Pediatric Head and Neck Textbook: Pathology, Surgery and Imaging 3030592634, 9783030592639

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Paolo Campisi · Vito Forte · Bo-Yee Ngan  Glenn Taylor   Editors

Pediatric Head and Neck Textbook Pathology, Surgery and Imaging

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Pediatric Head and Neck Textbook

Paolo Campisi  •  Vito Forte Bo-Yee Ngan • Glenn Taylor Editors

Pediatric Head and Neck Textbook Pathology, Surgery and Imaging

Editors Paolo Campisi Department of Otolaryngology – Head & Neck Surgery University of Toronto Toronto, ON Canada Bo-Yee Ngan Division of Pathology, Paediatric Laboratory Hospital for Sick Children Division of Pathology Toronto, ON Canada

Vito Forte Department of Otolaryngology – Head & Neck Surgery University of Toronto Toronto, ON Canada Glenn Taylor Division of Pathology, Department of Laboratory Medicine (retired) Hospital for Sick Children Toronto, ON Canada

ISBN 978-3-030-59263-9    ISBN 978-3-030-59265-3 (eBook) https://doi.org/10.1007/978-3-030-59265-3 © Springer Nature Switzerland AG 2021 This work is subject to copyright. 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

Foreword

In North America, pediatric otolaryngology evolved into a recognized subspecialty of otolaryngology during the 1970s—the first decade of my 36-year career at the Hospital for Sick Children in Toronto. Fellowship Programs, 1 or 2 years in duration, blossomed especially in the 1980s as training in this subspecialty area became increasingly more sought after by young fully qualified otolaryngology-head and neck surgeons. Over the years after retirement in 2007, a question frequently asked of me has been: “What aspect of your practice changed the most as the years went by?” This question was easy to address—the ability to image the presenting clinical problem. Traditional “X-ray departments” evolved into departments of diagnostic imaging with the advent of CT and MRI scans. The explosion of new imaging techniques was staggering. A close second were the advances and developments in the diagnostic tests available to most departments of pathology as they evolved from their traditional histologic descriptions to provide more information such as immunologic and genetic cell markers. The editors of this textbook—Vito Forte, Paolo Campisi, Bo-Yee Ngan, and Glenn Taylor— have corralled a group of international experts to author the various chapters that focus on pediatric head and neck diseases emphasizing those that require surgical management. Each chapter describes the clinical and imaging presentation of a specific head and neck problem, an age-specific differential diagnosis, and the diagnostic histopathologic features. In addition, the book is well illustrated. So, why is the advent of this textbook so exciting? Well, not only will it be relevant to those that work entirely in the pediatric field, it will be of much greater assistance to that larger group of head and neck surgeons around the world who manage mainly adults and the occasional child referred with a head and neck issue. Exciting! The arrival of this new textbook is applauded. William S. Crysdale, Professor Emeritus, University of Toronto Chief of Otolaryngology 1985–2000 Hospital for Sick Children Toronto, ON, Canada

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Foreword

This textbook is the culmination of collaborative efforts by a consortium of international experts in pediatric pathology. The editors of this book—Vito Forte, Paolo Campisi, Bo-Yee Ngan, and Glenn Taylor—have gathered together a group of international experts to author the various chapters that focus on pediatric head and neck diseases. In this multiauthor book, the expertise of outstanding experts on the pediatric pathology of the head and neck is reflected. The high-quality images were selected carefully to illustrate the criteria, problems, and pitfalls associated with this often problematic subdiscipline. The chapters are characterized by the desire to correlate pathology with all necessary information on clinical features, epidemiology, pathogenesis, and molecular genetics. Pathology in recent years is a rapidly evolving discipline with an enormous amount of new information that impacts on the daily practice of surgical pathology. Nowhere is this more evident than in the area of molecular biology and genetics. Data derived from this new discipline, once considered to be of research interest only, now continuously expand our diagnostic and prognostic capabilities. Although these new technologies are exciting, they only supplement and do not replace the “H&E slide,” which is, and will continue to be, the foundation of surgical pathology, the approach being reflected properly in this textbook. The past years have seen remarkable advances in many fields of pathology, including that of the head and neck. There is a need for a book that integrates surgical pathology with molecular genetics, epidemiology, clinical behavior, and biology. This book provides a comprehensive description of the manifold aspects of the morphology and pathology of the organs of the head and neck region in children. The authors have not attempted to be encyclopedic, but rather have aimed at providing concise, yet adequate knowledge. They are therefore to be warmly commended for providing us with an excellent book, which will prove useful to surgical pathologists involved in the pediatric pathology of the head and neck. Alena Skálová Department of Pathology Faculty of Medicine of Charles University Plzen, Czech Republic

