroid gland, with a focus of increased tracer activity inferior to the thyroid gland, midline and slightly to the right of midline (arrow). On 1-hour delayed images (middle row), there

is partial tracer washout from each lobe of the thyroid gland, and a persistent focus of increased tracer activity inferior to the thyroid gland, midline and slightly to the right of midline (arrow). On 3-hour delayed images (bottom row), there is adequate tracer washout from each lobe of thyroid gland, with a persistent focus of increased tracer activity inferior to the thyroid gland midline and to the right of midline, compatible with a parathyroid adenoma (arrows). (e) The 2-hour SPECT/CT examination shows tracer washout from each lobe of the thyroid gland, with a persistent focus of increased tracer activity inferior to the thyroid gland, midline and slightly to the right of midline (arrow). No ectopic tracer activity is identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver. Tr-trachea

60

A. L. Shifrin and P. K. Thind

c

C T

SA

Fig. 5.3 (continued)

Tr

5  Right Inferior Parathyroid Adenoma

d

Fig. 5.3 (continued)

61

62

e

Fig. 5.3 (continued)

A. L. Shifrin and P. K. Thind

5  Right Inferior Parathyroid Adenoma

63

a

b

T

T C

Tr

c

d

T Tr C

Fig. 5.4 (a–c) Parathyroid ultrasound identifies a right inferior parathyroid adenoma (arrow) in the form of a solid, hypoechoic mass located posteriorly and inferiorly to the inferior pole of the right thyroid lobe (T), seen in transverse view (a) and longitudinal view (b). A Doppler flow study in transverse view (c) shows the absence of blood flow within the right inferior parathyroid adenoma (arrow). Tr-trachea. (d–i) Parathyroid scan with SPECT/CT (SPECT CT sestamibi). (d) Anterior Tc 99 m sestamibi static planar image of the neck and chest. The arrow points to a parathyroid adenoma at the level of the lower pole of the right lobe of the thyroid gland. (Of incidental note, the right submandibular gland is absent.) (e) Static planar images from a Tc 99  m sestamibi scan. The top row depicts immediate static and pinhole views. The arrow points to focal increased uptake at the level of the right

lobe of the thyroid gland. The middle row—1-hour delayed images—demonstrates partial washout from the thyroid gland, with a persistent focus of increased activity at the level of the lower pole of the right lobe (arrow). The bottom row—3-hour delayed images—shows appropriate washout from the thyroid gland; the arrow points to the parathyroid adenoma. (f) The top left images depict coronal and sagittal CT images from the SPECT-CT scan. The bottom right images display the fused CT and SPECT images. The bottom right corner image is the coronal scintigraphic image. (g) On the axial Tc 99 m sestamibi images, the arrows point to the retained tracer at the level of the right lobe of the thyroid gland. (h) Sagittal SPECT images; the arrow points to the parathyroid adenoma. (i) Coronal SPECT images; the arrows point to the right-sided parathyroid adenoma

64

e

Fig. 5.4 (continued)

A. L. Shifrin and P. K. Thind

5  Right Inferior Parathyroid Adenoma

f

Fig. 5.4 (continued)

65

66

A. L. Shifrin and P. K. Thind

g

Fig. 5.4 (continued)

5  Right Inferior Parathyroid Adenoma

h

Fig. 5.4 (continued)

67

68

A. L. Shifrin and P. K. Thind

i

Fig. 5.4 (continued)

5  Right Inferior Parathyroid Adenoma

Suggested Reading Eslamy HK, Ziessman HA.  Parathyroid scintigraphy in patients with primary hyperparathyroidism: 99mTc sestamibi SPECT and SPECT/CT. Radiographics. 2008;28:1461–76. Haber RS. Parathyroid ultrasound imaging. In: Pertsemlidis D, Inabnet 3rd WB, Gagner M, editors. Endocrine surgery. 2nd ed. Boca Raton, FL: CRC Press; 2017. p. 217–20. Johnson NA, Tublin ME, Ogilvie JB. Parathyroid imaging: technique and role in the preoperative evaluation of primary hyperparathyroidism. AJR Am J Roentgenol. 2007;188:1706–15. Kuzminski SJ, Sosa JA, Hoang JK.  Update in parathyroid imaging. Magn Reson Imaging Clin N Am. 2018;26:151–66. Lavely WC, Goetze S, Friedman KP, Leal JP, Zhang Z, Garret-Mayer E, et al. Comparison of SPECT/CT, SPECT, and planar imaging with single- and dual-phase (99m)Tc-sestamibi parathyroid scintigraphy. J Nucl Med. 2007;48:1084–9.

69 Machac J.  Parathyroid radionuclide imaging. In: Pertsemlidis D, Inabnet 3rd WB, Gagner M, editors. Endocrine surgery. 2nd ed. Boca Raton, FL: CRC Press; 2017. p. 221–30. Mitmaker EJ, Grogan RH, Duh QY. Guide to preoperative parathyroid localization testing. In: Randolph GW, editor. Surgery of the thyroid and parathyroid glands. 2nd ed. Philadelphia: Elsevier Saunders; 2013. p. 539–45. Scheri RP, Sosa JA. Localization studies in primary hyperparathyroidism. In: Clark OH, Duh QY, Kebebew E, Gosnell JE, Shen WT, editors. Textbook of endocrine surgery. 3rd ed. New Delhi: Jaypee Brothers Medical Publishers; 2016. p. 723–36. Shifrin AL.  Advances in the diagnosis and surgical management of primary hyperparathyroidism. In: Shifrin AL, editor. Advances in treatment and management in surgical endocrinology. Philadelphia: Elsevier; 2019. p. 71–83. Slough CM, Kamani D, Randolph GW.  In-office ultrasonographic evaluation of neck masses/thyroid nodules. Otolaryngol Clin N Am. 2019;52:559–75.

6

Left Superior Parathyroid Adenoma Alexander L. Shifrin and Pritinder K. Thind

Figures 6.1, 6.2, 6.3, 6.4, and 6.5 show images from five cases of left superior parathyroid adenomas—masses that ultrasound shows to be located posteriorly to the superior pole of the left thyroid lobe. When sestamibi scans are used, in some cases persistent tracer activity within each lobe of the thyroid gland severely limits evaluation for a parathyroid adenoma, even on 3 hour delayed imaging. When viewed in

light of the ultrasound findings, however, a very mild persistent focus of increased tracer activity may be identified. More accurate testing to detect a parathyroid adenoma would consist of a SPECT/CT sestamibi scan (rather than a regular sestamibi scan) in combination with a dedicated parathyroid ultrasound study or 4D CT scan.

A. L. Shifrin (*) Department of Surgery, Jersey Shore University Medical Center, Neptune, NJ, USA P. K. Thind University Radiology Group, New Brunswick, NJ, USA Jersey Shore University Medical Center, Department of Radiology, Neptune, NJ, USA © Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_6

71

72

A. L. Shifrin and P. K. Thind

a

b

T

Tr

c

T

T Tr

C

C E

E

d

Fig. 6.1 (a–c) Parathyroid ultrasound of a left superior parathyroid adenoma (arrow), seen as a solid, hypoechoic mass located posteriorly to the superior pole of the left thyroid lobe (T). (a) transverse view; (b) longitudinal view; (c) Doppler flow study in transverse view showing the absence of blood flow within the left superior parathyroid adenoma (arrow), compared with the presence of flow in the carotid artery (C). (d) Static planar and pinhole views from a Tc 99  m sestamibi scan (SPECT CT sestamibi). On the immediate images (top row), the thyroid gland is not enlarged. There is uniform tracer activity within each lobe of the thyroid gland. No hot or cold defects are identified at the level of either lobe. On the 1-hour delayed images (middle row), there is slight tracer washout from each lobe of the thyroid gland, with no persistent foci of increased tracer activity at the level of either lobe. On the 3-hour delayed images (bottom row), there is persistent tracer activity within

each lobe of the thyroid gland, which severely limits evaluation for a parathyroid adenoma. No discrete foci of increased tracer activity are identified in either lobe, and no foci of ectopic tracer activity are identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver. Although no discrete, persistent foci of increased tracer activity at the level of either lobe to indicate a parathyroid adenoma, evaluation is severely limited because of the impaired tracer washout from each lobe. In correlation with ultrasound findings of the left superior parathyroid adenoma, a very minimal increased focus of tracer activity can be appreciated on the LAO view at 1 hour (middle row, arrow), along with a very mild persistent focus of increased tracer activity on the left side on the LAO view at 3  hours (bottom row, arrow). (e) Pathology: gross image of the parathyroid adenoma. E-esophagus, Tr-trachea

6  Left Superior Parathyroid Adenoma

73

e

Fig. 6.1 (continued)

a

b

T

C

c

T

T

C

Tr Tr E E

d

Fig. 6.2 (a–c) Parathyroid ultrasound of a left superior parathyroid adenoma (arrow), seen as a solid, hypoechoic mass located posteriorly to the superior pole of the left thyroid lobe (T) next to the esophagus (E). (a) transverse view; (b) longitudinal view; (c) Doppler flow study in transverse view showing the absence of blood flow within the left superior parathyroid adenoma (arrow). (d) Immediate and 3-hour delayed images from a Tc 99 sestamibi scan. On the immediate image (left), there is uniform activity

within each lobe. On the delayed image (right), tracer retention within the gland severely limits evaluation for a parathyroid adenoma. No discrete foci of retained tracer activity are identified. There is no definitive scintigraphic evidence of a parathyroid adenoma based on sestamibi scan alone, but in correlation with the ultrasound findings of the left superior parathyroid adenoma, it is possible to appreciate a mild persistent focus of increased tracer activity on the left side (arrow). C-carotid artery, Tr-trachea

74

A. L. Shifrin and P. K. Thind

a

b

Tr

c

T T

T

Tr

C

E

d

Fig. 6.3 (a–c) On parathyroid ultrasound, a left superior parathyroid adenoma (arrow) is seen as a solid, hypoechoic mass located posteriorly to the superior pole of the left thyroid. (a) transverse view; (b) longitudinal view; (c) Doppler flow study in transverse view showing the absence of blood flow within the left superior parathyroid adenoma (arrow). (d) The top row of images demonstrate static and pinhole anterior views from a parathyroid Tc 99 m sestamibi scan. There is uniform activity within the thyroid gland. On the delayed images (bottom row), there is minimal retained tracer activity within the thyroid gland. There

are no persistent foci of increased activity at the level of either lobe to indicate a parathyroid adenoma, and no ectopic activity is identified. Physiologic activity is seen in the salivary glands, myocardium, and liver. It is apparent that a sestamibi scan alone has limited ability to detect a small retrothyroidal superior parathyroid adenoma and would be read as “negative.” More accurate testing to detect a parathyroid adenoma would consist of a SPECT/CT sestamibi scan in combination with a dedicated parathyroid ultrasound study. C-carotid artery, E-esophagus, T-thyroid lobe, Tr-trachea

6  Left Superior Parathyroid Adenoma

a

75

b

Tr

T

C

c

T

E

Tr

T

C

E

d

Fig. 6.4 (a–c) On parathyroid ultrasound, a left superior parathyroid adenoma (arrow) is seen as a solid, hypoechoic mass located posteriorly to the superior pole of the left thyroid lobe (T), superior and lateral to the esophagus (E). (a) transverse view; (b) longitudinal view; (c), Doppler flow study in transverse view showing the absence of blood flow within the left superior parathyroid adenoma (arrow), with the presence of blood flow in the left carotid artery (C). (d–f) Parathyroid scan with SPECT/CT (SPECT CT sestamibi). Parathyroid scintigraphy was performed in the standard manner following the intravenous administration of 25.5 millicuries of Technetium 99  m sestamibi. (d) On the immediate images (top row), there is asymmetrically increased uptake within the lower half of the left lobe (arrow). Elsewhere, there is uniform tracer activity within each

lobe. On the 1-hour delayed images (middle row), there is tracer washout from each lobe of the thyroid gland, with a persistent focus of increased tracer activity at the level of the lower half of the left lobe (arrow). The 3-hour delayed images (bottom row) show further tracer washout from the thyroid gland, with persistent focal uptake at the level of the lower half of the left lobe of the thyroid gland (arrow), compatible with a parathyroid adenoma. No foci of ectopic tracer activity are identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver. The 2-hour SPECT/CT examination ((e) coronal view; (f) sagittal view) showed tracer washout from each lobe of the thyroid gland, with a persistent focus of increased tracer activity at the level of the lower half of the left lobe of the thyroid gland (arrows). Tr-trachea

76

e

Fig. 6.4 (continued)

A. L. Shifrin and P. K. Thind

6  Left Superior Parathyroid Adenoma

f

Fig. 6.4 (continued)

77

78

A. L. Shifrin and P. K. Thind

a

b

Tr

c

T

T

T C E

Tr E

d

Fig. 6.5 (a–c) On parathyroid ultrasound, a left superior parathyroid adenoma (arrow) is seen as a solid, hypoechoic mass located posteriorly to the superior pole of the left thyroid lobe (T), superior and lateral to the esophagus (E). (a) transverse view; (b) longitudinal view; (c), Doppler flow study in transverse view showing the absence of blood flow within the left superior parathyroid adenoma (arrow), compared with the presence of flow in the carotid artery (C). (d–h) Parathyroid scan with SPECT/CT (SPECT CT sestamibi). Parathyroid scintigraphy was performed in the standard manner following the intravenous administration of 25.5 millicuries of Technetium 99 m sestamibi. (d) On the immediate images (top row), there is a focus of increased tracer activity (arrow) at the level of the upper half of the left lobe of the thyroid gland. Elsewhere, tracer activity is uniform. On the 1-hour delayed images (middle row), there is partial tracer washout from each lobe of the thyroid gland, with

a persistent focus of increased tracer activity at the level of the upper half of the left lobe of the thyroid gland (arrow). The 3-hour delayed images (bottom row) show appropriate tracer washout from each lobe of the thyroid gland, with a persistent focus of increased tracer activity at the level of the upper half of the left lobe of the thyroid gland (arrow), compatible with a parathyroid adenoma. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver. (e–h) The 2-hour SPECT-CT examination ((e) axial SPECT images; (f) sagittal images; (g) coronal images; (h), fused CT and SPECT and SPECT images) demonstrate tracer washout from each lobe of the thyroid gland, with a persistent focus of increased tracer activity at the level of the upper half of the left lobe. No foci of ectopic tracer activity are identified. (i) Pathology: Gross image of the parathyroid adenoma measuring approximately 2 cm in length. C-carotid artery, Tr-trachea

6  Left Superior Parathyroid Adenoma

e

Fig. 6.5 (continued)

79

80

f

Fig. 6.5 (continued)

A. L. Shifrin and P. K. Thind

6  Left Superior Parathyroid Adenoma

g

h

Fig. 6.5 (continued)

81

82

A. L. Shifrin and P. K. Thind

i

Fig. 6.5 (continued)

Suggested Reading Eslamy HK, Ziessman HA.  Parathyroid scintigraphy in patients with primary hyperparathyroidism: 99mTc sestamibi SPECT and SPECT/CT. Radiographics. 2008;28:1461–76. Haber RS. Parathyroid ultrasound imaging. In: Pertsemlidis D, Inabnet 3rd WB, Gagner M, editors. Endocrine surgery. 2nd ed. Boca Raton, FL: CRC Press; 2017. p. 217–20. Johnson NA, Tublin ME, Ogilvie JB. Parathyroid imaging: technique and role in the preoperative evaluation of primary hyperparathyroidism. AJR Am J Roentgenol. 2007;188:1706–15. Kuzminski SJ, Sosa JA, Hoang JK.  Update in parathyroid imaging. Magn Reson Imaging Clin N Am. 2018;26:151–66. Lavely WC, Goetze S, Friedman KP, Leal JP, Zhang Z, Garret-Mayer E, et al. Comparison of SPECT/CT, SPECT, and planar imaging with single- and dual-phase (99m)Tc-sestamibi parathyroid scintigraphy. J Nucl Med. 2007;48:1084–9. Machac J.  Parathyroid radionuclide imaging. In: Pertsemlidis D, Inabnet 3rd WB, Gagner M, editors. Endocrine surgery. 2nd ed. Boca Raton, FL: CRC Press; 2017. p. 221–30. Mitmaker EJ, Grogan RH, Duh QY. Guide to preoperative parathyroid localization testing. In: Randolph GW, editor. Surgery of the thyroid and parathyroid glands. 2nd ed. Philadelphia: Elsevier Saunders; 2013. p. 539–45. Scheri RP, Sosa JA. Localization studies in primary hyperparathyroidism. In: Clark OH, Duh QY, Kebebew E, Gosnell JE, Shen WT, editors. Textbook of endocrine surgery. 3rd ed. New Delhi: Jaypee Brothers Medical Publishers; 2016. p. 723–36. Shifrin AL.  Advances in the diagnosis and surgical management of primary hyperparathyroidism. In: Shifrin AL, editor. Advances in treatment and management in surgical endocrinology. Philadelphia: Elsevier; 2019. p. 71–83. Slough CM, Kamani D, Randolph GW.  In-office ultrasonographic evaluation of neck masses/thyroid nodules. Otolaryngol Clin N Am. 2019;52:559–75.

7

Left Inferior Parathyroid Adenoma Alexander L. Shifrin and Pritinder K. Thind

A left inferior parathyroid adenoma—a mass identified as adjoining the inferior pole of the left thyroid lobe—can be identified through imaging with ultrasound and Tc 99 m ses-

tamibi SPECT/CT scans, as illustrated in the four cases seen in Figs. 7.1, 7.2, 7.3, and 7.4.

A. L. Shifrin (*) Department of Surgery, Jersey Shore University Medical Center, Neptune, NJ, USA P. K. Thind University Radiology Group, New Brunswick, NJ, USA Jersey Shore University Medical Center, Department of Radiology, Neptune, NJ, USA © Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_7

83

84

A. L. Shifrin and P. K. Thind

a

b

T

Tr

c

C

T

7  Left Inferior Parathyroid Adenoma

85

d

Fig. 7.1 (continued)

Fig. 7.1 (a, b) Parathyroid ultrasound shows a left inferior parathyroid adenoma (arrow), seen as a solid, hypoechoic mass located inferiorly and medially to the inferior pole of the left thyroid lobe (T). (a) transverse view; (b) longitudinal view. (c–h) Parathyroid scintigraphy was performed in the standard manner following the intravenous administration of 23.6 millicuries of Technetium 99  m-sestamibi. (c) The immediate images (top row) show uniform tracer activity within each lobe of the thyroid gland. There is a focus of increased tracer activity inferior to the lower pole of the left lobe (arrow). No foci of ectopic tracer activity are identified. On the 1-hour delayed images (middle row), minimal tracer washout from each lobe is seen, with a persistent focus of increased tracer activity inferior to the lower pole of the left lobe (arrow). On the 3-hour delayed images (bottom row), there is mild

retained tracer activity within each lobe of the thyroid gland; the persistent focus of increased tracer activity inferior to the lower pole of the left lobe is compatible with a parathyroid adenoma (arrow). No foci of ectopic tracer activity are identified. (d–f) The 2-hour SPECT-CT examination ((d) coronal SPECT images; (e) axial images; (f) sagittal images) shows tracer washout from each lobe of the thyroid gland, with a persistent focus of increased tracer activity inferior to the lower pole of the left lobe (arrow). No foci of ectopic tracer activity are identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver. (g) SPECT planar scintigraphic images; (h) Axial CT image. The arrows demonstrate the adenoma. (i) Pathology. Gross image of the parathyroid adenoma measuring approximately 2  cm in length. C-carotid artery, Tr-trachea

86

e

Fig. 7.1 (continued)

A. L. Shifrin and P. K. Thind

7  Left Inferior Parathyroid Adenoma

f

Fig. 7.1 (continued)

87

88

A. L. Shifrin and P. K. Thind

g

h

Fig. 7.1 (continued)

i

7  Left Inferior Parathyroid Adenoma

a

89

b

c

T Tr

C

T

T

d

Fig. 7.2 (a–c) Parathyroid ultrasound shows a left inferior parathyroid adenoma (arrow), seen as a solid, hypoechoic mass located inferiorly to the inferior pole of the left thyroid lobe (T). (a) transverse view; (b) longitudinal view; (c) Doppler study (longitudinal view) shows a hypervascular left inferior parathyroid adenoma (arrow). (d–g) Parathyroid scan with SPECT/CT (SPECT CT sestamibi). Parathyroid scintigraphy was performed in the standard manner following the intravenous administration of 26.3 millicuries of Technetium 99  m-sestamibi. (d) Immediate, 1-hour, and 3-hour delayed images centered over the neck were obtained in the anterior, LAO, and RAO projections using pinhole collimation. On the immediate images (top row), there is faint tracer activity within the lobe of the thyroid gland. The patient has a history of hypothyroidism. A focus of increased tracer activity is seen in the expected location of the lower pole of the left lobe (arrow). On

the 1-hour delayed images (middle row), there is faint tracer activity within the thyroid gland, with a persistent focus of increased tracer activity at the expected level of the lower pole of the left lobe (arrow). On the 3-hour delayed images (bottom row), a persistent focus of increased tracer activity is seen in the expected location of the lower pole of the left lobe of the thyroid gland (arrow), compatible with a parathyroid adenoma. No foci of ectopic tracer activity are identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver. (e–g) The 2-hour SPECT-CT examination ((e) coronal SPECT images; (f) sagittal images; (g) axial images) shows no tracer activity within either lobe of the thyroid gland, but there is a persistent focus of increased tracer activity at the expected level of the lower pole of the left lobe (arrows). C-carotid artery, Tr-trachea

90

A. L. Shifrin and P. K. Thind

e

f

Fig. 7.2 (continued)

7  Left Inferior Parathyroid Adenoma

91

g

Fig. 7.2 (continued)

a

b

c

T C

T

T

Tr

Fig. 7.3 (a–c) Parathyroid ultrasound shows a left inferior parathyroid adenoma (arrow), seen as a solid, hypoechoic mass located inferiorly to the inferior pole of the left thyroid lobe (T) and medially to the left carotid artery (C). (a) transverse view; (b) longitudinal view; (c) Doppler study (transverse view) showing a small feeding vessel to the parathyroid adenoma (arrow). (d–g) Parathyroid scan with SPECT/CT (SPECT CT sestamibi). Parathyroid scintigraphy was performed in the standard manner following the intravenous administration of 26.7 millicuries of Technetium 99 m-sestamibi. (d) On the immediate images (top row), there is uniform tracer activity within each lobe of thyroid gland. There is a focus of increased tracer activity subjacent to the lower pole of the left lobe (arrow). The 1-hour delayed images (middle row) show partial tracer washout from each lobe of the thyroid gland,

C

Tr

with a persistent focus of increased tracer activity subjacent to the lower pole of the left lobe (arrows). On the 3-hour delayed images (bottom row), there is appropriate tracer activity within each lobe of thyroid gland, and a persistent focus of increased tracer activity subjacent to the lower pole of the left lobe (arrow). No foci of ectopic tracer activity are identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver. (e–g) The 2-hour SPECT-CT examination ((e) coronal SPECT images; (f) sagittal images; (g) axial images) shows tracer washout from each lobe of the thyroid gland with a persistent focus of increased tracer activity subjacent to the lower pole of the left lobe (arrows). No foci of ectopic tracer activity are identified. Tr-trachea

92

d

e

Fig. 7.3 (continued)

A. L. Shifrin and P. K. Thind

7  Left Inferior Parathyroid Adenoma

f

g

Fig. 7.3 (continued)

93

94

A. L. Shifrin and P. K. Thind

a

b

C Tr E

c

d

T T

Fig. 7.4 (a–f) Parathyroid ultrasound identifies a left inferior parathyroid adenoma (arrow), which is seen as a solid, hypoechoic mass located inferiorly to the inferior pole of the left thyroid lobe (T) and anteriorly to the esophagus (E). (a, b) transverse views; (c, d) longitudinal views; (e, f) Doppler flow study transverse views show a feeding vessel towards the left inferior parathyroid adenoma (arrow) with the absence of blood flow within the adenoma, and the presence of blood flow in the left carotid artery (C). (g–l) Parathyroid scan with SPECT/ CT (SPECT CT sestamibi). Parathyroid scintigraphy was performed in the standard manner following the intravenous administration of 25 millicuries of Technetium 99  m-sestamibi. (h) On the immediate images (top row), uniform tracer activity is seen within each lobe of the thyroid gland, along with a focus of increased tracer activity subjacent to the lower pole of the left lobe (arrow). On the correlative ultrasound,

there is a soft tissue nodule inferior to the left lobe. The 1-hour delayed images (middle row) show partial tracer washout from each lobe of the thyroid gland. There is a persistent focus of increased tracer activity at the level of the lower pole of the left lobe (arrow). On the 3-hour delayed images (bottom row and (g)), there is adequate tracer washout from each lobe of the thyroid gland, with a persistent focus of increased tracer activity at the level of the lower pole of the left lobe of the thyroid gland, compatible with a parathyroid adenoma (arrow). No foci of ectopic tracer activity are identified. (i–l) On the 2-hour SPECT-CT examination, tracer washout from each lobe of the thyroid gland is seen, with a persistent focus of increased tracer activity at the level of the lower pole of the left lobe (arrows). (i) coronal SPECT images; (j), sagittal images; (k) axial images; (l) CT images (top), SPECT images (middle), and fused SPECT and CT images (bottom). Tr-trachea

7  Left Inferior Parathyroid Adenoma

e

95

f

C C

Tr E

g

Fig. 7.4 (continued)

96

h

i

Fig. 7.4 (continued)

A. L. Shifrin and P. K. Thind

7  Left Inferior Parathyroid Adenoma

j

k

Fig. 7.4 (continued)

97

98

A. L. Shifrin and P. K. Thind

l

Fig. 7.4 (continued)

Suggested Reading Eslamy HK, Ziessman HA.  Parathyroid scintigraphy in patients with primary hyperparathyroidism: 99mTc sestamibi SPECT and SPECT/CT. Radiographics. 2008;28:1461–76. Haber RS. Parathyroid ultrasound imaging. In: Pertsemlidis D, Inabnet 3rd WB, Gagner M, editors. Endocrine surgery. 2nd ed. Boca Raton, FL: CRC Press; 2017. p. 217–20. Johnson NA, Tublin ME, Ogilvie JB. Parathyroid imaging: technique and role in the preoperative evaluation of primary hyperparathyroidism. AJR Am J Roentgenol. 2007;188:1706–15. Kuzminski SJ, Sosa JA, Hoang JK.  Update in parathyroid imaging. Magn Reson Imaging Clin N Am. 2018;26:151–66. Lavely WC, Goetze S, Friedman KP, Leal JP, Zhang Z, Garret-Mayer E, et al. Comparison of SPECT/CT, SPECT, and planar imaging with single- and dual-phase (99m)Tc-sestamibi parathyroid scintigraphy. J Nucl Med. 2007;48:1084–9.

Machac J.  Parathyroid radionuclide imaging. In: Pertsemlidis D, Inabnet 3rd WB, Gagner M, editors. Endocrine surgery. 2nd ed. Boca Raton, FL: CRC Press; 2017. p. 221–30. Mitmaker EJ, Grogan RH, Duh QY. Guide to preoperative parathyroid localization testing. In: Randolph GW, editor. Surgery of the thyroid and parathyroid glands. 2nd ed. Philadelphia: Elsevier Saunders; 2013. p. 539–45. Scheri RP, Sosa JA. Localization studies in primary hyperparathyroidism. In: Clark OH, Duh QY, Kebebew E, Gosnell JE, Shen WT, editors. Textbook of endocrine surgery. 3rd ed. New Delhi: Jaypee Brothers Medical Publishers; 2016. p. 723–36. Shifrin AL.  Advances in the diagnosis and surgical management of primary hyperparathyroidism. In: Shifrin AL, editor. Advances in treatment and management in surgical endocrinology. Philadelphia: Elsevier; 2019. p. 71–83. Slough CM, Kamani D, Randolph GW.  In-office ultrasonographic evaluation of neck masses/thyroid nodules. Otolaryngol Clin N Am. 2019;52:559–75.

Part III Intrathyroidal Parathyroid Adenoma, Cystic Parathyroid Adenoma, and Parathyroid Carcinoma

8

Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid Adenoma Alexander L. Shifrin and Pritinder K. Thind

This chapter presents eight cases of intrathyroidal parathyroid adenoma (Figs. 8.1, 8.2, 8.3, 8.4, 8.5, and 8.6) or cystic

parathyroid adenoma (Figs. 8.7 and 8.8), which are all identified using ultrasound and SPECT/CT imaging.

A. L. Shifrin (*) Department of Surgery, Jersey Shore University Medical Center, Neptune, NJ, USA P. K. Thind University Radiology Group, New Brunswick, NJ, USA Jersey Shore University Medical Center, Department of Radiology, Neptune, NJ, USA © Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_8

101

102

A. L. Shifrin and P. K. Thind

a

b T

Tr

T

Tr C

C

c

d

T

Tr

T

C

E

e

f

T

Fig. 8.1 Left superior intrathyroidal parathyroid adenoma. (a–g) Parathyroid ultrasound shows a large, well-defined, solid, hypoechoic nodule within the superior pole of the left thyroid lobe (arrow). In correlation with the sestamibi scan, the finding was compatible with left intrathyroidal parathyroid adenoma. Intraoperative frozen section diagnosis and the final pathological diagnosis were consistent with parathyroid adenoma. (a) Transverse view, superior pole of the left thyroid lobe (T); (b) transverse view, superior pole to middle of the left thyroid lobe; (c) transverse view, middle of the left thyroid lobe; (d–f) longitudinal view, medial to lateral sections, superior pole of the left thyroid lobe; (g) Doppler flow study (longitudinal view) showing the flow surrounding the adenoma (arrow) within the left thyroid lobe. C carotid artery, E esophagus, Tr trachea. (h–l) Parathyroid scan with SPECT/CT (SPECT CT sestamibi) demonstrating a left intrathyroidal parathyroid adenoma (arrows). (h) (top row), On the immediate images, there is increased tracer activity at the level of the upper half of the left lobe of the thyroid

T

gland. Elsewhere, there is uniform tracer activity within each lobe. (h) (middle row), One-hour delayed images show mild tracer washout from each lobe of the thyroid gland, with persistent increased activity at the level of the upper half of the left lobe. (h) (bottom row), On the 3-hour delayed images, there is appropriate tracer washout from each lobe of the thyroid gland, as well as persistent increased activity at the level of the upper pole of the left lobe compatible with a parathyroid adenoma. No foci of ectopic tracer activity are identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver. (i) CT SPECT, CT/SPECT fusion. (j) Sagittal SPECT. (k) Axial SPECT. (l) Coronal SPECT.  On the 2-hour SPECT-CT examination, there is further tracer washout from each lobe of the thyroid gland. There is a persistent focus of increased tracer activity at the level of the upper half of the left lobe. No foci of ectopic tracer activity are identified. On the localizing CT scan, there is a 1.54 × 1.1 cm noncalcified soft tissue nodule at the level of the upper pole of the left lobe of the thyroid gland

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

g

T

h

Fig. 8.1 (continued)

103

104

i

Fig. 8.1 (continued)

A. L. Shifrin and P. K. Thind

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

j

Fig. 8.1 (continued)

105

106

k

Fig. 8.1 (continued)

A. L. Shifrin and P. K. Thind

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

l

Fig. 8.1 (continued)

107

108

A. L. Shifrin and P. K. Thind

a

b

c

T

Tr

C

T

E

d

e T

Tr

C

E

Fig. 8.2 Left superior intrathyroidal parathyroid adenoma. (a–d) Parathyroid ultrasound shows a large, well-defined, solid, hypoechoic nodule within the superior pole of the left thyroid lobe (arrow). In correlation with the sestamibi scan, the finding was compatible with left intrathyroidal parathyroid adenoma. (a) Transverse view, superior pole of the left thyroid lobe (T); (b) transverse view, superior to mid left thyroid lobe; (c) logitudinal view, medial to lateral sections, superior pole of the left thyroid lobe; (d) Doppler flow study (transverse view) of the left superior intrathyroidal parathyroid adenoma (arrow) showing the feeding vessel at the anterior medial part of the adenoma within the left thyroid lobe. C-carotid artery, E-esophagus, Tr-trachea. (e–j) Parathyroid scan with SPECT/CT (SPECT CT sestamibi) scan showing the left intrathyroidal parathyroid adenoma (arrows). On the immediate images, the thyroid gland is not enlarged. There is a focus of increased tracer activity within

the midpole of the left lobe. No foci of ectopic tracer activity are identified. On 1-hour delayed images, there is no significant tracer washout from either lobe of the thyroid gland, and a persistent focus of increased tracer activity is seen at the level of the midpole of the left lobe. No foci of ectopic tracer activity are identified. The 2-hour SPECT CT examination ((h) axial SPECT images; (i) coronal images; (j) sagittal images) shows partial tracer washout from each lobe of the thyroid gland, with a focus of persistent increased tracer activity at the level of the mid to lower pole of the left lobe. No foci of ectopic tracer activity are identified. On the 3-hour delayed images, there is a persistent focus of increased tracer activity at the level of the mid to lower pole of the left lobe, compatible with a parathyroid adenoma. Physiologic tracer activity is identified within the salivary glands, myocardium and liver

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

f

g

Fig. 8.2 (continued)

109

110

A. L. Shifrin and P. K. Thind

h

i

Fig. 8.2 (continued)

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

j

Fig. 8.2 (continued)

111

112

A. L. Shifrin and P. K. Thind

a

b

T T Tr C

c

d

T T C

Tr

e

Fig. 8.3 Right superior intrathyroidal parathyroid adenoma. (a–d). Parathyroid ultrasound shows a large, well defined, solid, hypoechoic nodule (arrow) occupying the posterior aspect of the mid part and superior pole of the right thyroid lobe. In correlation with the sestamibi scan, the finding was compatible with a right intrathyroidal parathyroid adenoma. (a) Transverse view, mid part of the right thyroid lobe (T); (b, c) logitudinal view of the right thyroid lobe; (d) Doppler flow, study, transverse view,

showing the right superior intrathyroidal parathyroid adenoma (arrow) with no Doppler vascular flow, but small flow at the feeding vessel at the upper pole of the adenoma on the right. C-carotid artery, Tr-trachea. (e) Sestamibi scan showing persistent uptake at 4 hours at the superior pole of the right thyroid lobe, consistent with a right superior intrathyroidal parathyroid adenoma (arrow)

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

113

b

a

T Tr

T

Tr

C C E

c

d

T Tr

C

T

C

E

e

f

T T

Tr

C

C

Fig. 8.4 Left inferior intrathyroidal parathyroid adenoma. (a–g) Parathyroid ultrasound shows a large, well defined, solid, hypoechoic nodule (arrow) within the inferior pole of the left thyroid lobe. In correlation with the sestamibi scan, the finding was compatible with a left inferior intrathyroidal parathyroid adenoma. Intraoperative frozen section diagnosis, as well as the final pathological diagnosis, were consistent with parathyroid adenoma. (a) Middle of the left thyroid lobe (T), transverse view; (b, c) inferior pole of the left thyroid lobe, transverse view; (d) logitudinal view, laterally; (e) logitudinal view, medially;

(f,   g) Doppler flow study, transverse view, showing flow within the carotid artery (C) and a small flow within the feeding vessel of the left inferior intrathyroidal parathyroid adenoma (arrow). (f) Transverse view; (g) logitudinal view. E-esophagus, Tr-trachea. (h–l) Parathyroid scan with SPECT/CT (SPECT CT sestamibi). Immediate images (h, i) and delayed images (j, k) from a Tc 99 m sestamibi scan demonstrating a left inferior intrathyroidal parathyroid adenoma (arrow). (l) The finding is confirmed on transaxial SPECT images (arrow)