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Preface

In 2003, members of the Departments of Otolaryngology-Head and Neck Surgery and Laboratory Medicine and Pathobiology at the Hospital for Sick Children combined their efforts to organize a series of teaching rounds to review interesting cases that were encountered on service. This initiative was immediately recognized as an important educational experience for resident trainees, clinical fellows, and faculty members. The goal of the individual case presentations was to correlate the clinical findings with diagnostic imaging and histopathology. This integration of perspectives substantially improved our understanding of the pathophysiology of disease and, in turn, the quality of patient care. By the end of the first year of this initiative, a considerable number of cases involving all areas of the head and neck had been reviewed. It became abundantly clear that this valuable educational resource should be shared more broadly with colleagues and trainees at other institutions. The decision to develop a textbook that combined the clinical, diagnostic imaging, and pathology findings of head and neck disease in children was therefore realized. Moving forward, cases were documented with great detail and stored in a database. Many of those cases were used to create this first textbook to focus on the presentation of head and neck pathology in children. The scope of the textbook includes a wide variety of head and neck pathologies but emphasizes diseases where a surgical intervention and the retrieval of biologic tissue were required. To underline the importance of both the clinical and pathological aspects of disease, the textbook has been organized in sections based on anatomic location or disease category. Each section typically includes two corresponding chapters that review the clinical presentation and management or the histopathology. The clinical chapters are not intended to provide a detailed review of the management of specific clinical conditions but rather to provide a generalized overview of the clinical presentation and management. The corresponding chapters were authored by either a surgeon or pathologist and their efforts were coordinated to ensure a clinicopathologic correlation of the cases. The authors of the clinical chapters also share a common experience of having completed their fellowship training at the Hospital for Sick Children— the origin of this textbook. We hope that this textbook will serve as an important resource for trainees and practicing clinicians in various specialties. The content is relevant to the fields of otolaryngology-head and neck surgery, pediatric surgery, diagnostic imaging, and pathobiology. The content should also be relevant to the surgeon or pathologist who primarily treats adults but may occasionally encounter the pediatric patient. Our aspiration is that all colleagues will benefit from this collaborative effort and collection of knowledge to provide the highest quality care to our young patients. The pathology sections of this textbook reflect the ongoing initiative with my surgical colleagues in pediatric head and neck surgery to enhance the practice and knowledge in both the surgical management and diagnosis by the appropriate imaging analyses followed by the appropriate applications of diagnostic procedures specifically for pediatric head and neck surgical diseases. We in the pathology discipline recognize that many pathological disease conditions in children are different than that of adults and require specific approaches to make the appropriate diagnoses. To this extent, it is our intentions to thoroughly describe these c­ onditions ix

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Preface

in tandem with the surgical disease management chapters. This textbook will provide an excellent educational resource to resident trainees, surgical pathology fellows, and faculty members. The pathology knowledge offered in these chapters also fulfills the potential pathology practice gaps related to practice realities faced by many of my pathology colleagues as the number of stand-alone health care centers solely dedicated to the treatment of childhood disease are much fewer as compared with adult medical centers and, as a result, many of my pathology colleagues who practice in adult disease centers have to provide diagnostic services to children. The pathology chapters in this textbook will play an essential role to bridge a potential knowledge gap. Many of the pathology chapters are contributed by our clinical and pathology colleagues with whom we shared many years of interactive educational events and disease diagnoses at Hospital for Sick Children in Toronto. As knowledge in diseases shares no geographic borders, we have also invited several of our national and international pediatric pathology colleagues who are leading experts in pediatric surgical head and neck disease to share this common educational goal to contribute their expert knowledge in selected pathology topics and together we are providing the most up to date and state-of-the-art knowledge in pediatric surgical disease for every pathologist who provides diagnostic care to pediatric surgical head and neck diseases. I also like to take this opportunity to thank our colleagues from many health science centers from other provinces of Canada and from several countries, notably Australia, Italy, Japan, and the UK for their pathology contributions. Toronto, ON, Canada   

Paolo Campisi Vito Forte Bo-Yee Ngan Glenn Taylor

Contents

Part I Pediatric Head and Neck Surgery and Pathology Practice: Introduction 1 Principles and Practice of Surgical Consultation for the Diagnosis of Pediatric Head and Neck Diseases�������������������������������������������������������   3 Paolo Campisi and Vito Forte 2 Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases�������������������������������������������������������   9 Sunitha Palasamudram and Manohar Shroff 3 Principles and Practice of Surgical Pathology for the Diagnosis of Pediatric Head and Neck Diseases�����������������������������������������������������������������������������  33 Bo-Yee Ngan Part II Pediatric Surgical Diseases of the Ear and Temporal Bone 4 Clinical and Surgical Management of Pediatric Diseases of the Ear and Temporal Bone���������������������������������������������������������������������������������������������  47 Adrian James 5 Pediatric Surgical Pathology of the Ear and Temporal Bone���������������������������������  83 Martin D. Hyrcza Part III Pediatric Surgical Diseases of the Nasal Cavity, Paranasal Sinuses, and Skull Base 6 Clinical and Surgical Management of Pediatric Diseases of the Nasal Cavity, Paranasal Sinus, and Skull Base ������������������������������������������������������� 101 Neil K. Chadha 7 Pediatric Surgical Pathology of the Nasal Cavity, Paranasal Sinuses, and Skull Base������������������������������������������������������������������������������������������������������������� 125 Bo-Yee Ngan, Catherine Chung, and Yukichi Tanaka Part IV Pediatric Surgical Diseases of Nasopharynx and Sella Turcica 8 Clinical and Surgical Management of Pediatric Diseases of the Nasopharynx and Sella Turcica��������������������������������������������������������������������������������� 151 Faisal Zawawi and Lily H. P. Nguyen 9 Pediatric Surgical Pathology of the Nasopharynx and Sella Turcica��������������������� 179 Marie-Anne Bründler and Alfredo Pinto