114

A. L. Shifrin and P. K. Thind

g

h

T

j

l

Fig. 8.4 (continued)

k

i

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

a

b

c

T

Tr

T

115

T Tr

Tr

C

C

C

d

e

T

f

T

T

g T

Tr

C

Fig. 8.5 Right inferior intrathyroidal parathyroid adenoma. (a–g) Parathyroid ultrasound a well-circumscribed, solid, uniformly hypoechoic, well-­defined nodule measuring 1.37  ×  1.16  ×  1.02  cm within the inferior pole of the right thyroid lobe. In correlation with the sestamibi scan, this finding is compatible with a right inferior intrathyroidal parathyroid adenoma. Intraoperative frozen section diagnosis and the final pathological diagnosis were consistent with parathyroid adenoma. (a–c) Transverse views, inferior pole of the left thyroid lobe; (d–f) logitudinal views; (g) Doppler flow study, transverse view, showing the right inferior intrathyroidal parathyroid adenoma (arrow). Flow is seen within the carotid artery (C), and increased color Doppler flow surrounding the parathyroid adenoma shows small feeding vessel flow going within the adenoma. T-thyroid lobe, Tr-trachea. (h–l) Static and SPECT/CT Tc 99  m sestamibi images demonstrating a right inferior intrathyroidal parathyroid adenoma (arrows). Following the intravenous administration of 24.7  mCi of Tc 99  m sestamibi, immediate, 1-hour, and 3-hour delayed images centered in the neck were obtained, with anterior, LAO, and RAO projections using pinhole collimation. In addition, at these times, static planar images centered over the neck and chest were obtained in the anterior projection. At 2 hours, a SPECT CT

examination of the neck was performed. The data is reformatted in the sagittal (j), coronal (k), and transaxial (l) planes. On the immediate images, the right lobe of the thyroid gland is larger than the left. There are foci of increased tracer activity at the levels of each lower pole. The uptake is more pronounced on the right than on the left, and there is prominence of the thyroid isthmus. On the 1-hour delayed images, partial tracer washout from each lobe of the thyroid gland is seen, with a persistent focus of increased tracer activity at the level of the lower pole of the right lobe. The SPECT CT examination shows increased tracer activity at the level of the lower poles of each lobe of the thyroid gland, with more discrete focal uptake at the level of the lower pole of the right lobe. No foci of ectopic tracer activity are identified on the SPECT CT examination. On the 3-hour delayed images, there is tracer washout from each lobe of the thyroid gland, with a persistent focus of increased tracer activity at the level of the lower pole of the right lobe compatible with a parathyroid adenoma. No foci of ectopic tracer activity are identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver

116

A. L. Shifrin and P. K. Thind

h

j

Fig. 8.5 (continued)

i

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

k

Fig. 8.5 (continued)

117

118

A. L. Shifrin and P. K. Thind

l

Fig. 8.5 (continued)

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

a

119

b T C

T C

Tr

c

Tr

d T

Fig. 8.6  Right inferior intrathyroidal parathyroid adenoma. (a–d) Parathyroid ultrasound showing a solid, hypoechoic nodule (arrow) occupying the posterior aspect of the mid part and inferior pole of the right thyroid lobe (T). In correlation with the sestamibi scan, the finding was compatible with a right inferior intrathyroidal parathyroid adenoma. (a, b) Transverse view of the right thyroid lobe; (c) Logitudinal view of the right thyroid lobe. (d) Doppler flow study (logitudinal view) show a feeding vessel within the adenoma. C-carotid artery, Tr-trachea. (e–h) Parathyroid scan with SPECT/CT (SPECT CT sestamibi) showing a right inferior intrathyroidal parathyroid adenoma (arrow) on the delayed view. Parathyroid scintigraphy was performed in the standard manner following the intravenous administration of 25.5 millicuries of Technetium 99  m-sestamibi. Immediate, 1-hour, and 3-hour delayed images centered over the neck were obtained in the anterior, LAO, and RAO projections using pinhole collimation. In addition, at these times, static planar images centered on the neck and chest were obtained in the

T

anterior projection. At 2 hours, a SPECT CT examination centered over the neck and upper chest was performed. The data were reformatted in the sagittal (g), coronal (h), and transaxial planes. On the immediate images, there are no discrete foci of increased tracer activity at the level of either lobe. The 1-hour delayed images show mild tracer washout from each lobe of the thyroid gland, with a focus of increased activity at the level of the right midpole. On the 2-hour SPECT-CT examination, there is further tracer washout from each lobe of the thyroid gland, and a persistent focus of uptake at the level of the right lobe. On the 3-hour delayed images, there is a persistent focus of tracer retention within the right lobe of the thyroid gland compatible with parathyroid adenoma. No foci of ectopic tracer activity are identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver. There is a photopenic defect secondary to the patient’s left shoulder prosthesis. The scintigraphic finding corresponds to the ultrasound finding

120

e

Fig. 8.6 (continued)

A. L. Shifrin and P. K. Thind

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

f

Fig. 8.6 (continued)

121

122

g

Fig. 8.6 (continued)

A. L. Shifrin and P. K. Thind

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

h

Fig. 8.6 (continued)

123

124

A. L. Shifrin and P. K. Thind

a

b T T

Tr

C Tr

c

d T

T

T

C

e

T T

Fig. 8.7  Left superior cystic intrathyroidal parathyroid adenoma. (a– g) Parathyroid ultrasound showing a large nodule measuring 3.59 × 1.26 × 1.83 cm, with a central cystic component and a peripheral rim of solid, hypoechoic tissue. In correlation with a sestamibi scan, the finding was compatible with a cystic intrathyroidal parathyroid adenoma. (a) Transverse view, middle of the left thyroid lobe (T); (b) transverse view, inferior pole of the left thyroid lobe; (c–e) logitudinal views; (f, g) Doppler flow study showing hypervascularity within the peripheral solid rim of the left cystic intrathyroidal parathyroid adenoma (arrow). (f) Transverse view; (g) logitudinal view. C-carotid artery, Tr-trachea. (h–l) Parathyroid scan with SPECT/CT (SPECT CT sestamibi) documenting a left-sided parathyroid adenoma (arrows). Parathyroid scintigraphy was performed in the standard manner following the intravenous administration of 25.9 millicuries of Technetium 99  m-sestamibi. Immediate, 1-hour, and 3-hour delayed images centered over the neck were obtained in the anterior, LAO, and RAO projections using pinhole collimation. In addition, at these times, static

planar images centered on the neck and chest were obtained in the anterior projection. At 2 hours, a SPECT CT examination centered over the neck and upper chest was performed ((j) sagittal view; (k) coronal view; (l) axial view). The immediate images show an area of increased tracer uptake within the majority of the left thyroid lobe, and there is a subtle central photopenic defect. On the 1-hour delayed images, there is tracer washout from each lobe and persistent increased tracer activity at the level of the left lobe, with a subtle area of photopenia. On the 2-hour SPECT CT examination, persistent tracer uptake is seen at the level of the left lobe. No foci of ectopic tracer activity are identified. The abnormal activity corresponds to a hypodense lesion at the level of the left lobe of the thyroid gland on the localizing CT scan. On the 3-hour delayed images, there is persistent tracer activity at the level of the left lobe, with a small central photopenic component. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver. The scintigraphic finding corresponds to the abnormality with a large central cystic component identified on the ultrasound

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

f

g T C

h

Fig. 8.7 (continued)

125

126

i

Fig. 8.7 (continued)

A. L. Shifrin and P. K. Thind

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

j

Fig. 8.7 (continued)

127

128

k

Fig. 8.7 (continued)

A. L. Shifrin and P. K. Thind

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

l

Fig. 8.7 (continued)

129

130

A. L. Shifrin and P. K. Thind

a

b

T

T C Tr

d

c

T C

T Tr

Fig. 8.8  Right superior cystic parathyroid adenoma. (a–d) Parathyroid ultrasound shows a large, well-defined, cystic, markedly hypoechoic mass posterior to the superior pole of the right thyroid lobe (T). The black color of the mass makes it rsembled to a fluid filled cyst or the carotid artery (C). Solid parathyroid adenoma is hypoecoic but not as dark as the cyst. Due to its large size it appeared to be descended from the superior thyroid pole down to the inferior thyroid pole and on the level of inferior parathyroid gland, consistent with the right descended superior parathyroid adenoma. In correlation with the sestamibi scan, the finding was compatible with a right cystic parathyroid adenoma. (a) Transverse view; (b) longitudinal view. (c, d) Doppler flow study shows the right superior cystic parathyroid adenoma (arrow) with no Doppler vascular flow within the adenoma, compared with the flow within the carotid artery. (C) Transverse view; (d) Longitudinal view. Tr-trachea.

(e) Parathyroid sestamibi scan. On the immediate images (top row), there is uniform uptake within the thyroid gland. On the 1-hour delayed images (middle row), there is a subtle focus of retained tracer activity within the lower pole of the right lobe, which is best appreciated on the LAO view (arrow). The 3-hour delayed images (bottom row) show appropriate tracer washout from the thyroid gland. There is some subtle uptake which is persistent at the lower pole of the right lobe of the thyroid. The activity here however is quite low and no significant abnormality is noted on the immediate and 1 hour films. The appearance is not specific but is not typical of a parathyroid adenoma. However, on the 3-hour delayed images anterior view, RAO, and LAO views, there is a persistent focus of tracer activity at the level of the lower pole of the right thyroid lobe left lobe of the thyroid gland (arrow), compatible with a parathyroid adenoma

8  Ultrasonography, Sestamibi Scan, and SPECT/CT Sestamibi Scan of Intrathyroidal Parathyroid Adenoma and Cystic Parathyroid…

e

Fig. 8.8 (continued)

131

132

Suggested Reading Arora S, Balash PR, Yoo J, Smith GS, Prinz RA.  Benefits of surgeon-­ performed ultrasound for primary hyperparathyroidism. Langenbeck’s Arch Surg. 2009;394(5):861–7. Deutmeyer C, Weingarten M, Doyle M, Carneiro-Pla D.  Case series of targeted parathyroidectomy with surgeon-performed ultrasonography as the only preoperative imaging study. Surgery. 2011;150(6):1153–60. Devcic Z, Jeffrey RB, Kamaya A, Desser TS.  The elusive parathyroid adenoma: techniques for detection. Ultrasound Q. 2013;29(3):179–87. Johnson NA, Carty SE, Tublin ME. Parathyroid imaging. Radiol Clin N Am. 2011;49(3):489–509. vi Kamaya A, Quon A, Jeffrey RB. Sonography of the abnormal parathyroid gland. Ultrasound Q. 2006;22(4):253–62. Review.

A. L. Shifrin and P. K. Thind Mazeh H, Kouniavsky G, Schneider DF, Makris KI, Sippel RS, Dackiw AP, Chen H, Zeiger MA.  Intrathyroidal parathyroid glands: small, but mighty (a Napoleon phenomenon). Surgery. 2012;152(6):1193–200. Papavramidis TS, Chorti A, Pliakos I, Panidis S, Michalopoulos A. Parathyroid cysts: a review of 359 patients reported in the international literature. Medicine (Baltimore). 2018;97(28):e11399. Sahli ZT, Karipineni F, Zeiger MA. A garden of parathyroid adenomas. BMJ Case Rep. 2017;2017. pii: bcr-2017-221130. Slough CM, Kamani D, Randolph GW.  In-office ultrasonographic evaluation of neck masses/thyroid nodules. Otolaryngol Clin N Am. 2019;52(3):559–75. Yabuta T, Tsushima Y, Masuoka H, Tomoda C, Fukushima M, Kihara M, et  al. Ultrasonographic features of intrathyroidal parathyroid adenoma causing primary hyperparathyroidism. Endocr J. 2011;58(11):989–94.

9

Imaging of the Parathyroid Carcinoma Alexander L. Shifrin, Pritinder K. Thind, Hubert H. Chuang, and Nancy D. Perrier

Parathyroid carcinoma is a rare malignant neoplasm of the parathyroid gland accounting for approximately 0.5–1% of patients with primary hyperparathyroidism. Because of the rarity of this cancer, the diagnosis is difficult to establish. The diagnosis could be suspected from findings of a very high serum calcium level usually higher than 14–16 mg/dL with corresponding elevation of serum parathyroid hormone level 10–15-fold higher than the normal range. The 5- and 10-year survival rates for patients with parathyroid carcinoma are 78–85% and 49–70%, respectively. There are no

good imaging studies that can clearly establish the diagnosis of parathyroid carcinoma, but some imaging modalities such as ultrasound and CT scan can be helpful in the initial evaluation of patients with a suspected diagnosis of parathyroid carcinoma. Sestamibi scans can also help in localization. This chapter presents imaging studies of three cases of parathyroid carcinoma suspected preoperatively, which were confirmed during and after surgery by pathological evaluation (Figs. 9.1, 9.2, and 9.3).

A. L. Shifrin (*) Department of Surgery, Jersey Shore University Medical Center, Neptune, NJ, USA P. K. Thind University Radiology Group, New Brunswick, NJ, USA Jersey Shore University Medical Center, Department of Radiology, Neptune, NJ, USA H. H. Chuang Department of Nuclear Medicine, University of Texas, The University of Texas MD Anderson Cancer Center, Houston, TX, USA N. D. Perrier Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA © Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_9

133

134

A. L. Shifrin et al.

b

a

T

c

C

C

T

Tr E

T

Tr

E

E

d

e

T T

Fig. 9.1 (a–j) Parathyroid ultrasound. Left superior parathyroid carcinoma (arrow). A large (3.7 cm × 2.1 cm × 1.9 cm), solid, hypoechoic mass located posterior to the superior pole of the left thyroid lobe (T), with a thick, hyperechoic rim and irregular margins. It is intimately attached to the posterior aspect of the left thyroid lobe and undistinguished from the wall of the esophagus (E). Preoperatively, calcium level in the patient was elevated to 14–15 mg/dL (normal, 8.5–10.2 mg/ dL) and PTH levels of 536 pg/mL (normal, 14–64 pg/mL). During surgical exploration, the mass appeared to have invaded into the superficial layers of the esophageal wall, the recurrent laryngeal nerve, and the thyroid lobe. (a) Transverse view, middle of the left thyroid lobe; (b) Transverse view, mid to superior pole of the left thyroid lobe; (c) Transverse view, superior pole of the left thyroid lobe; (d–g) Longitudinal views; (h–j) Ultrasound Doppler flow study showing the absence of flow within the parathyroid tumor with surrounding vessel at the inferior aspect of the mass, and the presence of flow within the carotid artery (C). (h) Ultrasound Doppler flow study transverse view; (i, j) Ultrasound Doppler flow study longitudinal view. C-carotid artery, Tr-trachea. (k–p) Sestamibi scan. Parathyroid scintigraphy was performed in the standard manner following the intravenous administration of 26.1 millicuries of Technetium 99m-sestamibi. Immediate, 1-hour, and 3-hour delayed images centered over the neck were

obtained in the anterior, LAO, and RAO projections using pinhole collimation. In addition, at these times, static planar images centered on the neck and chest were obtained in the anterior projection. At 2 hours, a SPECT CT examination centered over the neck and upper chest was performed. The data was reformatted in the coronal (n), sagittal (o), and transaxial (p) planes. On the immediate images (k, top row), the thyroid gland is not enlarged. There is asymmetrically increased activity within the left thyroid lobe, as compared with the right. On the 1-hour delayed images (k, middle row), there is minimal tracer washout from each lobe of the thyroid gland, but persistent asymmetrically increased activity within the left thyroid lobe (particularly the lower two thirds), as compared with the right. On the 2-hour SPECT-CT examination (l–p), there is further tracer washout from each lobe of the thyroid gland, but there is persistent increased tracer activity at the level of the lower two thirds of the left thyroid lobe (arrows). (l, m) depicts the CT-fused images showing persistent increased tracer activity at the level of the lower two thirds of the left thyroid lobe (L) (arrow). On the 3-hour delayed images (k, bottom row), there is adequate tracer washout from each lobe of the thyroid gland, with persistent uptake at the level of the lower two thirds of the left thyroid lobe (arrows). No foci of ectopic tracer activity are identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and liver

9  Imaging of the Parathyroid Carcinoma

135

f

g

T

T

i

h

Tr

Fig. 9.1 (continued)

T

C

j T T

136

A. L. Shifrin et al.

k

l

Fig. 9.1 (continued)

m

9  Imaging of the Parathyroid Carcinoma

n n

o

Fig. 9.1 (continued)

137

138

A. L. Shifrin et al.

p

Fig. 9.1 (continued)

a

b

T T

C C

Tr

Tr E

E

Fig. 9.2 (a–e) Parathyroid ultrasound. Left inferior, partially intrathyroidal, parathyroid carcinoma (arrow). A small (1.4 cm × 0.89 cm × 0.65 cm), solid, hypoechoic mass located partially within the posterior aspect of the inferior pole of the left thyroid lobe (T). It has irregular margins with infiltrating pattern. Posteriorly, the margin is difficult to distinguish owing to invasion into the surrounding structures, such as the esophagus (E). During the surgical exploration, the mass appeared to be invaded into the superficial muscular layers of the esophageal wall and into the left thyroid lobe. Frozen and permanent pathology sections were consistent with parathyroid carcinoma. The patient had en bloc resection of the tumor with the left thyroid lobe and superficial layers of the esophagus and remained asymptomatic for more than 6 years of follow-up. (a, b) Ultrasound, transverse view; (c, d) Ultrasound, longitudinal views; (e) Ultrasound, Doppler flow study showing the absence of flow within the parathyroid carcinoma and the presence of flow within the left common carotid artery (C). Tr-trachea. (f) Sestamibi scan. Parathyroid scintigraphy was performed in the stan-

dard manner following the intravenous administration of 25.6  mCi of Technetium 99m Sestamibi. Immediate, 1-hour, and 3-hour delayed images centered in the neck were obtained in the anterior, LAO, and RAO projections using pinhole collimation. In addition, at these times, static planar images centered over the neck and chest were obtained in the anterior projection. On the immediate images (f, top row), the thyroid gland is not enlarged. There is a focus of increased tracer activity at the level of the lower pole of the left lobe (arrow). On the 1-hour images (f, middle row), there is partial washout of the radiopharmaceutical from the thyroid gland. There is a persistent focus of increased tracer activity at the level of the lower pole of the left thyroid lobe (arrow). On the 3-hour delayed images (f, bottom row), there is a focus of persistent tracer activity at the level of the lower pole of the left lobe of the thyroid gland (arrow). No foci of ectopic tracer activity are identified. Physiologic tracer activity is identified within the salivary glands, myocardium, and visualized portion of the liver

9  Imaging of the Parathyroid Carcinoma

c

139

d

T

e

T C Tr

E

Fig. 9.2 (continued)

140

f

Fig. 9.2 (continued)

A. L. Shifrin et al.

9  Imaging of the Parathyroid Carcinoma

a

141

c

LSG

RSG

b

d

Fig. 9.3 (a) 4D-CT study. 4D-CT scan showing mass corresponding to the right superior parathyroid tumor (carcinoma) (yellow arrow). Patient had preoperative measurements of calcium 10.9  mg/dL, with albumin 4.4 g/dL, and parathyroid hormone level (PTH) level of 167 pg/ mL. (b, c) Sestamibi SPECT/CT scan. Fusion image from SPECT/CT (b), and MIP image (c), showing uptake at the level of the right superior parathyroid gland consistent with parathyroid carcinoma (yellow arrow). There is an incidental findings of lobulated left submandibular

e

salivary gland (LSG). RSG–Right submandibular salivary gland; LSG– left submandibular salivary gland. (d, e) Pathology. Gross and microscopic images of the parathyroid carcinoma. (d) Gross view of the parathyroid carcinoma measuring 2.0 cm, weight 1.6 gm, with invasion into the recurrent laryngeal nerve (arrow). It was adherent to muscle and thyroid but no gross invasion identified. (e) Microscopic image of parathyroid carcinoma with lymphovascular invasion and soft tissue extension. Hematoxylin and eosin, ×100

142

Suggested Reading Al-Kurd A, Mekel M, Mazeh H. Parathyroid carcinoma. Surg Oncol. 2014;23:107–14. Asare EA, Sturgeon C, Winchester DJ, Liu L, Palis B, Perrier ND, et al. Parathyroid carcinoma: an update on treatment outcomes and prognostic factors from the National Cancer Data Base (NCDB). Ann Surg Oncol. 2015;22:3990–5. Mohebati A, Shaha A, Shah J.  Parathyroid carcinoma: challenges in diagnosis and treatment. Hematol Oncol Clin North Am. 2012;26:1221–38.