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Part V Pediatric Surgical Diseases of the Larynx and Trachea 10 Clinical and Surgical Management of Congenital and Iatrogenic Lesions of the Pediatric Larynx and Trachea����������������������������������������������������������� 203 Paolo Campisi, Vito Forte, and Glenn Taylor 11 Pediatric Surgical Pathology of the Larynx and Trachea��������������������������������������� 219 Glenn Taylor, Bo-Yee Ngan, Vito Forte, and Paolo Campisi Part VI Pediatric Surgical Diseases of the Oral Cavity, Maxilla, and Mandible 12 Clinical and Surgical Management of Pediatric Diseases of the Oral Cavity, Maxilla, and Mandible������������������������������������������������������������������������� 245 Raanan Cohen-Kerem 13 Pediatric Surgical Pathology of the Oral Cavity, Maxilla, and Mandible������������� 283 Jane E. Dahlstrom and Hedley Coleman Part VII Pediatric Surgical Diseases Arising from Branchial and Congenital Anomalies 14 Clinical and Surgical Management of Pediatric Branchial and Congenital Anomalies of the Head and Neck������������������������������������������������������������������������������� 325 Timothy J. Martin and Stephen F. Conley 15 Pediatric Surgical Pathology of Branchial and Congenital Anomalies of the Head and Neck������������������������������������������������������������������������������������������������� 367 Marta C. Cohen and Irene Scheimberg Part VIII Pediatric Surgical Diseases of the Salivary Glands 16 Clinical and Surgical Management of Pediatric Diseases of the Salivary Glands����������������������������������������������������������������������������������������������������������� 381 Keith Trimble 17 Pediatric Surgical Pathology of the Salivary Gland ����������������������������������������������� 403 Rose Chami Part IX Pediatric Surgical Diseases of the Thyroid, Parathyroid, and Thymus 18 Clinical and Surgical Management of Pediatric Diseases of the Thyroid, Parathyroid, and Thymus������������������������������������������������������������������������������������������� 423 Jonathan D. Wasserman and Vito Forte 19 Pediatric Surgical Pathology of the Thyroid and Parathyroid������������������������������� 447 Gino R. Somers Part X Pediatric Surgical Diseases of the Paraganglionic System 20 Clinical and Surgical Management of Pediatric Diseases of the Nervous and Paraganglionic System������������������������������������������������������������������������� 473 William J. Parkes 21 Pediatric Surgical Pathology of Head and Neck Tumors of the Peripheral Nerve and Paraganglionic System��������������������������������������������������������� 489 Viktor Sikhar, Cynthia E. Hawkins, and Lili-Naz Hazrati

Contents

Contents

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Part XI Pediatric Surgical Diseases of the Vascular and Lymphoid Systems 22 Clinical and Surgical Management of Pediatric Diseases of the Vascular System ��������������������������������������������������������������������������������������������������������� 501 Faisal Zawawi and Sam J. Daniel 23 Pediatric Surgical Pathology of Head and Neck Vascular Lesions������������������������� 517 Glenn Taylor 24 Clinical and Surgical Management of Pediatric Diseases of the Lymphoid System������������������������������������������������������������������������������������������������������� 537 Morgan Bliss and Anna H. Messner 25 Pediatric Lymphoma and Abnormalities Affecting the Pediatric Thymus: Pathology��������������������������������������������������������������������������������������������������������������������� 565 Bo-Yee Ngan and Yukichi Tanaka Part XII Pediatric Fibroinflammatory Tumors of the Head and Neck 26 Clinical and Surgical Management of Pediatric Fibroinflammatory Diseases and Tumors of the Head and Neck������������������������������������������������������������� 635 Alok Sharma 27 Pediatric Surgical Pathology of Fibro-­Inflammatory Diseases and Tumors��������� 651 Rita Alaggio and Gaetano Magro Part XIII Pediatric Surgical Diseases of the Skin of the Head and Neck 28 Clinical Pediatric Dermatology of the Head and Neck������������������������������������������� 669 Alexandra Pennal and Elena Pope 29 Pediatric Surgical Pathology of Head and Neck Skin Lesions������������������������������� 685 Glenn Taylor Part XIV Pediatric Disease of the Nasal and Tracheal Cilia 30 Clinical Concepts and Surgical Pathology of Pediatric Disorders of the Cilia in the Sinonasal and Respiratory Tract����������������������������������������������������������� 717 Sharon D. Dell and Ernest Cutz Part XV Pediatric Soft Tissue Neoplasms of the Head and Neck 31 Pediatric Surgical Pathology of Sarcomas of the Head and Neck ������������������������� 743 Rita Alaggio and Gaetano Magro

Part I Pediatric Head and Neck Surgery and Pathology Practice: Introduction

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Principles and Practice of Surgical Consultation for the Diagnosis of Pediatric Head and Neck Diseases Paolo Campisi and Vito Forte

History of Presentation The most important component of a surgical consultation is a thorough and systematic history. The history should begin with questions about the pregnancy, the birth, developmental milestones, and the general medical background. Details about the course of the pregnancy, the nature of the delivery (spontaneous vaginal, caesarean, use of forceps or suction), gestational age at birth, and birth weight are very important to understand the context of the presenting clinical problem. The medical history of the family (parents, siblings, and extended family) is also important if the clinician suspects a syndromic or inherited cause of the anomaly. Finally, the details of the onset, duration, changes in size, and associated symptoms must be obtained with questions relevant to the clinical presentation.