A. L. Shifrin et al. Shifrin A, LiVolsi V, Zheng M, Erler B, Matulewicz T, Davis J, et al. Primary and metastatic parathyroid malignancies: a rare or underdiagnosed condition? J Clin Endocrinol Metab. 2015;100:E478–81. Shifrin AL, LiVolsi VA, Zheng M, Lann DE, Fomin S, Naylor EC, et al. Neuroendocrine thymic carcinoma metastatic to the parathyroid gland that was reimplanted into the forearm in patient with multiple endocrine neoplasia type 1 syndrome: a challenging management dilemma. Endocr Pract. 2013;19:e163–7.

Part IV CT Scan of the Neck in Evaluation of Parathyroid Glands

Motivation for Imaging Studies

10

L. Daniel Neistadt

Single-Gland Disease

Multigland Disease

Minimally invasive parathyroidectomy guided by noninvasive localization studies has become the standard surgical approach to primary hyperparathyroidism. About 80% of the time, primary hyperparathyroidism is due to a solitary parathyroid adenoma, so accurate identification on screening studies will usually result in the desired limited surgery, verified by a drop of intraoperative parathormone level. The limited surgery may be converted to a four-gland exploration if the intraoperative parathormone does not drop. Four-gland exploration will be planned if multigland disease is diagnosed (or highly suspect) or if all studies are negative [1]. If a mediastinal adenoma is diagnosed and no enlarged parathyroid gland is identified in the neck, mediastinal surgery is performed before a neck exploration. Ultrasound, sestamibi scan, contrast CT scan, and MRI are the noninvasive modalities available to find the starting point in evaluating patients with clinically diagnosed primary hyperparathyroidism. A parathyroid search should only be made for surgical planning and should not be performed to diagnose hyperparathyroidism. Concordance of two modalities is usually desired, as some combinations yield incremental improvement in the success of localization. Failed parathyroidectomy requires the same studies to direct the operative approach, with the possible addition of more invasive radiologic procedures (angiography or selective venous sampling). In this setting, concordance of two studies is usually required.

Multigland disease, requiring a four-gland exploration, is usually due to hyperplasia, which is found in about 15% of patients with primary hyperparathyroidism. Two concurrent adenomas are found in about 5%. Of the group with hyperplasia, about 30% have inherited or familial disorders (familial hyperparathyroidism or MEN1 syndromes). The accuracy reported for all modalities in determining multigland disease is usually lower than for the identification of a single adenoma. The misses on the planned single-gland excisions will end up converted to a four-gland exploration. Of note, the resection of a single enlarged parathyroid gland may result in drop of intraoperative parathormone level to normal (taken to mean a single adenoma in most studies), but hyperparathyroidism may recur in only a couple of years, indicating that the disease is actually multigland, usually a primary hyperplasia. The abnormal glands are not always active at the same time.

Ectopic Glands Identification of an ectopic location of an enlarged parathyroid gland (occurring up to 20% of the time [2]) is the most helpful finding in planning the approach. Preoperative identification of a likely ectopic location is useful even when an initial four-gland exploration is planned. It may shorten the surgery time by directing the search to difficult regions to access in the neck and the upper portion of the superior mediastinum or by ending the search after three glands are identified, when the fourth gland is in a mediastinal location that is inaccessible from the neck approach. Autopsy series show the presence of a supernumerary gland (or very rarely, more than a fifth gland) in a location distant from the four identified glands in 3–5% of cases [3, 4].

L. D. Neistadt (*) Lenox Hill Radiology, Manhattan Diagnostic Radiology, New York, NY, USA © Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_10

145

146

Diagnostic Terminology The microscopic pathologic distinction of adenoma versus hyperplasia is not definitive. An adenoma is clearly present when a rim of fat-rich normal parathyroid tissue is displaced by the abnormal hypercellular parathyroid, but many adenomas may not have this identifiable remnant of normal tissue. The radiologic description is probably best labelled as an “enlarged gland” rather than an “adenoma.” Calling an enlarged gland an “adenoma” is an interpretative best guess and is verified only by surgical findings and long-term follow-­up. It is a convenience to use the simple, shorter description of “adenoma” in a report, but always with the understanding that this is a good best guess.

Sestamibi Scan Sestamibi scan, usually paired with sonography, has been the routine first-line screening in most regions. This is the approach in Part I and II of this book.

Mechanism of Radionuclide Uptake Technetium-labelled sestamibi sticks to mitochondria, which are plentiful in parathyroid oxyphil cells but not in the parathormone-­producing chief cells. Uptake is a function of perfusion of parathyroid tissue and the number and metabolic activity of oxyphil cells in the target tissue. The technique has poor sensitivity for hyperplasia, which is usually almost completely chief cells.

L. D. Neistadt

Increasing spatial resolution by use of pinhole camera imaging with the dual-isotope subtraction technique produces the best accuracy in some studies. In the dual-phase scan technique, a 2-hour to 3-hour delayed scan identifies parathyroid tissue by taking advantage of the usually slower washout of sestamibi from parathyroid tissue compared with normal thyroid tissue. A persistent hot spot on the washout of thyroid activity identifies the parathyroid tissue and is not limited by the low resolution of the technique. This technique does not work if the thyroid tissue washout is slow because of Hashimoto’s thyroiditis or sestamibi-avid thyroid nodules. In addition, 10–15% of parathyroid adenomas do not have delayed washout [5]. The slow washout does not occur with most hyperplastic glands. This dual-phase technique for dealing with thyroid tissue is more commonly used than the double-tracer technique because it is technically simpler and less time-­ consuming. Some protocols employ both techniques.

Ectopic Parathyroid Activity When the parathyroid target is ectopic and quite separate from the thyroid, the identification is much easier and may be performed on the early-phase study, when uptake in parathyroid tissue is maximal.

Value of the Sestamibi Study

The enlarged parathyroid gland or adenoma is identified as a hot spot on images. For an isolated hot spot in a low-activity background, the inherently low resolution of the nuclear medicine technique does not severely decrease sensitivity. The major problem in this hot-spot imaging is separating the parathyroid adenoma from nearby or adjacent thyroid tissue and thyroid nodules, which also take up the radionuclide. In the upper neck, the normal salivary gland uptake may obscure an undescended parathyroid adenoma.

Identification of parathyroid adenoma is up to 90% when the adenoma is larger than 500  mg, but about 50% or less for smaller adenomas. The radionuclide localization only points to a region; details of the anatomy are not available to the surgeon unless the study is performed with a SPECT/CT protocol with a sufficiently robust CT technique to provide a diagnostic CT image. Good-quality CT images are obtained with state-of-­ the-art 16-slice CT scanners linked with a state-of-the-art gamma camera. With high-quality SPECT/CT, a spatial separation of thyroid and parathyroid may be obtained even without iodinated contrast. Ultrasound is usually added to obtain good anatomic detail, although it usually will not provide anatomic reference points as clear as CT scan images.

Dealing with Thyroid Activity

Ultrasound

Thyroid tissue uptake may be subtracted from the image by administering thyroid gland–specific agents (I-123 or technetium pertechnetate), the double-tracer technique.

Ultrasound, a safe and economical routine study for all parathyroid screening approaches, is quite sensitive when guided by sestamibi scan or CT scan. In very expe-

Imaging

10  Motivation for Imaging Studies

rienced hands, ultrasound may find or corroborate enlarged parathyroid gland(s) 80% to 90% of the time, but most sonographers in radiology sonography departments or offices have insufficient experience (and feedback from the radiologist) to find the lesion; their accuracy is very low. Sonography performed by a parathyroid surgeon experienced with ultrasound is quite good and may match the level of the very best radiology sonographers [6].

CT Scan Contrast CT scan, particularly with the 4D technique, has developed over the past decade as a highly accurate modality. When performed by experienced radiologists, it has replaced sestamibi scan as the initial approach. The technique is fully detailed in an excellent “How to” paper by Hoang et al. [7]. Routine pairing of this technique with sonography is the approach to screening used in this section of the book.

147

References 1. Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY, et al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016;151:959–68. https://doi.org/10.1001/jamasurg.2016.2310. 2. Roy M, Mazeh H, Chen H, Sippel RS. Incidence and localization of ectopic parathyroid adenomas in previously unexplored patients. World J Surg. 2013;37:102–6. https://doi.org/10.1007/s00268-012-1773-z. 3. Wang C.  The anatomic basis of parathyroid surgery. Ann Surg. 1976;183:271–5. 4. Akerström G, Malmaeus J, Bergström R.  Surgical anatomy of human parathyroid glands. Surgery. 1984;95:14–21. 5. Greenspan BS, Dillehay G, Intenzo C, Lavely WC, O’Doherty M, Palestro CJ, et  al. SNM practice guideline for parathyroid scintigraphy 4.0. J Nucl Med Technol. 2012;40:111–8. https://doi. org/10.2967/jnmt.112.105122. 6. Untch BR, Adam MA, Scheri RP, Bennett KM, Dixit D, Webb C, et al. Surgeon-performed ultrasound is superior to 99Tc-sestamibi scanning to localize parathyroid adenomas in patients with primary hyperparathyroidism: results in 516 patients over 10 years. J Am Coll Surg. 2011;212:522–9.; discussion 529–31. https://doi. org/10.1016/j.jamcollsurg.2010.12.038. 7. Hoang JK, Sung WK, Bahl M, Phillips CD. How to perform parathyroid 4D CT: tips and traps for technique and interpretation. Radiology. 2014;270:15–24. https://doi.org/10.1148/radiol.13122661.

Contrast CT Approach

11

L. Daniel Neistadt

Basis for the CT Approach Derived from glands with rich capillary networks, hyperplastic parathyroid glands and parathyroid adenomas are hypervascular and have a vascular stain on arteriography, described by Dr. John Doppman in a 1969 report [1]. This hypervascularity is displayed as prominent, distinctive enhancement on CT scan. The rich microvasculature in the normal-sized gland also results in prominent enhancement on CT scan. Increased metabolic activity of hyperactive glands probably increases the vascularity as well but may not be as important as the underlying vascular anatomy in detecting increased enhancement on CT.  Chronic suppression of the gland by an adenoma may result in atrophy of the gland (described by Wang [2]) and the capillary bed, reducing enhancement. The hypervascularity of normal and enlarged glands may be detected on Color or Power Doppler ultrasound. The ovoid parathyroid gland is on a vascular pedicle that enters the gland at an end and may enlarge with the increased blood flow of an enlarged gland. The vascular pedicle entering a pole of the nodule, designated the “polar vessel sign,” is recognizable on CT and on Color Doppler (60–80% of the time in large glands) and aids in characterizing the nodule [3, 4].

 ccuracy of the CT-Based Screening A Approach Rodgers et al. [5] reported in 2006 on 75 patients undergoing four-dimensional (4D) CT scan and separate sestamibi and ultrasound studies, which were interpreted without the CT results. All but 10 of the CT scans were read without access to the ultrasound and sestamibi scans. With 4D CT, the contrast enhancement over time (the fourth dimension) is

L. D. Neistadt (*) Lenox Hill Radiology, Manhattan Diagnostic Radiology, New York, NY, USA

obtained with pre-contrast, arterial, and venous phases, identifying the abnormal parathyroid by rapid uptake and washout. The CT scan had improved sensitivity in lateralizing hyperfunctioning parathyroid glands (88%) over sestamibi imaging (65%) and ultrasound (57%). Sensitivity for localization to the quadrant of the neck was 70% for CT, 33% for sestamibi, and 29% for ultrasonography. The paper also introduced a classification scheme to locate the position of parathyroid glands (known as the Perrier classification scheme; see Chap. 17, section ““Perrier” Classification Scheme to Locate Parathyroid Glands”), which was felt to aid radiologists’ communication with surgeons and endocrinologists. Kutler et al. [6] reported in 2011 on their decade-long experience with 179 patients examined with contrast CT scan followed by directed correlative ultrasound, showing 94% sensitivity and 96% specificity in regard to lateralizing abnormal parathyroid glands to the correct side of the neck and 82% and 93% for lateralizing to a specific quadrant. Multiglandular disease was identified in 24 (69%) of the 35 patients who had multiglandular disease (20% of the total) [6]. Dr. Elias Kazam, the radiologist among these authors, developed a combined ultrasound and contrast CT approach in a setting where CT and ultrasound were performed in succession at the same site in an interactive approach [6]. CT directed the sonography to regions of concern, and sonography verified CT interpretation, particularly important when CT findings were borderline because of small size, obscuration by streak artefacts, or blurring due to motion. In this approach, the ultrasound is usually performed after the CT scan. If ultrasound has already been performed, the patient is re-examined with ultrasound after the CT scan, if the prospective ultrasound did not address all the questions raised by CT. Kelly et al. [7] reported in 2014 on 208 patients examined with three-phase and four-phase 4D CT scans, correctly identifying 82% of lesions. 4D-CT correctly identified

© Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_11

149

150

­unilateral vs. bilateral disease in 90% of patients and localized parathyroid lesions in 86% of unilateral cases. In one recent large study, the addition of high-quality sestamibi SPECT/CT to 4D CT failed to show incremental improvement of accuracy in a setting of routine initial screening. Yeh et  al. [8] retrospectively evaluated 400 patients with 4D CT and concurrent state-of-the-art sestamibi SPECT/CT for preoperative localizations (first surgery). 4D CT provided superior preoperative localization compared with sestamibi SPECT/CT in patients with single and multigland disease. The combination of the two modalities did not improve diagnostic performance compared with 4D CT alone. Numerous other studies with fewer cases and a variety of protocols have yielded similar findings for CT [9–12]. Several studies have shown 85% to 95% sensitivity for CT in patients with negative sestamibi scans [13–16].

Value of the CT Study CT provides high accuracy for both large and small adenomas and has the best sensitivity for detecting multigland disease. CT scans provide superior anatomic detail and precise localization of parathyroid glands relative to anatomic reference points that is superior to sestamibi and ultrasound alone. Thus it provides the best preoperative guide to the surgeon.

Non-contrast CT In patients with contrast allergy or renal compromise that prevents safe contrast administration, non-contrast CT is also useful for parathyroid identification when used as a supplement to ultrasound and sestamibi studies. Retropharyngeal and retroesophageal nodules are found in regions that are not usually the site of lymph nodes, so a nodule identified in these locations in the setting of hyperparathyroidism is usually an enlarged parathyroid gland. Careful attention to these regions on review of sestamibi scans and performance of ultrasound will improve the sensitivity of these modalities.

References 1. Doppman JL, Hammond WG, Melson GL, Evens RG, Ketcham AS.  Staining of parathyroid adenomas by selective arteriography. Radiology. 1969;92:527–30. 2. Wang C.  The anatomic basis of parathyroid surgery. Ann Surg. 1976;183:271–5.