Timing of Presentation Head and neck lesions may be first detected in the antenatal period by ultrasound during normal obstetrical care. Anomalies detected in utero may be very distressing for parents. As such a gentle and empathetic approach must be used when discussing findings with the parents. Lesions that are commonly detected antenatally include lymphatic malformations and cystic teratomas involving the anterior neck and face. Craniofacial and airway anomalies may also result in congenital high airway obstructive syndrome (or CHAOS). In these instances, the lesion or anomaly may result in significant airway obstruction soon after birth. As a result, a planned delivery by EXIT procedure may be required with

P. Campisi (*) · V. Forte Department of Otolaryngology – Head & Neck Surgery, University of Toronto, Toronto, ON, Canada e-mail: [email protected]; [email protected]

experienced maternal fetal medicine and pediatric otolaryngology specialists. Anomalies that are evident at the time of birth are called congenital and they have an embryologic origin. The most common anomalies are the branchial anomalies, which can present as a cyst, sinus, fistula, or a combination of the aforementioned. Other common embryological remnants include the thyroglossal duct cyst and dermoid cysts. These congenital lesions have a typical pattern of physical presentation that is highly indicative of the diagnosis. The location of these common congenital anomalies of the head and neck is illustrated in Fig. 1.1. Lesions that become evident later in life may also follow typical patterns of timing of presentation. For example, infantile hemangiomas are not evident at birth but manifest during the second to third months of life as this corresponds to a period of rapid proliferation. If the hemangioma is in the parotid gland, the patient may present with an enlarging facial mass. A subglottic hemangioma, on the other hand, will cause recurrent croup-like symptoms and stridor as early as 2 months of age. Another example is the juvenile angiofibroma that is typically diagnosed in an adolescent male presenting with nasal obstruction and epistaxis. Finally, pediatric head and neck malignancies also follow typical patterns of timing of presentation. The timing of common benign and malignant neoplasms is summarized in Table 1.1.

Rate of Growth The rate of growth of the lesion may indicate the nature of the pathology illustrated in Table  1.2. In general, benign lesions grow slowly or at a rate commensurate with the growth of the child. In contrast, rapidly growing lesions may be indicative of a malignancy. There are also lesions that may fluctuate in size as a result of infection, inflammation, or hemorrhage. This is commonly seen with venolymphatic malformations. It should be noted that these general comments about the rate of growth do not necessarily apply to all

© Springer Nature Switzerland AG 2021 P. Campisi et al. (eds.), Pediatric Head and Neck Textbook, https://doi.org/10.1007/978-3-030-59265-3_1

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P. Campisi and V. Forte

Fig. 1.1  Location of congenital anomalies of the head and neck. [a. preauricular sinus and cyst (above the external auditory meatus); b. first branchial anomalies (below the external auditory meatus to upper neck); c. Table 1.1  Common benign and malignant lesions of the head and neck according to the timing of presentation during childhood Timing of presentation Antenatal

Congenital

Infantile

Pre-­ Adolescent

Adolescent

Benign lesions Lymphatic and vascular malformations Teratoma Branchial anomalies Lymphatic and vascular malformations Lipoma Teratoma Dermoid cyst Pre-auricular anomalies Epulis Thyroglossal duct cyst Torticollis (sternocleidomastoid muscle tumor of infancy) Hemangioma Lymphatic and vascular malformations Torticollis (sternocleidomastoid muscle tumor of infancy) Lipoma Lymphadenopathy Thyroglossal duct cyst Branchial cysts Calcifying epithelioma Neurofibromatosis Aggressive fibromatosis Giant cell reparative granuloma Aneurysmal bone cyst (ABC or venous malformation of bone) Thyroglossal duct cyst Branchial cysts Thyroid lesions Juvenile angiofibroma

Malignant lesions Malignant teratoma

Malignant teratoma

second branchial anomalies; d. nasal dermoid cyst; e. thyroglossal duct cyst and midline fusion defects; f. dermoid cyst or sinus; g. third/fourth branchial anomalies; h. dermoid, thymic cyst; i. lymphatic malformation]

Table 1.2  Common benign and malignant lesions of the head and neck that present with a slow, rapid or fluctuating rate of growth Rate of growth Slow growing

Rapidly growing

Neuroblastoma Rhabdomyosarcoma Fluctuating

Rhabdomyosarcoma Ewing sarcoma Osteogenic sarcoma

Benign Dermoid cyst PTGC (progressive transformation of germinal centers) Neurofibroma Lipoma Fibrous dysplasia Lymphatic malformation (infection, trauma, or hemorrhage) Melanotic tumor of infancy Aggressive fibromatosis Infectious mononucleosis Aneurysmal bone cysts Giant cell reparative granuloma Venolymphatic malformations Branchial cysts Thyroglossal duct cyst

Malignant MFH (malignant fibrous histiocytoma) Posttransplant lymphoproliferative disease (PTLD) Squamous cell carcinoma Neuroblastoma Rhabdomyosarcoma Lymphoma (B cell) Ewing sarcoma Osteogenic sarcoma

Posttransplant lymphoproliferative disease (PTLD)

head and neck masses. There are several examples of ­malignancies that are slow growing and in these cases a biopsy may be the only method to confirm the diagnosis.

Associated Symptoms Lymphoproliferative Disorders Thyroid malignancies Ewing sarcoma Osteogenic sarcoma

Depending on the location of the presenting lesion, a focused history should be elicited of associated symptoms. For example, a patient presenting with a lesion in the outer or

1  Principles and Practice of Surgical Consultation for the Diagnosis of Pediatric Head and Neck Diseases Table 1.3  Symptoms associated with localized head and neck lesions Head and neck location Ear Nasal cavity and nasopharynx Oral cavity and oropharynx Thyroid Larynx, trachea, and lower airways

Associated symptoms Otalgia, otorrhea, tinnitus, hearing loss, vertigo Obstruction, rhinorrhea, epistaxis, anosmia, vision change, hearing loss, headache Dysphagia, odynophagia, dysgeusia, speech abnormality, dental symptoms Hyper/hypothyroid symptoms, voice changes, compressive symptoms, dysphagia Stridor, dyspnea, dysphonia, cough, dysphagia, hemoptysis

middle ear should be asked about the presence of otalgia, otorrhea, tinnitus, hearing loss, and vertigo. A similar approach of eliciting a focused history applies to other areas of the head and neck as summarized in Table 1.3. As a general rule, head and neck lesions that present with a history of pain or tenderness are most likely to be caused by an inflammatory condition or have an infectious cause. This is most commonly encountered by clinicians assessing children with acute enlargement of neck masses or lymphadenopathy temporally related to an upper respiratory tract infection. However, nontender, enlarged lymph nodes are commonly encountered in preadolescent children, which raise concern about the possibility of a diagnosis of a lymphoproliferative disorder such as lymphoma. In contrast, pain, pressure, and tenderness can also be caused by malignant lesions as a result of local tissue destruction, dislocation of joints (e.g., tempormandibular joint), and involvement of sensory nerves.

Physical Examination Inspection and Palpation A thorough and systematic physical examination is another important component of the surgical consultation. The physical examination should begin with a general inspection of the head and neck. One of the general principles of inspection is symmetry. The position of the ears, eyes, facial muscles, and cervical structures at rest and with movement should be symmetrical. Asymmetry implies the presence of a congenital or acquired pathology. The location of congenital lesions, for example, generally follow very specific patterns as shown in Fig. 1.1. In addition to the location, the color, size, consistency, and tenderness of the anomaly should be assessed. Erythema and tenderness are usually associated with an inflammatory or infectious process. A firm, fixed lesion, nontender mass may raise concern for a malignancy. Palpation is also helpful to detect warmth, which may be a sign of infection or a vascular lesion

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with increased blood flow. Palpation of all lymph node groups and visceral organs in the head and neck must be performed. Particular attention should also be placed on the thyroid gland to detect any masses within the gland. Finally, palpation of the oral cavity and oropharynx may be required to detect lesions in the floor of mouth or base of tongue. Inspection of the head and neck also involves special maneuvers such as otoscopy, rhinoscopy, and flexible nasopharyngo-­ laryngoscopy. Otoscopy is used to detect lesions involving the ear canal, tympanic membrane, and middle ear. Other otologic assessments include tuning fork tests (to assess hearing), DixHallpike maneuvre, head-shake, gait, and cerebellar testing (to assess the vestibular system). Anterior rhinoscopy can be performed with a nasal speculum or a rigid or flexible endoscope. The nasopharynx, hypopharynx and larynx are routinely assessed at the same time with flexible nasopharyngo-laryngoscopy. Flexible endoscopy has become the workhorse of the internal head and neck physical examination. It is important to note that there are specific pathologies that typically manifest as left-sided lesions such as subglottic hemangiomas and pyriform sinus branchial anomalies. The presence of a cutaneous hemangioma, especially in the beard distribution, and atypical croup-like symptoms should raise the suspicion of a subglottic hemangioma. The sudden appearance of a painful mass over the thyroid gland with features of infection and abscess may be the first sign of a third or fourth branchial anomaly.

Percussion Percussion is rarely used in the head and neck region. One example is tapping over the zygoma to detect muscle twitches. This is called Chvostek’s sign and it indicates the presence of hypocalcemia. This is typically employed following thyroid or parathyroid surgery.

Auscultation Auscultation over the neck and chest should always be undertaken in all patients presenting with airway symptoms. The most common purpose of auscultation in these instances is to detect and characterize stridor. An inspiratory stridor typically suggests an airway obstruction involving the supraglottis. Biphasic stridor indicates a fixed obstruction at the level of the glottis or subglottis. Expiratory stridor, on the other hand, indicates an intrathoracic obstruction. Auscultation is also used to assess for differences in air entry between the right and left lung. This is particularly important in children with a suspected foreign body aspiration. Auscultation is also used to assess nasal airflow in neonates presenting with stertor and upper airway obstruction.

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Finally, auscultation can be used to assess for bruits, which indicate vascular anomalies with high blood flow.

Growth Curve The growth curve is an important component of the assessment of infants with respiratory compromise. Children that must work to breath have difficulties with feeding and the “work” consumes energy resulting in poor weight gain or weight loss. The growth curve is the most sensitive way to determine if infants with laryngomalacia require a surgical intervention.

Investigations There are several investigative tools available to complement a surgical consultation. They should be used judiciously and appropriately as dictated by the clinical presentation. This section of the chapter is not intended to be a thorough overview of all available investigations. Rather, the goal is to provide a brief summary of the most common investigations and how they are most appropriately used.

Audiometry Audiometric investigations include pure tone audiometry, play audiometry, tympanometry, otoacoustic emissions (OAEs) and auditory brainstem response (ABR) testing. These investigations, performed by audiologists, assess the functioning of the auditory system. They are used in the screening of newborns, children, and adolescents to detect and characterize the severity and nature of hearing loss.