L. D. Neistadt 3. Bahl M, Muzaffar M, Vij G, Sosa JA, Choudhury KR, Hoang JK. Prevalence of the polar vessel sign in parathyroid adenomas on the arterial phase of 4D CT. AJNR Am J Neuroradiol. 2014;35:578– 81. https://doi.org/10.3174/ajnr.A3715. 4. Lane MJ, Desser TS, Weigel RJ, Jeffrey RB Jr. Use of color and power Doppler sonography to identify feeding arteries associated with parathyroid adenomas. AJR Am J Roentgenol. 1998;171:819–23. 5. Rodgers SE, Hunter GJ, Hamberg LM, Schellingerhout D, Doherty DB, Ayers GD, et al. Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. Surgery. 2006;140:932–40. discussion 940–1 6. Kutler DI, Moquete R, Kazam E, Kuhel WI. Parathyroid localization with modified 4D-computed tomography and ultrasonography for patients with primary hyperparathyroidism. Laryngoscope. 2011;121:1219–24. https://doi.org/10.1002/lary.21783. 7. Kelly HR, Hamberg LM, Hunter GJ. 4D-CT for preoperative localization of abnormal parathyroid glands in patients with hyperparathyroidism: accuracy and ability to stratify patients by unilateral versus bilateral disease in surgery-naive and re-exploration patients. AJNR Am J Neuroradiol. 2014;35:176–81. https://doi.org/10.3174/ ajnr.A3615. 8. Yeh R, Tay YD, Tabacco G, Dercle L, Kuo JH, Bandeira L, et al. Diagnostic performance of 4D CT and sestamibi SPECT/CT in  localizing parathyroid adenomas in primary hyperparathyroidism. Radiology. 2019;291:469–76. https://doi.org/10.1148/ radiol.2019182122. 9. Chazen JL, Gupta A, Dunning A, Phillips CD. Diagnostic accuracy of 4D-CT for parathyroid adenomas and hyperplasia. AJNR Am J Neuroradiol. 2012;33:429–33. https://doi.org/10.3174/ajnr.A2805. 10. Bahl M, Sepahdari AR, Sosa JA, Hoang JK.  Parathyroid adenomas and hyperplasia on four-dimensional CT scans: three patterns of enhancement relative to the thyroid gland justify a three-phase protocol. Radiology. 2015;277:454–62. https://doi.org/10.1148/ radiol.2015142393. 11. Noureldine SI, Aygun N, Walden MJ, Hassoon A, Gujar SK, Tufano RP. Multiphase computed tomography for localization of parathyroid disease in patients with primary hyperparathyroidism: how many phases do we really need? Surgery. 2014;156:1300–6.; discussion 13006–7. https://doi.org/10.1016/j.surg.2014.08.002. 12. Ramirez AG, Shada AL, Martin AN, Raghavan P, Durst CR, Mukherjee S, et  al. Clinical efficacy of 2-phase versus 4-phase computed tomography for localization in primary hyperparathyroidism. Surgery. 2016;160:731–7. https://doi.org/10.1016/j. surg.2016.04.016. 13. Harari A, Zarnegar R, Lee J, Kazam E, Inabnet WB 3rd, Fahey TJ 3rd. Computed tomography can guide focused exploration in select patients with primary hyperparathyroidism and negative sestamibi scanning. Surgery. 2008;144:970–6.; discussion 976–9. https://doi. org/10.1016/j.surg.2008.08.029. 14. Twigt B, Vollebregt A, de Hooge P, Muller A, van Dalen T. Additional imaging following a negative sestamibi scan in primary hyperparathyroidism. Int J Otolaryngol Head Neck Surg. 2012;1:93–8. https://doi.org/10.4236/ijohns.2012.13019. 15. Lundstroem AK, Trolle W, Soerensen CH, Myschetzky PS.  Preoperative localization of hyperfunctioning parathyroid glands with 4D-CT. Eur Arch Otorhinolaryngol. 2016;273:1253–9. https://doi.org/10.1007/s00405-015-3509-9. 16. Zeina AR, Nakar H, Reindorp DN, Nachtigal A, Krausz MM, Itamar I, Shapira-Rootman M. Four-dimensional computed tomography (4DCT) for preoperative localization of parathyroid adenomas. Isr Med Assoc J. 2017;19:216–20.

12

The CT Technique L. Daniel Neistadt

General Description The four-dimensional (4D) CT protocol uses pre-contrast, arterial, and venous phases rendered in all three planes with high spatial resolution sections that are 1–2 mm thick. The fourth dimension is enhancement change over time. A parathyroid adenoma or enlarged parathyroid gland rapidly and prominently enhances in at least a portion of the lesion. This prominent enhancement is the key necessary feature for CT diagnosis. The good enhancement is followed by rapid washout in the venous phase.

I dentification of Normal-Size Parathyroid Glands This pattern also applies to many normal-size parathyroid glands that do not contribute to hyperparathyroidism. Identifying this pattern in minute structures allows the identification of many normal-size glands. When a structure in the bed of an upper parathyroid gland is identified in a typical location (which is not a typical node-bearing region), a lack of relative prominent enhancement may be due to abundant fat content, aberrant perfusion, or metabolic suppression.

Details of the Dynamic Process of Perfusion The details of this dynamic process were elucidated by Nael et al. [1] in a dynamic MRI study of 30 patients that employed a scan every 4 seconds following a rapid short bolus of gadolinium (essentially a delta function input), far exceeding the

time resolution achievable by CT scan. The time to peak contrast enhancement for parathyroid adenoma was 35 ± 13 seconds, compared with 49 ± 23 seconds for thyroid tissue and 64 ± 35 seconds for lymph nodes. The wash-in (slope of concentration–time activity curve) is significantly faster for parathyroid than thyroid tissue, and washout is also significantly faster. A compartmental analysis of parathyroid gland enhancement on CT utilizing these MR-derived parameters has not been published. On CT with a continuous infusion over 19–40  seconds, the peak enhancement would be expected to have a broader peak, and the time of the start of washout will be longer than the MRI curves. In many patients, the peak enhancement will not be reached, because it will be later than the 25- to 35-second sampling by CT. On a small study with three post-­ contrast phases (25, 50, and 80 seconds) following the infusion of 120 mL of contrast at 4 mL/s, washout of the enlarged parathyroid was complete at 80 seconds [2]. (With only one run in arterial phase, the wash-in rate of parathyroid vs. thyroid tissue could not be assessed.) On CT, nodes usually do not wash out and may have greater delayed enhancement, perhaps due to contrast in lymph draining into the node.

Performing the CT Scan Number of Detectors and Reconstructions The CT examination is usually performed with 16-detector or 64-detector CT scanners with 0.6  mm to 1.5  mm thick collimation (depending on the number of detectors).

L. D. Neistadt (*) Lenox Hill Radiology, Manhattan Diagnostic Radiology, New York, NY, USA © Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_12

151

152

64-detector machines are faster and provide a sharper arterial phase, but a slower 16-detector machine is adequate for the task. Axial, sagittal, and coronal sections 1 mm thick are generated from all the runs and can be used to perform angled reformations at the radiology imaging station.

Direction of the Scan The scan is usually performed in the caudal direction starting near the skull base and ending near the base of the heart. The scan may be performed in a rostral direction, chasing the rostral direction of the contrast bolus, to achieve great carotid opacification with little jugular vein enhancement in the lower neck. However, this technique also results in scanning the dense opacification of the subclavian vein, which is a source for streak artefacts, and the great opacification of the carotids does not equate with great parathyroid opacification, which occurs much later (based on MRI dynamics). The caudal direction of the scan is preferred, which allows time for subclavian vein washout. This technique also results in a slightly earlier arterial phase for the upper neck, where undescended parathyroid glands may be easily overlooked when there is great venous opacification.

L. D. Neistadt

Technical Tweaks The arterial phase should have sufficiently robust technique to obtain solid interpretable 1 mm thick sections. Tube heating limitations may limit x-ray tube output for the other runs, which will be relatively grainy. Shoulder artefacts may be reduced by elevating the upper back with a pad (shoulders falling back) and pulling the shoulders downward with straps. The scan should be performed with the patient lying flat on the scan table (not in a head holder), so that the position is close to the position for surgery and for ultrasound examination.

References 1. Nael K, Hur J, Bauer A, Khan R, Sepahdari A, Inampudi R, Guerrero M. Dynamic 4D MRI for characterization of parathyroid adenomas: multiparametric analysis. AJNR Am J Neuroradiol. 2015;36:2147– 52. https://doi.org/10.3174/ajnr.A4425. 2. Raghavan P, Durst CR, Ornan DA, Mukherjee S, Wintermark M, Patrie JT, et al. Dynamic CT for parathyroid disease: are multiple phases necessary? AJNR Am J Neuroradiol. 2014;35:1959–64. https://doi.org/10.3174/ajnr.A3978.

Individual CT Phases

13

L. Daniel Neistadt

Precontrast Phase Precontrast phase is essential to help distinguish thyroid tissue from parathyroid tissue by equating high density to iodine content. This is particularly important for distinguishing subcapsular parathyroid glands, but it is also critical in identifying ectopic rests of thyroid tissue. Tissue less than 60 Hounsfield Units (HU) in density is considered devoid of iodine content. The reconstruction kernel for the study should provide optimal distinction of tissue density, best obtained with a “soft tissue” algorithm or reconstruction kernel. If images are grainy, retrospective reformations with thicker sections may be quite helpful in defining low-density subcapsular structures. Streak artefacts may increase or decrease the apparent density of the nodule, and visual assessment of the nodule’s density by comparing it with thyroid or muscle at the same level of the streak artefact may be helpful.

Arterial Phase Timing of Arterial Phase Arterial phase is performed during contrast infusion that starts 20–45  seconds from the start of a rapid 3- or 4-mL/ second infusion of contrast followed by a saline flush. Most studies use a delay of 25–30 seconds. Timing by bolus tracking may also be used but is occasionally incorrect because of improper placement of the region of interest (technologist error) or because a streak artefact triggers early onset of the scan. There is a wide variation in protocols, but all seem adequate to demonstrate prominent parathyroid tissue enhancement for most patients. A relatively late arterial phase with considerable venous filling allows time to achieve peak parathyroid enhancement.

The carotid artery usually appears brighter than or as bright as the jugular vein in an adequate study. The carotid is a convenient marker of arterial phase flow, but the parathyroid arterial blood is derived from the inferior thyroid artery 80% of the time, or from the superior thyroid artery or vessels from the thyroid—a more circuitous route—and these small vessels vary in size. Occasionally the inferior thyroid artery is absent or so attenuated that it is difficult to identify. Variations in the small vessels may account for the wide standard deviation of transit time on the MRI dynamic study (see section “Details of the Dynamic Process of Perfusion”).

I dentifying the Parathyroid Gland on Arterial Phase A parathyroid adenoma or enlarged parathyroid gland is bright on arterial phase (usually greater than 120 HU density) and is easy to pick out as a bright spot when scrolling through the images. The degree of enhancement is usually a gestalt; numerous variable factors contribute to the precise region of interest measurement. A study of 30 patients by Marmin et  al. [1] rigorously determined the threshold for enhancement of adenoma as 114 HU density on an arterial phase started 45  seconds from the start of the injection. Scrolling through the arterial-phase axial sections is the first initial survey in reading the study. Any suspect nodule should be immediately correlated with the precontrast run to make sure it is not dense because of iodine content in thyroid tissue (possibly ectopic tissue). The sagittal arterial phase data set should then be scrolled through, looking for standout lesions just anterior to the spine, along the posterior and inferior surface of the thyroid, and below the thyroid, particularly along the strap muscles. The focus of attention is medial

L. D. Neistadt (*) Lenox Hill Radiology, Manhattan Diagnostic Radiology, New York, NY, USA © Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_13

153

154

to the carotid arteries, since parathyroid glands almost always lie medial to or towards medial aspect of the normal carotid arteries.

 treak Artefact Obscuring the Enhancing S Parathyroid Streak artefacts frequently alter the apparent enhancement of parathyroid glands in the lower neck; the gland may not be seen as an obvious bright spot, if it measures less than 120 HU density. The artefact may also increase the apparent density of a suspicious nodule. Streak artefacts commonly occur in large patients with broad shoulders and from high-density contrast of venous inflow, perhaps also refluxing into neck veins, particularly if the infusion is via the left arm and the left innominate vein is compressed by the sternum in patients with thin body habitus and/or marked kyphosis. Streak artefact producing high density in right or left subclavian or innominate veins may be due to pooling of the contrast at the tail end of the infusion, slightly slow infusion, decreased cardiac output, or unusual venous anatomy. A good saline flush (75–100 mL) following the contrast infusion reduces dependent pooling of the end of the infusion as a significant contributor to streak artefact. Use of a 75-mL bolus of contrast (rather than the more commonly used 100–120  mL), infused at 4  mL/second, finishes the infusion at 19 seconds, well before the onset of the arterial phase at 25  seconds; this usually avoids the high-density residual in the veins. With a 75-mL bolus, bright enhancement of carotids in the lower neck may diminish in patients with hyperdynamic cardiac state (from excitement) and the arterial phase does not “look” great, but this does not necessarily prevent good arterial-phase enhancement in the parathyroid glands, which should occur on average at 35  seconds from a delta-type input (MR dynamic information).

Venous Phase Timing of Venous Phase Venous phase usually starts 60–90 seconds after the start of the infusion, or 30  seconds after the arterial phase, in different protocols. Some protocols use both 60- and 90-second runs (three post-contrast phases), which has the advantage of catching peak enhancement if the arterial phase is early owing to increased transit time from dimin-

L. D. Neistadt

ished cardiac output in elderly patients. The added radiation dose of an additional run in elderly patients is of less concern than the risk that the study will be of poor quality or uninterpretable, requiring repetition that is often difficult to arrange.

Parathyroid Gland Behavior in Venous Phase The parathyroid gland or adenoma washes out in the venous phase. Enhancing nodes usually have no washout or increase in enhancement. Nodes rarely enhance to more than 120 HU density, but if they are over 100 HU density, they will look like a parathyroid adenoma that has not reached peak enhancement. These nodules will usually be recognized as nodes on the delay phase. Distinguishing hyperemic mildly to moderately enhancing nodes is the chief value of the venous phase. To save radiation exposure, some protocols drop the venous phase with little loss in overall accuracy, though these studies have usually evaluated only 50–60 patients.

Variations in Quality of the Venous Phase This delayed phase may end up being a late arterial phase if delay is 60 seconds and the contrast infusion is slow or cardiac output is decreased; high-density contrast may still fill the subclavian vein on the side of the infusion. In this situation, the parathyroid may not show significant washout on a 60-second run. If the arterial phase is early and peak enhancement is not obtained, this second run may even show greater enhancement of the enlarged parathyroid gland or adenoma. A late arterial phase usually will not occur at a 60-second delay if a 75-mL bolus is employed. An 80- to 90-second delay probably will never be a late arterial phase if 100– 120 mL of contrast is employed [2]. A late 90-second venous phase or delay is more reliable in distinguishing nodes from parathyroid glands than a 60-second run. This 90-second run is the run usually dropped in efforts to save radiation dose, which is not a problem if the study is a perfect study with peak enhancement obtained on the 25- to 30-­second run. Of course, perfect studies are not as frequent as we would like.

 alue of Venous Phase in Identifying V a Parathyroid Nodule If the adenoma abuts the thyroid or is within the thyroid and is isodense with the thyroid parenchyma in arterial

13  Individual CT Phases

phase, the washout of activity in venous phase may make the adenoma more conspicuous, if it ends up hypodense relative to thyroid parenchyma. This is important when streak artefact, grainy images, or Hashimoto’s thyroiditis obscures the presence of the nodule on the precontrast run. Venous phase also may be helpful in distinguishing normal-­size parathyroid glands from small vessels as washout occurs in the glands while veins have relatively greater enhancement.

155

References 1. Marmin C, Toledano M, Lemaire S, Boury S, Mordon S, Ernst O. Computed tomography of the parathyroids: the value of density measurements to distinguish between parathyroid adenomas of the lymph nodes and the thyroid parenchyma. Diagn Interv Imaging. 2012;93:597–603. https://doi.org/10.1016/j.diii.2012.05.008. 2. Raghavan P, Durst CR, Ornan DA, Mukherjee S, Wintermark M, Patrie JT, et al. Dynamic CT for parathyroid disease: are multiple phases necessary? AJNR Am J Neuroradiol. 2014;35:1959–64. https://doi.org/10.3174/ajnr.A3978.

Sources of False Positive and False Negative Enlarged Parathyroid Glands

14

L. Daniel Neistadt

 hyroid Tissue and Thyroid Nodules T as Source of False Positive Enhancing parathyroid tissue must be separated from similar enhancing lobulations or excrescences of normal thyroid tissue and thyroid nodules. Most false positives on contrast CT are due to thyroid nodules or lobulations of thyroid tissue. Iodine content makes lobular thyroid tissue and many thyroid nodules appear relatively high-density on the precontrast run. The precontrast run is essential to find low density candidates for intrathyroidal or subcapsular parathyroid glands and to identify dense ectopic and nodular exophytic thyroid tissue, which is fairly common. Artefacts and grainy images on the precontrast run may obscure the presence or absence of iodine content. Thicker reformations may help in improving the quality of the image. Correlative ultrasound shows parathyroid tissue as usually echo-poor and vascular, whereas typical thyroid tissue and colloid nodules are often hyperechoic. This ultrasound correlate will be especially helpful if the precontrast run has many artefacts. The ultrasound interpretation may be confounded by hemorrhage and fibrosis in parathyroid nodules, rendering the nodule echogenic or at least producing small echogenic components. On occasion, a parathyroid adenoma will be diffusely echogenic on ultrasound for no obvious reason, rendering the sonogram less helpful. In this situation, the vascularity or configuration of the nodule may identify the nodule as parathyroid tissue. The thyroid rate of enhancement is slightly slower than that of parathyroid tissue, but this difference is only helpful in a very early arterial phase.