Radiography Plain radiographs of the neck and chest are commonly used and readily available in most clinical settings. The lateral neck X-ray, for example, may be used to assess the size of the tonsils and adenoids and the degree to which they obstruct the upper airway. Neck and chest radiographs are also commonly used to assess children presenting with a history suggestive of a foreign body ingestion or aspiration. If an aspiration is suspected, inspiratory, expiratory, and lateral decubitus views may be required to detect air trapping in the distal airway. Chest X-rays are also used to assess for mediastinal adenopathy in children and adolescents presenting with cervical adenopathy suggestive of a lymphoproliferative disorder.

P. Campisi and V. Forte

Ultrasonography Ultrasound has become the “workhorse” for the investigation of a variety of neck anomalies. Ultrasonography is readily available, cost-effective, well tolerated by children, and avoids radiation exposure and can be performed without the use of sedation or a general anesthetic. Ultrasound can differentiate cystic from solid lesions and provide accurate localization and measurement information. It can be used to characterize lymphadenopathy and reliably detect concerning features such as a round shape, loss of hilar fat, and the presence of cystic change or microcalcifications suggestive of metastatic thyroid disease. In fact, ultrasound has been established as the best modality to detect and monitor thyroid lesions.

Cross-Sectional Imaging Cross-sectional imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) provide detailed images of lesions and the surrounding anatomy. They are used to characterize the nature and extent of the pathology. For complex lesions and lesions in challenging anatomical locations, cross-sectional imaging provides a surgical roadmap required to define the extent of surgery required and alert the surgeon to potential risks. CT images are derived with X-rays and should be used judiciously to avoid unnecessary radiation exposure to young patients. CT is very useful to assess bony structures such as the temporal bones, nasal sinuses, and craniofacial skeleton. MRI, on the other hand, is more appropriately used to assess and discriminate soft tissues, congenital soft tissue anomalies, and the brain. For many young patients, MRI can only be completed with sedation or a general anesthetic due to the length of time needed to acquire the images and the importance of remaining motionless during the acquisition. Regardless of the modality used, sedation should not be given to patients with a precarious airway unless supervised by the anesthesia and surgical team.

Special Imaging Modalities Special imaging techniques are occasionally required to supplement or provide very specific information about the presenting lesion. Examples of special imaging techniques include angiography, positron emission tomography (PET), fluoroscopy, and various upper gastrointestinal imaging assessments. Detailed information regarding these modalities is beyond the scope of this chapter.

1  Principles and Practice of Surgical Consultation for the Diagnosis of Pediatric Head and Neck Diseases

Biopsy The retrieval of tissue through a biopsy may be required for a definitive diagnosis if a malignancy is suspected. Biopsy can be performed with a fine needle, core needle, or open surgical approach. Fine needle biopsy is most commonly used to sample thyroid lesions and lymph nodes suspected of harboring a metastasis. Core biopsies are useful when more tissue is required, in particular if the lesion is not amenable to an open surgical approach. An open surgical biopsy is most commonly employed in the pediatric population to retrieve an abnormal lymph node (excisional biopsy) or sample a larger mass in the neck, oral, and nasal cavities.

Summary In summary, a surgical consultation in children requires a thorough and systematic approach. The consultation process may be very distressing for parents and caregivers. As such a

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gentle and empathetic approach must be used when discussing management and prognosis. A genuine heart-felt concern must underpin all discussions with both patient and family regardless of the complexity of the medical condition or severity of the prognosis. In very young children, the pregnancy, birth, and developmental history may be particularly relevant. Benign lesions are more common than malignancies and they often present with a specific pattern if embryologic in origin. The history and physical examination typically lead to the correct diagnosis. The appropriate use of investigations is helpful to confirm the diagnosis, characterize the nature of the lesion, and provide a surgical roadmap. An understanding of the attributes and limitations of investigations leads to expeditious and cost-effective care and avoids unnecessary harm to the patient.

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Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases Sunitha Palasamudram and Manohar Shroff

Introduction

Why Is Pediatric Imaging Challenging?

The head and neck location includes the face, eye and orbit, nasal cavity and paranasal sinuses, ear and temporal bone, oral cavity, jaw, and neck. Head and neck pathologies in pediatric population differ from adults by the types and nature of occurrence. Neck pathologies in children commonly have an inflammatory, infective, or congenital cause. Neoplastic lesions are less common comprising of only 5% of childhood cancers arising in the head and neck region [1]. Imaging is necessary to characterize and assess the extent of head and neck mass lesions. In case of malignant disease, it helps to analyze the metastatic spread and in follow-up to detect the response to treatment. Imaging can also be used to guide fine-needle aspiration (FNA) or needle biopsy. In this chapter, we describe various imaging techniques used to assess lesions of the head and neck in children, guidelines and indications of their utility, radiation and contrast-related concerns specific to children and then review imaging findings of ten important subsets of head and neck pathologies in pediatric population. Important clinical features that need to be considered when interpreting imaging include [2]: age of the child, duration and nature of onset of the mass, location of the mass, characteristic imaging features (e.g., mineralization, vascularity, intensity of enhancement, cystic areas, diffusion restriction) and whether the child has a known mutation.

Imaging kids is challenging as compared to the imaging of adults. This is because of the following:

S. Palasamudram Division of Neuroradiology, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, ON, Canada M. Shroff (*) Division of Neuroradiology, Department of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada e-mail: [email protected]

• It requires dedicated imaging protocols for image acquisition with special considerations for signal to noise due to smaller sizes. • There is need for sedation or general anesthesia for procedures like MRI, which takes longer time. • Specific training is required for the healthcare personnel involved. Good knowledge and expertise need to be applied for evaluating the images. • It also requires an understanding of optimum radiation exposure, if ionizing radiation is being used.