L. D. Neistadt (*) Lenox Hill Radiology, Manhattan Diagnostic Radiology, New York, NY, USA

Ectopic Thyroid Tissue as False Positive Ectopic thyroid tissue is fairly common and has prominent enhancement, simulating parathyroid tissue on arterial phase, but it is dense prior to contrast. Small rests of ectopic thyroid tissue are frequent just below the thyroid and in the thyrothymic ligament and may occur along the course of the embryologic thyroid descent. On an intraoperative evaluation of 180 sides of the thyroid gland in 100 consecutive patients, Sackett et  al. [1] found thyroid rests in the thyrothymic area in 53 patients, or on 83 separate sides of the thyroid (46%). In patients who had rests identified, 30 (57%) had bilateral rests, with 16 (30%) only on the right, and 7 (13%) only on the left. Of the identified rests, 80% were attached to the thyroid proper by a pedicle of thyroid tissue, but 20% were entirely separate. Most rests were small, with 88% less than 1 cm in diameter. The precontrast run should cover the entire neck and superior mediastinum; it should not be limited only to coverage of the thyroid level.

 ashimoto’s Thyroiditis as Source of False H Positives and False Negatives Hashimoto’s thyroiditis is one form of chronic autoimmune thyroiditis. Imaging characteristics of Hashimoto’s parenchyma are similar to imaging characteristics of parathyroid tissue on CT and ultrasound. On CT, the parenchyma has nonuniform, substantially diminished stores of iodine, which may be completely absent in focal regions and diffusely absent in advanced cases. Enhancement is usually moderate to marked, with venous washout similar to parathyroid tissue behavior. On ultrasound, the Hashimoto’s parenchyma is heterogenous and echo-poor (similar to or approaching the echogenicity of strap muscle). Its vascularity is increased, identical to parathyroid tissue. The Hashimoto’s gland is frequently lobular or irregular, and the nodular tissue may mimic an enlarged parathyroid that is contiguous with the

© Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_14

157

158

thyroid or subcapsular. In some cases, this appearance is quite striking and results in a false positive reading. These nodular foci, which may be either enlarged parathyroid gland or nodular Hashimoto’s parenchyma, should be clearly described in the report, because they may direct the surgeon to the next-best candidate for resection if the parathormone level does not drop sufficiently after resection of a clear-cut enlarged parathyroid. Hashimoto’s thyroiditis also can totally obscure intracapsular and partially subcapsular parathyroid glands, resulting in a false negative, as illustrated by Fig. 20.23d in Chap. 20. Hashimoto’s thyroiditis also produces fibrosis and lymphocytic infiltration, atrophy, and eosinophilic changes in thyroid cells. When only lymphocytic infiltration is present, the histologic diagnosis is lymphocytic thyroiditis. Silent (or painless) thyroiditis and postpartum thyroiditis are other manifestations of autoimmune thyroiditis [2]. Graves’ disease, a related autoimmune thyroid disease, has the same ultrasound imaging characteristics as Hashimoto’s thyroiditis and also may use up iodine stores, so it has similar CT characteristics. Chronic autoimmune thyroiditis has two clinical forms: a goitrous form (Hashimoto’s disease) and an atrophic form (called atrophic thyroiditis). There is no clear evidence that the goitrous form evolves into the atrophic form [2]. Therefore, when atrophic thyroiditis is clearly present, there is no concern that a large, exophytic nodule of goitrous Hashimoto’s tissue is simulating a substantial parathyroid adenoma. In atrophic chronic thyroiditis, the tiny thyroid has mild or minimal enhancement in arterial phase and better enhancement in venous phase. If this scarring process is nonuniform, a focus of moderate arterial-phase enhancement within the small thyroid may stand out from the rest of the thyroid parenchyma and mimic a very small subcapsular parathyroid adenoma or a slightly enlarged parathyroid gland. At most, this may produce slight lobulation of the contour, and a substantial adjacent parathyroid adenoma will be readily distinguished. On ultrasound, the atrophic gland is usually echo-poor (similar to parathyroid echogenicity) but may have hyperechoic components from advanced fibrosis. Chronic autoimmune thyroiditis is common when all variants are considered. Autopsy has shown a prevalence of some degree of focal thyroiditis in 40–45% of women and 20% of men in the United States and United Kingdom. The prevalence of severe thyroiditis (5–15% in women and 1–5% in men) is much less [2]. Though mild thyroiditis is probably clinically irrelevant and may not be clinically diagnosable, it probably alters the

L. D. Neistadt

imaging characteristics of the thyroid. Diminished iodine stores of some degree are very common on CT, and this decreases the conspicuity of iodine-deficient subcapsular parathyroid glands. Heterogeneity or patchy decreased echogenicity of thyroid parenchyma on ultrasound is very common and also obscures subcapsular nodules. These imaging findings are usually considered nonspecific, but many of these cases of mild parenchymal abnormality may be due to chronic autoimmune thyroiditis. This speculation needs further study.

 alse Negative Due to Subcapsular Location F in Normal Thyroid Parenchyma Enlarged parathyroid glands in subcapsular locations are frequently missed and may not be identified even in retrospect. Poor-quality images on the precontrast study often fail to identify iodine-deficient nodules even when the parenchyma of the thyroid has normal iodine stores. Ultrasound may be successful in finding these enlarged glands if they have the common echo-poor character, but some glands are echogenic and hard to differentiate from the echogenic thyroid parenchyma.

 alse Positives or False Negatives F Due to Lymph Nodes In arterial phase, normal-size lymph nodes are usually minimally or mildly enhancing and are ignored on scrolling through the images. Active nodes may look relatively bright in arterial phase, mildly to moderately enhancing to over 100 HU density. They can simulate parathyroid glands, particularly if the arterial phase is early and peak parathyroid enhancement is not obtained. Though nodes typically have no washout or increase in enhancement in venous phase, some hyperemic nodes may wash out, resulting in a false positive study. Node vasculature enters the node hilum, and parathyroid glands have vessel entry at the poles. This “polar vessel sign,” described on ultrasound in 1998 [3] and CT in 2014 [4], may distinguish an active node from an enlarged parathyroid. In practice, however, this distinction may be difficult, as the nodule may be rotated in a way that makes it hard to distinguish the hilum from the end of the nodule. Directed ultrasound may help distinguish nodes by showing no vascularity or only vascularity in the echogenic hilum. Always bear in mind that eccentric echogenic foci are not always node hila. Small echogenic foci are frequent in the mostly echo-poor enlarged parathyroid.

14  Sources of False Positive and False Negative Enlarged Parathyroid Glands

Pathologic enhancing nodes from thyroid cancer (possibly occult) also may look like parathyroid tissue, a false positive. When multiple lymph nodes are present, such as reactive nodes in a Hashimoto’s thyroiditis, a small parathyroid adenoma or mildly enlarged parathyroid gland may be buried among the nodes, with its focal enhancement easily overlooked or difficult to separate from normal vessels between nodes. The result is a false negative. In this circumstance, ultrasound may help in distinguishing a parathyroid gland (with the polar vessel sign) from the nodes, but an extraordinary sonographer is required.

 ultinodular Goiter as Source of False M Negative Large multinodular goiters frequently obscure enlarged parathyroid glands, in part because of compression of the glands (false negative). Careful attention to subcapsular nodules on CT and sonogram, looking for ovoid and teardrop-­shaped nodules, may find the enlarged parathyroid gland. Finding a suspicious nodule on ultrasound will direct attention to this region on CT to determine whether the nodule is iodine-deficient, with enhancing characteristics of parathyroid tissue. Finding a suspicious nodule on CT will direct ultrasound evaluation to the nodule, perhaps finding a typical parathyroid nodule that is much smaller than the thyroid nodules and may have been ignored or overlooked among the multiple nodules. This reciprocal analysis requires interaction between the sonographer and radiologist.

159

 ctopic Parathyroid Glands as False E Negatives Mediastinal parathyroid glands may be overlooked because of obscuration by pulsation and motion artefacts of adjacent great vessels. A gated MR angiogram may find a subtle lesion in this situation (see Case 35  in Chap. 20). Slightly enlarged ectopic mediastinal lesions on the order of 1 cm or less in size are easily overlooked, mistaken for nodes or overlooked in surrounding thymic tissue that is not fat-­ replaced (see Case 42). Sestamibi scans with early-phase SPECT may show subtle lesions, particularly when correlated with small nodules on CT or MRI. Undescended markedly enhancing parathyroid glands are easily overlooked as enhancing veins. Careful attention to all planes is required when no enlarged parathyroid is identified in the mid and lower neck.

References 1. Sackett WR, Reeve TS, Barraclough B, Delbridge L. Thyrothymic thyroid rests: incidence and relationship to the thyroid gland. J Am Coll Surg. 2002;195:635–40. 2. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med. 1996;335:99–107. 3. Lane MJ, Desser TS, Weigel RJ, Jeffrey RB Jr. Use of color and power Doppler sonography to identify feeding arteries associated with parathyroid adenomas. AJR Am J Roentgenol. 1998;171:819–23. 4. Bahl M, Muzaffar M, Vij G, Sosa JA, Choudhury KR, Hoang JK. Prevalence of the polar vessel sign in parathyroid adenomas on the arterial phase of 4D CT. AJNR Am J Neuroradiol. 2014;35:578– 81. https://doi.org/10.3174/ajnr.A3715.

Correlative Ultrasound

15

L. Daniel Neistadt

A directed ultrasound should always follow the CT study [1, 2]. This is the approach used by Dr. Kazam and is the approach for all the cases in this section.

 ltrasound Characteristics of Parathyroid U Glands On ultrasound, enlarged parathyroid glands and parathyroid adenomas are usually predominantly echo-poor relative to the thyroid, and vascularity is usually demonstrated on color Doppler. The vascularity is typically at the upper pole and may continue in an arcuate distribution (vascular arc sign), with perforators extending into the nodule (occasionally identified). The vascularity may be minimal and only at the pole, or it may be diffuse. Tracing a vascular pedicle to the nodule is helpful but requires great technical expertise. For intracapsular nodules, a completely circumferential vascular rim is more typical of a thyroid nodule. The enlarged parathyroid typically has an elongated oval shape, frequently with a tapered end that gives a teardrop configuration. Borders of the nodule tend to flatten where the pliable enlarging parathyroid tissue is restricted by adjacent normal structures. The configuration and texture distinguish it from thyroid nodules when the enlarged parathyroid glands are subcapsular. Thyroid nodules, in contrast, tend to be rounded. Ultrasound will also help distinguish exophytic thyroid nodules from small parathyroid adenomas or enlarged parathyroid glands abutting the thyroid. Parathyroid glands in contact with the thyroid usually have a hyperechoic thin line at the interface. Absence of the line or an incomplete line may occur if the gland is intracapsular or partially intracapsular. As the parathyroid enlarges, it may indent the thyroid parenchyma, in part from the applied transducer pressure pushing the thyroid against the parathyroid.

L. D. Neistadt (*) Lenox Hill Radiology, Manhattan Diagnostic Radiology, New York, NY, USA

Small subcapsular parathyroid adenomas or enlarged parathyroid glands appear as subtle lobulations on CT. These are easily overlooked, but stand out as obvious lesions on ultrasound. Though the parathyroid adenoma is typically diffusely echo-poor (at least 50% of the time), echogenic components may be seen within the enlarged parathyroid or adenoma, particularly the larger nodules. These often reflect hemorrhage and fibrosis. Cystic components and occasional calcification also may be seen in larger adenomas. About 90% of the time, the dominant component of the nodule is hypoechoic relative to the thyroid. Two concentric layers of different echogenicity, a peripheral layer (usually echo-poor) surrounding a central zone (usually echogenic), has been described as the “dual concentric echo sign” and may occur in 20% of parathyroid adenomas (see Fig. 20.38b in Chap. 20). This sign frequently correlates with central edema and/or ectatic vessels [3]. Occasionally the enlarged parathyroid is diffusely hyperechoic. This appearance may be due to extensive fat content in the rare lipoadenoma or in the very rare water–clear cell adenoma (see Case 46  in Chap. 20). It may also occur for unknown reasons (see Case 5). Normal-size parathyroid glands are frequently echogenic because of their fat content, which increases with age and may account for up to 50% of the normal gland. The shape and textural character of the enlarged parathyroid has no significant correlation with parathormone level or calcium level. The chief value in recognizing internal echogenic patterns is to avoid identifying the nodule as a lymph node with fatty hilum and missing a parathyroid adenoma, a frequent mistake.

CT Guidance for the Ultrasound Search Ultrasound identification of a deep-lying, enlarged parathyroid gland is frequently aided by CT scan identification of a suspicious nodule. The sonographer may focus on this region

© Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_15

161

162

of concern, employing considerable applied pressure. Such pressure is usually tolerated by the patient when there is only one location, but it is not tolerated when applied in a survey fashion to all quadrants. Even a noncontrast CT scan is useful in directing the sonographer to nodules suspicious for enlarged parathyroid glands. When concerns about renal compromise or allergy prevent the use of contrast, a noncontrast CT prior to ultrasound is still valuable.

Ultrasound Technique The ultrasound study is centered on and around the thyroid but must use a field of view that extends posterior to encompass the longus colli muscle. Scanning should get as low as possible, to the suprasternal notch, and as high in the neck as possible, around the carotid, to look for undescended parathyroid glands. A high-frequency linear transducer (15–18 MHz) should be used at thyroid depth level, and a slightly lower-frequency transducer (such as 9 MHz) for the region deep to the thyroid. The neck should be maximally extended. The initial survey should be with color Doppler, looking for a hypervascular focus medial to the carotid. The search for retroesophageal/pharyngeal and retrotracheal parathyroid adenomas suspected on CT can be aided by medially directed applied pressure over the sternocleidomastoid muscles, with and/or without turning of the head away from the side of the examination. The adenoma will slowly emerge from complete obscuration during the application of pressure. This ultrasound verification of these deep glands is usually not critical, as the enhancing characteristics

L. D. Neistadt

and location (completely separate from thyroid and nodes) makes the CT diagnosis definitive, but if there are obscuring streak artefacts (from motion, shoulders, or cervical spine hardware) or if the CT must be performed without contrast, the sonographic depiction may be essential. The position of the parathyroid gland relative to the thyroid may appear lower on ultrasound than on CT because the maximally extended neck position for sonography elevates the thyroid, while the parathyroid remains relatively fixed. A swallowing maneuver that elevates the thyroid may show sliding of an abutting enlarged parathyroid along the thyroid, indicating complete separation of the nodule from the thyroid and confiming a parathyroid nodule. Movement of the nodule with the thyroid does not exclude an enlarged parathyroid gland, however, because the enlarged parathyroid may be partially intracapsular or tethered to the thyroid by adhesions (such as from Hashimoto’s thyroiditis) or location in the thyrothymic ligament.

References 1. Kutler DI, Moquete R, Kazam E, Kuhel WI. Parathyroid localization with modified 4D-computed tomography and ultrasonography for patients with primary hyperparathyroidism. Laryngoscope. 2011;121:1219–24. https://doi.org/10.1002/lary.21783. 2. Zeina AR, Nakar H, Reindorp DN, Nachtigal A, Krausz MM, Itamar I, Shapira-Rootman M.  Four-dimensional computed tomography (4DCT) for preoperative localization of parathyroid adenomas. Isr Med Assoc J. 2017;19:216–20. 3. Acar T, Ozbek SS, Ertan Y, Kavukcu G, Tuncyurek M, Icoz RG, et al. Variable sonographic spectrum of parathyroid adenoma with a novel ultrasound finding: dual concentric echo sign. Med Ultrason. 2015;17:139–46. https://doi.org/10.11152/mu.2013.2066.172.tka.

Shape, Number, and Size of Parathyroids

16

L. Daniel Neistadt

Shape of Parathyroid Glands Normal-size parathyroid glands have a variety of shapes: oval, teardrop, pancake, spherical, leaf, sausage, rod, bean [1, 2]. Some glands are bilobed. The glands vary in color from light yellow (cells with a high fat content) to reddish-brown (cells with dense parenchymal content). The parathyroid gland is soft and pliable. Slightly enlarged intrathyroidal parathyroid glands maintain the same configurations. As they enlarge, they mold to the adjacent structures and tend to have flattened surfaces and tapered ends. Slender, rod-like, enlarged upper parathyroid glands are usually slightly oblique to the longitudinal axis of the neck, and their length may be underestimated on routine sagittal and coronal views. Targeted oblique reformations will show their full length. The slender, long, rod-like glands may be markedly enhancing to the same degree as vessels (120–150 HU density). Suspect nodules must be traced to determine connection with enhancing vessels, particularly when there is good enhancement of the small nodule. Because the gland is supplied by a small vessel, the candidate nodule must be traced in the opposite direction to determine if it is a blind end rather than a focal ectasia of a vessel. A slender nodule with tubular, vessel-like appearance on routine views may look disc-like on customized oblique views (quite different from an ectatic vein). When a disc-like parathyroid is suspected on review of standard sections, directed reformations are oriented along the long axis of the structure and rotated on the orthogonal axis until it looks like a disc. On ultrasound, the slender, long parathyroid may have the same color Doppler signal as vessels (veins) and may be overlooked by the sonographer. Parathyroids that are similar

L. D. Neistadt (*) Lenox Hill Radiology, Manhattan Diagnostic Radiology, New York, NY, USA

to superficial veins may be distinguished by applying pressure that collapses adjacent veins.

Parathyroid Gland Number There are typically four parathyroid glands, but supernumerary glands occur about 10% of the time. Usually there is a fifth gland, but occasionally more numerous glands are found, particularly in individuals with MEN syndromes and with secondary or tertiary hyperplasia. In a detailed study of 503 autopsy cases, Akerström et al. [1] found more than four glands in 13% of cases. Three glands were identified in 3%, probably due to missing the fourth gland, as the total weight of the glands was less in these cases.

Size of the Parathyroid Gland Normal parathyroid glands measure between 2 and 7 mm in length, 2 and 4  mm in width, and 0.5–2  mm in thickness. Their weight is usually 30–40 mg. Any individual gland over 60 mg is considered enlarged and abnormal. In the approach we use, the volume of the gland is calculated by the formula for volume of a prolate ellipsoid (length × width × AP dimension × 0.52) and the weight is derived assuming a specific gravity of 1.0. With this approach, the upper normal weight for a parathyroid gland is taken as 50 mg [3]. This size estimate depends on enhancement of the parathyroid, but all portions of the enlarged gland may not enhance. Displacement of fat by an adenoma to the periphery of the gland will result in a small decrease in the observed dimension of the gland. Frequently the venous phase measurement is 1–2  mm larger than in the arterial phase as peripheral tissue achieves enhancement. For small adenomas or slightly enlarged glands, a 1- to 2-mm underestimate will yield a relatively large difference in calculated volume. In view of these uncertainties, borderline enlarged or upper-­

© Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_16

163

164

normal glands (45–50  mg) should be viewed with some suspicion. One would think the oblate ellipsoid formula is not a suitable geometric approximation for the volume of long rod-­ like and disc-shaped glands. In practice, volume calculation for small glands by the Simpson rule of adding area measurements of successive 1 mm–thick sections of the glands (possible in small glands with just a few sections) yields volumes that are remarkably close to the value obtained with the prolate ellipsoid estimate. Despite efforts to measure glands precisely, there is frequent discrepancy with pathology reports of gland weights. In some instances, this may be due to the assumption of prolate ellipsoid and not including specific gravity of the tissue in the calculation. The pathology report of linear measurements may be close to the measurements on images, whereas the measured weights are quite different from the calculated

L. D. Neistadt

weight. This difference requires further systematic study, at least for small and slightly enlarged glands, where accurate size is relevant to diagnosis of an abnormal versus normal gland. Perhaps an empiric formula using orthogonal linear measurements and precontrast density (that takes account of fat content) may give a good weight estimate for adenomas and hyperplastic glands.

References 1. Akerström G, Malmaeus J, Bergström R.  Surgical anatomy of human parathyroid glands. Surgery. 1984;95:14–21. 2. Wang C.  The anatomic basis of parathyroid surgery. Ann Surg. 1976;183:271–5. 3. Kutler DI, Moquete R, Kazam E, Kuhel WI. Parathyroid localization with modified 4D-computed tomography and ultrasonography for patients with primary hyperparathyroidism. Laryngoscope. 2011;121:1219–24. https://doi.org/10.1002/lary.21783.