Preferences in Pediatric Imaging Environment The objective of acquiring good quality images in children involves gaining a child’s trust and co-operation before and throughout the examination. Children are irritable and not comfortable around strangers and unfamiliar environments. To encourage improved patient experience, the external environment in the radiology department should be made more child-friendly, for example, walls can be painted with colorful characters (Fig. 2.1), and there can be children’s books in the waiting room. Support from parents is always appreciated. It may be sometimes necessary to sedate the child or use immobilizers for longer studies like MRI. Commonly used sedatives are diazepam, midazolam, and ketamine. Techniques and equipment need to be hired to minimize the need for sedation as it has its own harmful effects. Where sedation or anesthesia is required, there should be dedicated pediatric specialists who help in recovery. Child life specialists and Innovative methods like dog therapy and virtual r­eality are also successful in

© Springer Nature Switzerland AG 2021 P. Campisi et al. (eds.), Pediatric Head and Neck Textbook, https://doi.org/10.1007/978-3-030-59265-3_2

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S. Palasamudram and M. Shroff

Fig. 2.1  Showing the colorful walls leading to MRI at SickKids Hospital, Toronto

avoiding sedation and anesthesia in appropriately selected subjects [3]. The emotional needs of parents should also be addressed when considering any pediatric imaging service.

Equipment and Protocols Dedicated pediatric imaging department with dedicated pediatric technologists may result in greater compliance with the pediatric protocols and significantly reduced patient dose. Imaging needs to be child-focused and must be tailored according to the age of the child. The standardization of the techniques and protocols is also important. Child-appropriate protocols need to be implemented for all the modalities.

Training It must be ensured that only the staff with appropriate training in Pediatric imaging are employed and their performance should be reviewed regularly. Also, radiologists reporting pediatric cases must have a good knowledge and expertise, as pathologies afflicting children are different and peculiar than that occur in adults. Also, because of the dynamic anatomy in children, normal variants look like pathology. Proper knowledge of these variants helps avoid making such mistakes. The pediatric radiologist also decides the appropriate modality of choice.

Quality Assurance Regular audits and quality checks for the equipment need to be ensured for optimum performance and calibration for pediatric use. There should also be quality assurance with respect to technique and reporting.

Radiation Protection • Considerable advances in technology have reduced the amount of radiation required to achieve images of diagnostic quality. Although stochastic effects have not been demonstrated at radiation doses encountered in diagnostic radiology, the risk for cancer induction is thought to be greater in children than adults [4]. Significant efforts must be made to ensure that delivered radiation doses are low. • Measured application of ionizing radiation remains of critical importance and must be catered to clinical appropriateness and diagnostic task of the examination. • Development of a comprehensive quality assurance and quality control program is essential; ensuring that X-ray equipment is functioning within specific tolerances, delivering the exposures expected and appropriate, and is compliant with acceptable standards of installation and design. It is critical that radiologists, radiographers (medical radi-

2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases

ation technologists), and physicists develop standards for each institution. • Creation of institutional diagnostic reference levels (DRL) are necessary to ensure that radiation dose metrics are known, expected, and within specified and reasonable tolerances. Concerns which need to be considered while using conventional radiographic X-ray equipment for imaging in children include the following: [4] • Appropriate imaging protocols: must be applied for the diagnostic task, the body part to be imaged, and patient habitus • X-ray tube and generator: must operate at a high frequency, have sufficient power to facilitate short exposure times, and a large dynamic range of tube current and tube current-time product to accommodate a large range of body habitus. • Automatic exposure control (AEC): should be used in appropriate circumstances • Spectral filtration: the addition of aluminum and copper filters improves beam quality and reduces the proportion of lower-energy photons contributing to skin dose while improving penetration • Antiscatter grid: use of a grid may improve image contrast by reducing the proportion of scatter reaching the image receptor • Beam collimation needs: primary radiation must be limited to the area of interest • Immobilization devices should be used where applicable to reduce patient motion • Use of computed or digital radiography is recommended Concerns which need to be considered while using computed tomography (CT) for imaging in children include the following: [5] • Dedicated CT protocols for pediatric imaging must be implemented for all examinations to ensure appropriate image quality and radiation dose. This involves customization of tube voltage, tube current, tube current-time product, tube-current-modulation, image thicknesses, convolution kernel, and reconstruction technique (filtered back projection, iterative reconstruction, etc.) • Limit scan range to indication • A lower tube voltage can reduce radiation dose when used in studies with iodinated contrast • Shorter rotation times can reduce examination time and minimize the likelihood of patient motion • Patients must be centered in the gantry to ensure appropriate tube-current-modulation • Limit number of phases for IV contrast examinations and consider noisier technique for select phases if appropriate

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Advantages and Limitations of Each Imaging Modality in Head and Neck Location: [6] The indication for diagnostic imaging in the anatomically complex head and neck region should be established for a specific type of imaging modality on the basis of a thorough clinical examination. Main advantages and limitations of imaging modalities in the head and neck region are listed below. 1. Ultrasonography • Advantages –– Widely available –– No exposure to ionizing radiation • Limitations –– Limited to superficial regions –– Diagnostic value is examiner-dependent 2. Nuclear Imaging/PET CT • Advantages –– Whole-body evaluation –– Functional, not merely anatomical, evaluation • Limitations –– Limited structural information –– Cancer-specific diagnostic value of positron emission tomography (PET) not generally accepted 3. Conventional X-rays • Advantages –– Low cost –– Low radiation exposure • Limitations –– Poor risk–benefit profile, owing to diagnostic uncertainty from projection effects –– Therefore, restricted to certain specific indications (e.g., dental diagnosis) 4. Computed Tomography (CT) • Advantages –– 3D sectional imaging technique with high diagnostic value –– Widely available –– Best risk–benefit profile for standard care • Limitations –– Low-dose protocols have not yet come into use in all centers 5. Cone Beam CT (previously also known as Digital Volume Tomography) • Advantages –– 3D sectional imaging technique –– High spatial resolution –– Usually low radiation exposure (but depends on apparatus and examiner) • Limitations –– Cannot be used to examine soft tissues, incl. tumors