Location of Parathyroid Glands

17

L. Daniel Neistadt

Superior or Upper Parathyroid Glands

Inferior or Lower Parathyroid Glands

The superior parathyroid glands (featured in Cases 1–13 in Chap. 20) are derived from the fourth branchial pouch and attach to the posterior border of the descending thyroid. The inferior tips of the pyriform sinuses are also derived from the fourth branchial pouch, and superior parathyroid glands may remain attached to the posterior wall of the pyriform sinuses, resulting in a retropharyngeal location. (See Cases 9–11.) The incidence of retropharyngeal glands is 1–2%. The superior glands usually attach to the posterior surface of the migrating thyroid and end up along the posterior surface or in a subcapsular location at the posterior medial surface of the mid and upper pole of the thyroid. They may detach and fall posterior, close to the longus colli muscle. They are usually on a vascular pedicle that is lateral and posterior to the recurrent laryngeal nerve. If they enlarge, they may descend lower along the longus colli muscle, to the level of the lower pole of the thyroid or still lower into the posterior mediastinum. In 80% of cases, superior glands are found in a circumscribed area 2 cm in diameter, located about 1 cm above the intersection between the recurrent laryngeal nerve and the inferior thyroid artery [1, 2]. (See Case 2.). The position of the superior glands on one side is roughly symmetrical with the other side 80% of the time [2]. On CT, a normal-size superior parathyroid gland is frequently identifiable posteromedial to the mid to upper pole of the thyroid, if it is not subcapsular. This is not a typical location for lymph nodes, so an enhancing nodule separate from vessels is probably a parathyroid. Normal-size parathyroid glands have good contrast enhancement, with the same CT dynamics as enlarged parathyroid glands. Their enhancement may be similar to that of vessels, making that distinction quite difficult, but usually the glands’ enhancement is less than that of vessels, making identification easier.

The inferior parathyroid glands (featured in Cases 14–20 in Chap. 20) are derived from the third pharyngeal pouch (dorsal wing), along with the thymus (ventral wing), and are more variable in position than the upper glands. They usually descend with the thymus and usually detach from the thymus, ending up along or adjacent to the inferior margin or inferolateral margin of the lower pole of the thyroid. The position of the inferior glands on one side are roughly symmetrical with the other side aound 80% of the time [2]. The inferior glands may descend lower, following the thymus, and lie in the thyrothymic ligament (usually within 1 cm below the thyroid) or in the thymus in the mediastinum. If a supernumerary gland is present, it is frequently found in the thymus. The thyrothymic ligament is not explicitly defined on CT and ultrasound and is only definable at surgery; it is found in the region between the lower poles of the thyroid and the thoracic inlet, just deep to the strap muscles. The vascular pedicle of the inferior glands lies medial and anterior to the recurrent laryngeal nerve (whereas the superior parathyroid glands are posterolateral to the nerve). As they enlarge, they may stay in situ or fall anteriorly along the side of the trachea. For glands adjacent to the tracheo-­ esophageal groove, the gland may be anterior or posterior to the nerve. The nerve is not imaged on CT or ultrasound and is only defined at surgery. Inferior parathyroid glands may fail to descend and remain high in the neck, in close relation to the carotid sheath. Unlike normal-size superior or upper parathyroid glands, the inferior or lower glands are very difficult to identify because they must be distinguished from small lymph nodes, are frequently subcapsular, may be buried in thymic tissue or may be ectopic.

L. D. Neistadt (*) Lenox Hill Radiology, Manhattan Diagnostic Radiology, New York, NY, USA © Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3_17

165

166

 alue of Describing the Location V of Normal-­Size Glands All identifiable small or normal-size glands should be described adequately in the report because they may actually be enlarged if they are not completely enhancing or if the size is underestimated from the standard sections. Also, successful identification of three very small glands (not frequently achieved) will tell the surgeon where to look for the fourth gland, which may be subcapsular and difficult to distinguish (one of the frequent misses on these studies). A relatively dominant gland may be a small adenoma and will indicate the first site to inspect for directed surgery. If the first target gland looks normal, or if its resection does not drop the intraoperative parathormone level (owing to multigland disease), the next best guess may be provided by the listing of the normal-size glands. A small gland in an unusual location (retropharyngeal or retroesophageal) is especially important to describe, because these glands will take considerable time and persistence in surgical dissection. Knowing where to go will considerably shorten the surgery time.

Ectopic Locations Roy et  al. [3] analyzed 1562 patients over a decade at the University of Wisconsin, and found ectopic adenomas (90% single, 10% double) in 22%. After excluding patients with four-gland hyperplasia or reoperations, they found 38% of the ectopic parathyroid adenomas in the thymus; 31% were retroesophageal, and 18% were intrathyroidal.

Intrathyroidal Parathyroid Glands Completely intrathyroidal parathyroid adenomas, which can be derived from upper or lower parathyroid glands, are rare. (See Cases 21, 22, and 28 in Chap. 20.) These are not from the common subcapsular parathyroid gland that is readily shelled out at surgery, or from a gland in a thyroid fissure that may extend between nodules of a multinodular thyroid. On 4D CT, the intrathyroidal parathyroid adenoma has characteristics typical of parathyroid tissue (an iodine-deficient, moderately enhancing lesion with venous phase washout), but this does not exclude an iodine-deficient thyroid nodule. The ultrasound appearance is more distinctive, usually showing an elongated ovoid nodule that is very echo-poor and vascular. The nodule may have an extended echogenic component from hemorrhage and/or fibrosis, but usually the periphery remains echo-poor and there is a thin, hyperechoic line at the interface with the thyroid parenchyma. From 1060

L. D. Neistadt

patients over a decade, Ye et al. [4] found this thin, hyperechoic line in 13 of 15 cases of intrathyroidal parathyroid adenoma.

Undescended Parathyroid Glands Undescended parathyroid adenomas follow the course of thymic descent and lie close to the carotid. They may be quite high, close to the level of submandibular salivary glands, and they frequently have associated thymic tissue. Examples are seen in Cases 29–32 in Chap. 20.

Mediastinal Parathyroid Glands Anterior mediastinal parathyroid glands derive from inferior glands that follow the course of the thymus descent. Much rarer ectopic glands in the aortopulmonary (AP) window, middle mediastinum, and posterior mediastinum ususally derive from superior parathyroid glands and have no adjacent thymic tissue [5]. Some of the rare AP window enlarged parathyroid glands may derive from inferior parathyroid glands, as thymic tissue can extend into the AP window [6]. Examples are found in Cases 33–36 and Case 42 in Chap. 20. Enlarged ectopic mediastinal parathyroid glands are frequently supernumerary parathyroid glands. On evaluating failed parathyroid surgery with three glands identified at surgery, precise detail of the surgical findings may help to direct the search for a possible ectopic undescended or mediastinal parathyroid. Failed four-gland exploration that finds four glands usually requires a search for a fifth gland in the mediastinum. Mediastinal parathyroid adenomas are usually successfully identified by concordance of sestamibi scans and CT scan. If nodule enhancement on non-gated CT is obscured by pulsation and motion artifact, MRI with gated MR angiography may show a hypervascular nodule separate from the great vessels. Benjamin Wei et al. [7] reported on 17 patients undergoing video-assisted thoracic surgery (VATS) or mediastinoscopy with preoperative studies of sestamibi scan, CT scan, or selective venous sampling. When two studies were concordant, they had 100% cure. No parathyroid tissue was obtained in two patients, who had only one positive study (selective venous sampling).

Unusual Ectopic Locations Rarely, a parathyroid adenoma may arise from congenitally ectopic parathyroid tissue in the vagus nerve [8]. Other case reports

17  Location of Parathyroid Glands

167

of unusual ectopic locations, extensively reviewed by Noussios et al. [9], have included the pyriform sinus and pericardium.

Communicating the Location Findings

A G

Precise localization of the enlarged parathyroid gland is a major B strength of CT scan and provides the best preoperative mapping, D with clear demonstration of reference points and relation to vessels. The position of the enlarged gland relative to these reference E points should be detailed in the report. (Sestamibi scans with F C high-quality SPECT/CT may provide similar localization accuracy.) Distances and relation of the gland to reference points include relation to the thyroid, trachea, esophagus, longus colli muscle, carotid artery, cricoid cartilage, suprasternal notch, clavicular head (if adjacent), inferior thyroid artery (where possible), and carotid bulb and hyoid bone (if high in the neck). The image presentation should include labelled pictures of the lesion in axial, sagittal, and coronal planes, preferably Fig. 17.1  Illustration depicting the one dimensional position of glands using the nomenclature system. (Reprinted from Perrier et al. [11]; with in a single panel that makes it easy for the surgeon to cross-­ permission) correlate images without searching through a series of them. Oblique reformations performed by the radiologist aid in relating the parathyroid nodule to the entire lobe of the thyroid, which usually has its longitudinal axis in a parasagittal plane. Some protocols provide oblique reformations as standard, but the optimal degree of obliquity is different for each G patient, and oblique views are best made by the radiologist. A Special reformations are also useful in depicting relationE F ships to major vessels or to the airway. D B

“ Perrier” Classification Scheme to Locate Parathyroid Glands The original paper on 4D CT scan by Rodgers et  al. [10] (senior author, Dr. Nancy Perrier) and a subsequent article by Perrier et al. [11, 12], from The University of Texas M. D. Anderson Cancer Center, introduced a classification scheme to locate the position of parathyroid glands with the aim of aiding radiologist communication with surgeons (Figs. 17.1 and 17.2). Referred to by others as the “Perrier” classification scheme, the nomenclature is based on quadrants and anterior-posterior depth relative to the course of the recurrent laryngeal nerve and to the thyroid parenchyma. The system uses the letters A to G to describe exact gland locations. A subsequent study of 271 patients [13] determined the frequency of the locations of adenomas, shown in parentheses: Type A parathyroid gland (13%) is a gland that originates from a superior pedicle, lateral to the recurrent laryngeal nerve in proximity to the posterior surface of thyroid parenchyma or compressed within the capsule of the thyroid.

C

Fig. 17.2  With medial rotation and traction of the thyroid parenchyma, the parathyroid glands can usually be found in classic quadrants. Type A glands are close to the thyroid parenchyma; B glands are in the tracheoesophageal groove along the thyroid tissue; C glands are in the tracheoesophageal groove inferior to the thyroid tissue; D glands are immediately adjacent to the recurrent laryngeal nerve; E and F glands are anterior and medial to the course of the nerve; and G glands are in the thyroid parenchyma. (Reprinted from Perrier et al. [11]; with permission)

Type B gland (17%) is a superior gland that has fallen posteriorly into the tracheoesophageal groove and is in the same cross-sectional plane as the superior portion of the thyroid parenchyma. There is minimal or no contact between the gland and the posterior surface of the thyroid tissue. An undescended gland higher in the neck, above the upper pole of the thyroid and near the carotid bifurcation or mandible, may also be classified as a type B gland and labelled B+. Type C gland (14%) is a superior gland that has fallen posteriorly into the tracheoesophageal groove and lies at the

168

level of or below the inferior pole of the thyroid. This places the type C gland posterior to (and in many cases inferior to) the recurrent laryngeal nerve. Glands in the carotid sheath are either type B or C glands, depending on their craniocaudal relationship to the thyroid. A minus sign may be added to glands that have fallen more inferiorly than usual. Type D gland (12%)—“difficult” or “dangerous”—lies in the mid-region of the posterior surface of the thyroid parenchyma, near the junction of the recurrent laryngeal nerve and the inferior thyroid artery or middle thyroidal vein. Because of this location, dissection is difficult. The type D gland may be either a superior or inferior gland, depending on its exact relationship to the nerve, which generally cannot be determined on imaging. Type E gland (26%)—easy to identify—is an inferior gland close to the inferior pole of the thyroid parenchyma, lying in the lateral plane with the thyroid parenchyma and the anterior half of the trachea. Type F gland (7%)—fallen—is an inferior gland that has descended into the thyrothymic ligament or superior thymus; it may appear to be “ectopic” or within the superior mediastinum. An anterior-posterior view shows the type F gland to be anterior to the trachea. Type G gland (0.4%) is a rare, truly intrathyroidal parathyroid gland.

 ocation of Parathyroid Relative L to Recurrent Laryngeal Nerve A major surgical concern is preserving the function of the recurrent laryngeal nerve. Detailing the parathyroid lesion location helps determine its proximity to the course of the nerve, which is a rough guess by CT, since the nerve is not directly visualized. The Perrier classification highlights these problematic lesions by classifying them as “D adenoma” and is probably the most useful aspect of this classification, shortening the communication in the summation impression. An aberrant right subclavian artery is associated with a nonrecurrent right laryngeal nerve, an important feature to communicate to the surgeon. A routine statement as to the presence or absence of an aberrant vessel is a nice addition to the report. Patients with a right-sided aortic arch with an aberrant left subclavian artery have a nonrecurrent left laryngeal nerve if there is no aortic (Kommerell’s) diverticulum or there is situs inversus. If there is a Kommerell’s diverticulum at the origin of the aberrant left subclavian artery, there is a recurrent laryngeal nerve [14].

L. D. Neistadt

References 1. Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY, et  al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016;151:959–68. https://doi.org/10.1001/ jamasurg.2016.2310. 2. Akerström G, Malmaeus J, Bergström R.  Surgical anatomy of human parathyroid glands. Surgery. 1984;95:14–21. 3. Roy M, Mazeh H, Chen H, Sippel RS.  Incidence and localization of ectopic parathyroid adenomas in previously unexplored patients. World J Surg. 2013;37:102–6. https://doi.org/10.1007/ s00268-012-1773-z. 4. Ye T, Huang X, Xia Y, Ma L, Wang L, Lai X, et al. Usefulness of preoperative ultrasonographic localization for diagnosis of a rare disease: intrathyroid parathyroid lesions. Medicine (Baltimore). 2018;97:e10999. https://doi.org/10.1097/MD.0000000000010999. 5. Arnault V, Beaulieu A, Lifante JC, Sitges Serra A, Sebag F, et  al. Multicenter study of 19 aortopulmonary window parathyroid tumors: the challenge of embryologic origin. World J Surg. 2010;34:2211–6. https://doi.org/10.1007/s00268-010-0622-1. 6. Doppman JL, Skarulis MC, Chen CC, Chang R, Pass HI, Fraker DL, et  al. Parathyroid adenomas in the aortopulmonary window. Radiology. 1996;201:456–62. 7. Wei B, Inabnet W, Lee JA, Sonett JR.  Optimizing the minimally invasive approach to mediastinal parathyroid adenomas. Ann Thorac Surg. 2011;92:1012–7. https://doi.org/10.1016/j. athoracsur.2011.04.091. 8. Doppman JL, Shawker TH, Fraker DL, Alexander HR, Skarulis MC, Lack EE, Spiegel AM. Parathyroid adenoma within the vagus nerve. AJR Am J Roentgenol. 1994;163:943–5. 9. Noussios G, Anagnostis P, Natsis K.  Ectopic parathyroid glands and their anatomical, clinical and surgical implications. Exp Clin Endocrinol Diabetes. 2012;120:604–10. https://doi.org/10.105 5/s-0032-1327628. 10. Rodgers SE, Hunter GJ, Hamberg LM, Schellingerhout D, Doherty DB, Ayers GD, et al. Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. Surgery. 2006;140:932–40. discussion 940–1 11. Perrier ND, Edeiken B, Nunez R, Gayed I, Jimenez C, Busaidy N, et  al. A novel nomenclature to classify parathyroid adenomas. World J Surg. 2009;33:412–6. https://doi.org/10.1007/ s00268-008-9894-0. 12. Grubbs EG, Edeiken BS, Gule MK, Monroe BJ, Kim E, Vu T, Perrier ND.  Preoperative parathyroid imaging for the endocrine surgeon. In: Khan AA, Clark OH, editors. Handbook of parathyroid diseases: a case-based practical guide. New York: Springer; 2012. p. 19–40. 13. Moreno MA, Callender GG, Woodburn K, Edeiken-Monroe BS, Grubbs EG, Evans DB, et  al. Common locations of parathyroid adenomas. Ann Surg Oncol. 2011;18:1047–51. https://doi. org/10.1245/s10434-010-1429-x. 14. Masuoka H, Miyauchi A, Higashiyama T, Yabuta T, Kihara M, Miya A. Right-sided aortic arch and aberrant left subclavian artery with or without a left nonrecurrent inferior laryngeal nerve. Head Neck. 2016;38(10):E2508–11. https://doi.org/10.1002/hed.24492.

Multigland Disease

18

L. Daniel Neistadt

Primary Hyperplasia Multigland disease, which is more frequently due to a primary hyperplasia than a double adenoma, requires planning a 4 gland exploration. In primary hyperplasia, overactive parathyroid glands are usually increased in size, but they may be normal-size and may not all be overactive at the same time. The range in size is quite large. After identifying a dominant, clearly enlarged gland, the search for small and normal-size glands follows. Identification of an additional slightly enlarged parathyroid gland based on a calculation from all dimensions usually indicates multigland disease. If the slightly enlarged gland is not fully defined by enhancement or is in a subcapsular location obscured by thyroid tissue, the multigland state will be missed. One or more normal-size parathyroid glands (sometimes all four of them) are usually identifiable on good-quality studies. If no enlarged gland or prominent gland is identified on good-quality CT and a top-quality follow-up ultrasound by an experienced sonographer, and if there is no obscuring thyroid disease, one may offer the diagnosis of “probable primary hyperplasia due to normal-size hyperactive glands.”

 coring System for Assessing the Likelihood S of Multigland Disease Many studies show sensitivity for multigland disease to be lower than the detection rate for single-gland disease. One of the more recent large studies distinguished multigland from single-gland disease 96% of the time [1], a unique result. Recognizing the frequent relatively small size of parathyroid glands in multigland disease and the tendency to overlook additional lesions after detecting the first lesion, Sepahdari et al. developed a scoring system to indicate the

L. D. Neistadt (*) Lenox Hill Radiology, Manhattan Diagnostic Radiology, New York, NY, USA

likelihood of multigland disease from retrospective data [2], a system that was validated on a prospective study of 71 patients by Sho et  al. [3]. A composite multigland disease score (ranging from 0 to 6) was calculated from 4D-CT imaging findings and the Wisconsin Index, the product of the serum calcium (mg/dL) and parathyroid hormone levels (pg/ mL). A 4D-CT multigland disease score (ranging from 0 to 4) was obtained by using the CT data alone: • Number of candidate lesions identified on CT followed by score: –– single lesion: 0 –– multiple lesion: 2 –– no lesions: 2 • Maximum diameter of largest lesion on CT followed by score: –– >13 mm: 0 –– 7–13 mm: 1 –– 1600: 0 –– 800–1,600: 1 –– 0.67 seconds having optimal diagnostic power in distinguishing PTA from thyroid, with sensitivity 91% and specificity 95%.

 RI for Evaluation of Hyperparathyroidism M in the Post-surgical Neck The increased risks of second surgery can be reduced with accurate preoperative localization [26]. MRI has a role for preoperative evaluation in those with prior neck surgery, par-

J. L. Becker et al.

ticularly in those with persistent or recurrent hyperparathyroidism, with results often superior to those undergoing primary surgery. Conventional MRI alone has 75% sensitivity for detection of PTA in the post-surgical neck [3]; MIBI combined with conventional MRI has sensitivity of 82% [4]. MRI with dynamic DCE perfusion and a temporal resolution of 6  seconds has sensitivity of 93%, detecting abnormal glands between 6 mm and 28 mm in diameter [13].

Conclusion/Summary Dynamic contrast-enhanced (DCE) MRI is an attractive alternative to 4D CT, with slightly superior detection of abnormal glands. Like 4D CT, 4D DCE exploits the hypervascular perfusion characteristics of abnormal parathyroid glands. It produces high-resolution anatomic imaging without the risks arising from radiation exposure and can identify very small and ectopic glands. 4D MRI should be considered as an alternative to 4D CT for first-line investigation of primary hyperparathyroidism, particularly in young patients requiring imaging for primary or repeat surgery, in whom the risks of radiation are highest.

References 1. Rodgers SE, Hunter GJ, Hamberg LM, Schellingerhout D, Doherty DB, Ayers GD, et al. Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. Surgery. 2006;140:932–40. discussion 940–1 2. Hunter GJ, Schellingerhout D, Vu TH, Perrier ND, Hamberg LM.  Accuracy of four-dimensional CT for the localization of abnormal parathyroid glands in patients with primary hyperparathyroidism. Radiology. 2012;264:789–95. 3. Kluijfhout WP, Venkatesh S, Beninato T, Vriens MR, Duh QY, Wilson DM, et al. Performance of magnetic resonance imaging in the evaluation of first-time and reoperative primary hyperparathyroidism. Surgery. 2016;160:747–54. 4. Gotway MB, Reddy GP, Webb WR, Morita ET, Clark OH, Higgins CB. Comparison between MR imaging and 99mTc MIBI scintigraphy in the evaluation of recurrent of persistent hyperparathyroidism. Radiology. 2001;218:783–90. 5. Nael K, Hur J, Bauer A, Khan R, Sepahdari A, Inampudi R, Guerrero M. Dynamic 4D MRI for characterization of parathyroid adenomas: multiparametric analysis. AJNR Am J Neuroradiol. 2015;36:2147–52. 6. Argirò R, Diacinti D, Sacconi B, Iannarelli A, Diacinti D, Cipriani C, et  al. Diagnostic accuracy of 3T magnetic resonance imaging in the preoperative localisation of parathyroid adenomas: comparison with ultrasound and 99mTc-sestamibi scans. Eur Radiol. 2018;28:4900–8. 7. Gotway MB, Higgins CB. MR imaging of the thyroid and parathyroid glands. Magn Reson Imaging Clin N Am. 2000;8:163–82. ix 8. Lopez Hanninen E, Vogl TJ, Steinmuller T, Ricke J, Neuhaus P, Felix R.  Preoperative contrast-enhanced MRI of the parathyroid glands in hyperparathyroidism. Investig Radiol. 2000; 35:426–30. 9. Merchavy S, Luckman J, Guindy M, Segev Y, Khafif A. 4D MRI for the localization of parathyroid adenoma: a novel method in evolution. Otolaryngol Head Neck Surg. 2016;154:446–8.

23  MRI for Imaging Parathyroid Disease 10. Lee VS, Spritzer CE, Coleman RE, Wilkinson RH Jr, Coogan AC, Leight GS Jr. The complementary roles of fast spin-echo MR imaging and double-phase 99m Tc-sestamibi scintigraphy for localization of hyperfunctioning parathyroid glands. AJR Am J Roentgenol. 1996;167:1555–62. 11. Ozturk M, Polat AV, Celenk C, Elmali M, Kir S, Polat C. The diagnostic value of 4D MRI at 3T for the localization of parathyroid adenomas. Eur J Radiol. 2019;112:207–13. 12. McDermott VG, Fernandez RJ, Meakem TJ 3rd, Stolpen AH, Spritzer CE, Gefter WB. Preoperative MR imaging in hyperparathyroidism: results and factors affecting parathyroid detection. AJR Am J Roentgenol. 1996;166:705–10. 13. Aschenbach R, Tuda S, Lamster E, Meyer A, Roediger H, Stier A, et al. Dynamic magnetic resonance angiography for localization of hyperfunctioning parathyroid glands in the reoperative neck. Eur J Radiol. 2012;81:3371–7. 14. Sacconi B, Argirò R, Diacinti D, Iannarelli A, Bezzi M, Cipriani C, et al. MR appearance of parathyroid adenomas at 3 T in patients with primary hyperparathyroidism: what radiologists need to know for pre-operative localization. Eur Radiol. 2016;26:664–73. 15. Yao K, Singer FR, Roth SI, Sassoon A, Ye C, Giuliano AE. Weight of normal parathyroid glands in patients with parathyroid adenomas. J Clin Endocrinol Metab. 2004;89:3208–13. 16. Kang YS, Rosen K, Clark OH, Higgins CB. Localization of abnormal parathyroid glands of the mediastinum with MR imaging. Radiology. 1993;189:137–41. 17. Stevens SK, Chang JM, Clark OH, Chang PJ, Higgins CB. Detection of abnormal parathyroid glands in postoperative patients with recurrent hyperparathyroidism: sensitivity of MR imaging. AJR Am J Roentgenol. 1993;160:607–12. 18. Higgins CB, Auffermann W.  MR imaging of thyroid and parathyroid glands: a review of current status. AJR Am J Roentgenol. 1988;151:1095–106.

279 19. Reeder SB, McKenzie CA, Pineda AR, Yu H, Shimakawa A, Brau AC, et al. Water-fat separation with IDEAL gradient-echo imaging. J Magn Reson Imaging. 2007;25:644–52. 20. Gaddikeri S, Mossa-Basha M, Andre JB, Hippe DS, Anzai Y. Optimal fat suppression in head and neck MRI: comparison of multipoint Dixon with 2 different fat-suppression techniques, spectral presaturation and inversion recovery, and STIR.  AJNR Am J Neuroradiol. 2018;39:362–8. 21. Grayev AM, Gentry LR, Hartman MJ, Chen H, Perlman SB, Reeder SB. Presurgical localization of parathyroid adenomas with magnetic resonance imaging at 3.0 T: an adjunct method to supplement traditional imaging. Ann Surg Oncol. 2012;19:981–9. 22. Ramirez AG, Shada AL, Martin AN, Raghavan P, Durst CR, Mukherjee S, et  al. Clinical efficacy of 2-phase versus 4-phase computed tomography for localization in primary hyperparathyroidism. Surgery. 2016;160:731–7. 23. Starker LF, Mahajan A, Bjorklund P, Sze G, Udelsman R, Carling T. 4D parathyroid CT as the initial localization study for patients with de novo primary hyperparathyroidism. Ann Surg Oncol. 2011;18:1723–8. 24. Lundstroem AK, Trolle W, Soerensen CH, Myschetzky PS.  Preoperative localization of hyperfunctioning parathyroid glands with 4D-CT. Eur Arch Otorhinolaryngol. 2016;273:1253–9. 25. Sho S, Yuen AD, Yeh MW, Livhits MJ, Sepahdari AR.  Factors associated with discordance between preoperative parathyroid 4-­ dimensional computed tomographic scans and intraoperative findings during parathyroidectomy. JAMA Surg. 2017;152:1141–7. 26. Udelsman R.  Approach to the patient with persistent or recurrent primary hyperparathyroidism. J Clin Endocrinol Metab. 2011;96:2950–8.

Index

A Asymmetric primary hyperplasia, 208–211 Atrophic chronic thyroiditis, 158 B “Brightness-mode” (B-mode) images, 4 C Chronic autoimmune thyroiditis, 158 Contrast CT scan accuracy of, 149, 150 hypervascularity, 149 value of, 150 Correlative ultrasound characteristics, 161 CT guidance, 161 high-frequency linear transducer, 162 swallowing maneuver, 162 verification, 162 CT technique arterial phase identification, 153 streak artefacts, 154 timing of, 153 detectors and reconstructions, 151 direction of, 152 dynamic process of perfusion, 151 normal-size parathyroid glands, 151 precontrast phase, 153 protocol, 151 technical tweaks, 152 venous phase, 154, 155 Cystic parathyroid adenoma, 244 left superior, 124 right superior, 130 with hemorrhage, 248, 249 Cystic parathyroid lesions, 171 D Diagnostic terminology, 146 Double parathyroid adenoma, 277 E Ectopic glands, 145 Ectopic parathyroids activity, 146 glands, 159

undescended enlarged parathyroid gland, 224–226 C2-C3 levels, 224, 225 undescended parathyroid adenoma, 221, 223 Ectopic thyroid tissue, 157 Enlarged parathyroid gland, 253 F 18 F-choline PET/CT, 13 False positive and false negative enlarged parathyroid glands ectopic parathyroid glands, 159 ectopic thyroid tissue, 157 Hashimoto’s thyroiditis, 157, 158 lymph nodes, 158, 159 multinodular goiters, 159 normal thyroid parenchyma, 158 thyroid tissue and thyroid nodules, 157 Familial hyperparathyroidism, 23, 24 Familial hypocalciuric hypercalcemia (FHH), 23 Familial isolated hyperparathyroidism (FIHP), 23 Frozen section analysis, 24, 25 G Graves’ disease, 158 H Hashimoto’s thyroiditis, 146, 157, 158, 241, 253 Hounsfield Units (HU), 153 Hyperparathyroidism pathology, 16, 17 scintigraphy, 11 ultrasound, 3 Hyperparathyroidism–jaw tumor (HPT-JT), 23 Hypocalcemic stimulation, 257 Hypoparathyroidism, 26, 27 I Immunohistochemistry (IHC), 22 Inferior parathyroid gland inferior adenoma, 195, 196, 198 early arterial phase, 201, 202 partially intrathymic, 202, 203, 205 thyrothymic ligament, 199–201 ultrasound, 197, 199 normal-size, 195 small inferior adenoma, 195, 197

© Springer Nature Switzerland AG 2020 A. L. Shifrin et al. (eds.), Atlas of Parathyroid Imaging and Pathology, https://doi.org/10.1007/978-3-030-40959-3

281

282 Intrathyroidal adenoma past central hemorrhage, 206–208 post fine-needle aspiration, 205, 206 Intrathyroidal parathyroid adenoma left inferior, 113 left superior, 102, 108 right inferior, 115, 119 right superior, 112 Intrathyroidal parathyroid adenomas, 166 Iodine-123 (I-123) subtraction, 12 K Kommerell’s diverticulum, 168 L Large multicystic-appearing parathyroid adenoma due to hemorrhage, 245, 246, 248 Left inferior parathyroid adenoma, 83, 85, 89, 91, 94 Left superior parathyroid adenomas, 71–75, 78 Lipoadenoma, 19, 171 Low-lying bilateral superior parathyroid adenomas, 184–186 M Magnetic resonance imaging (MRI) conventional MRI sequences, 273 dynamic image interpretation, 278 fat saturation/suppression, 276 field of view, 274 hyperparathyroidism, 278 post-processing techniques, 278 T1 and T2 MRI sequences, 274, 275 time resolved MRI, 276, 277 Mediastinal parathyroids, 257–260 in anterior mediastinum, 226, 227 in aortopulmonary window, 226, 228, 229 in hyperplasia in left lobe of thymus, 226, 227 in middle mediastinum, 229, 230 Mild thyroiditis, 158 Multigland disease, 145 primary hyperplasia, 169 scoring system, 169, 170 secondary hyperplasia, 170 tertiary hyperplasia, 170 Multinodular goiters, 159 Multiple endocrine neoplasia type 1 (MEN1), 23 Multiple endocrine neoplasia type 2A (MEN2A), 23 N Neonatal severe hyperparathyroidism (NSHPT), 23 Non-contrast CT, 150 Normocalcemic PHPT, 3 Normohormonal PHPT, 3 O Occult enlarged parathyroid gland, 260–266 Oxyphil cells, 12 P Para-esophageal enlarged parathyroid glands, 190 Parathyroid adenoma

Index atypical parathyroid adenoma, 19 clinical findings, 17 double, 277 gross findings, 17 large, characteristics, 274 microscopic findings, 18, 19 with mildly atypical features, 275 small mediastinal, 276 ultrasound, 6–8 Parathyroid carcinoma, 171 clinical findings, 20, 21 diagnosis, 133 4D-CT scan, 141 gross findings, 21 microscopic findings, 22 prognosis, 22 ultrasound, 134, 138 Parathyroid contrast ablation, 262–269 Parathyroid cysts, 25, 26 Parathyroid embryology, 11 Parathyroid glands communicating, 167 ectopic locations intrathyroidal parathyroid adenomas, 166 mediastinal parathyroid glands, 166 undescended parathyroid adenomas, 166 unusual, 166 inferior/lower, 165 number, 163 “Perrier” classification scheme, 167, 168 recurrent laryngeal nerve, 168 shape, 163 size, 163, 164 small or normal-size glands, 166 superior/upper, 165 Parathyroid hormone production hypocalcemic stimulation, 257 mediastinal parathyroid, 257–260 occult enlarged parathyroid gland, 260–266 Parathyroid hyperplasia, 241, 243 clinical findings, 20 definition, 19 gross findings, 20 microscopic findings, 20, 21 secondary hyperparathyroidism, 20 tertiary hyperparathyroidism, 20 Parathyroid lipoadenoma, 171 Parathyroid localization parathyroid contrast ablation, 262–269 parathyroid hormone production hypocalcemic stimulation, 257 mediastinal parathyroid, 257–260 occult enlarged parathyroid gland, 260–266 Parathyroid ultrasound, 146 clavicle/anterior mediastinum, 6 hyperparathyroidism, 3 longitudinal view, 6, 7 operative planning, 4, 5 parathyroid adenoma, 6–8 patient position, 5, 6 principles, 4, 5 transverse position, 6 Parathyroidectomy, 4, 5 Parathyromatosis, 26, 172 Pathology anatomy, 15, 16

Index familial hyperparathyroidism, 23, 24 histology, 15, 16 hyperparathyroidism, 16, 17 hypoparathyroidism, 26, 27 parathyroid adenoma atypical parathyroid adenoma, 19 clinical findings, 17 gross findings, 17, 18 microscopic findings, 18, 19 parathyroid carcinoma clinical findings, 20, 21 gross findings, 21 microscopic findings, 22 prognosis, 22 parathyroid cysts, 25, 26 parathyroid hyperplasia clinical findings, 20 definition, 19 gross findings, 20 microscopic findings, 20, 21 secondary hyperparathyroidism, 20 tertiary hyperparathyroidism, 20 parathyroid lesions, intraoperative assessment of, 24, 25 parathyromatosis, 26 secondary tumors, 24, 25 Postsurgical cases parathyroid adenoma in post-thyroidectomy bed, 236, 237 recurrent adenoma, 229–231 recurrent hyperparathyroidism, 230, 232, 235, 236 renal secondary hyperparathyroidism, 238–241 Primary hyperparathyroidism (PHPT), 3, 11, 16 Primary hyperplasia, 169 Primary parathyroid hyperplasias, 214, 215, 217 asymmetric primary hyperplasia, 208–211 with dominant enlarged gland on CT, 217, 218 enlarged parathyroid glands, 211, 212, 214 with intrathyroidal parathyroid, 220, 221 with normal-size parathyroid glands, 218–220 R Radionuclide localization, 146 Radionuclide uptake, 146 Renal secondary hyperparathyroidism, 238–241 Right inferior parathyroid adenomas, 47, 48, 52, 59, 63 Right superior parathyroid adenoma, 35, 36, 39, 41, 43 S Scintigraphic imaging comparison of, 13 embryology, 11 false-negative imaging, 13 false-positive imaging, 13 18 F-choline PET/CT, 13 hyperparathyroidism, 11 I-123 subtraction, 12 selenomethionine 75, 11 SPECT/SPECT-CT, 12, 13 technetium 99m–thallium-201 subtraction, 12 technetium-99m pertechnetate, 12 technetium-99m sestamibi, 12 Secondary hyperparathyroidism, 11, 17, 20

283 Secondary parathyroid hyperplasia, 170 Selenomethionine 75, 11 Sestamibi scan ectopic parathyroid activity, 146 hot-spot imaging, 146 radionuclide uptake, 146 thyroid activity, 146 value of, 146 Single-gland disease, 145 Sipple syndrome, 23 Small inferior adenoma, 195, 197 Small mediastinal parathyroid adenoma, 276 Streak artefacts, 154 Superior adenomas attached to the esophagus bilateral adenomas, 191 enlarged parathyroid, 191, 193 Superior glands double adenoma, 181, 182 enlarged superior parathyroid gland in slightly higher position in broad contact with left lobe, 177–179 subcapsular, 179, 180 with unusual echogenic character on ultrasound, 180, 181 high superior parathyroid adenoma, slightly ectopic location, 186, 187 high superior retropharyngeal parathyroid adenoma, 186, 188 low-lying bilateral superior parathyroid adenomas, 184–186 normal, 175, 176 retropharyngeal parathyroid adenoma with thick vascular pedicle, 189 type D parathyroid adenoma, 183, 184 typical superior parathyroid adenoma in usual position with typical enhancement pattern, 175, 177 T Technetium-99m (Tc-99m), 12 Technetium-99m pertechnetate, 12 Technetium-99m sestamibi, 12 Tertiary hyperparathyroidism, 20 Tertiary parathyroid hyperplasia, 170 Thallium-201, 12 Thyroid activity, 146 Thyroid follicular neoplasms, 18 Type D parathyroid adenoma, 183, 184 U Ultrasonography (US), 3 Undescended enlarged parathyroid adenoma, 224–226 C2-C3 levels, 224, 225 Undescended parathyroid adenomas, 166, 221, 223 V Venous phase, 154, 155 W Water–clear cell bilateral adenomas, 248, 250–252 Water–clear cell hyperplasia and adenoma, 172 Wermer syndrome, 23