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6. Magnetic Resonance Imaging (MRI) • Advantages –– 3D sectional imaging technique with the highest diagnostic value –– Best modality for imaging the soft tissues –– No exposure to ionizing radiation • Limitations –– Requires expensive special equipment 7. Cerebral Angiography • Advantages –– Evaluates arteries of the head and neck before surgery –– Provides additional information on abnormalities seen on MRI or CT of the head, such as the blood supply to a tumor –– Basis for treatment, such as embolization of a neoplasm –– In preparation for minimally invasive treatment of a vessel abnormality • Limitations –– Invasive; procedure-related complications –– Involves ionizing radiation –– Contrast-related risks

S. Palasamudram and M. Shroff

to check the setting of a programmable ventriculoperitoneal shunt. Plain films of the skull were once commonly obtained in the evaluation of trauma cases. However, skull fractures that were recognizable on projection views poorly correlated with intracranial injuries, while the clinically relevant entity is not the skull fracture itself, but rather the intracranial hemorrhage that is associated with it. Jend et  al. in their study reported that only 40% of patients with a skull fracture had an associated intracranial injury as well; on the other hand, 44% of patients with an intracranial injury demonstrated no skull fracture [7]. Thus, CT is clearly the modality of choice. • Orbit Convention radiographs were used in the past almost exclusively for the evaluation of trauma cases. Conventional orbital X-rays have now been replaced by tomographic imaging for nearly all indications. As an exception, they can still be used to rule out the presence of metallic foreign bodies before MRI. Conventional orbital X-rays are not mentioned in the current AWMF guidelines; they are obsolete for orbital diagnosis. • Temporal Bone

Indications of the various imaging modalities in head and neck pathologies (6):

Conventional Radiographs (Plain X-rays): Conventional Radiographs now have a limited value for imaging in the head and neck area. They have been almost entirely replaced by cross-sectional imaging, except for a few specific indications like diagnostic assessment of the teeth and jaws. • PNS (Paranasal Sinus) Similarly, conventional X-rays of the paranasal sinuses are not indicated for screening purposes, for example, to evaluate headache, cystic fibrosis in children, asthma, or allergies; or for the detection of an infectious focus in patients with unclear inflammatory symptoms or as an exclusion of a particular disease in persons with an elevated risk. • Skull Some indications for conventional skull films still indicated are as follows: to exclude isolated fractures of the zygomatic bone, maxilla, mandible, or nasal bone; to diagnose congenital anomalies and premature synostoses; to demonstrate pneumocephalus after intracranial procedures; to detect metallic foreign bodies before MRI; and

The main conventional X-ray views of the temporal bone are Stenvers and Schüller. Stenvers view is still used today to document the position of the electrode carrier for cochlear implantation. However, it is obsolete for all other indications. Schüller view yields some information of the degree of pneumatization of the mastoid bone but does not permit any validity whether diminished pneumatization is due to a congenital anomaly, tympanic sclerosis, or chronic inflammation. Schüller views are still occasionally obtained in patients with suspected mastoiditis or otitis media; however, this has no medical justification. Conventional temporal bone X-rays are not approved to be taken preoperatively to demonstrate anatomical relationships, as an aid to surgery: projection effects make them unreliable for the identification and quantitative measurement of surgically relevant anatomical variants. Temporal bone X-rays are also not indicated for the assessment of trauma, malformations, and tumors of the temporal region. They have been replaced by sectional imaging—CT, DVT, or MRI, depending on the indication. • Dental and Maxillary Region The primary imaging modality for assessment of the teeth and jaws is still conventional radiography: specifically, intraoral dental views or an (extra oral) panoramic tomographic view (orthopantomogram, OPG). Intraoral dental views pro-

2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases

vide the assessment of endodontal and periodontal disease with high local resolution and minimal radiation exposure. OPG, on the other hand, enables a comprehensive survey of all of the teeth and the underlying bone, with a low radiation exposure. Dental views and OPG are currently used for evaluation of inflammatory diseases, orthopedic evaluation of the jaws, trauma assessment, evaluation of unclear symptoms, and planning of dental implantation procedures. Conventional lateral views are used (optionally) in orthognathic surgery. Tomographic imaging is indicated for the evaluation of large cysts, benign or malignant lesions of the jaws and for the evaluation of trauma with potentially extensive midface involvement. It is also used to plan implantation procedures. Compared to conventional X-rays, it gives a more accurate assessment of the bone substance, exact measurement of the height and width of the jaws, three-dimensional localization of the mandibular nerve canal, and an assessment of the topography of the maxillary sinuses and of inflammatory processes than may affect them. Cone Beam CT (CBCT) is superior to conventional X-rays (dental views and OPG) for the evaluation of dental trauma. The preferred methods of tomographic imaging are CT and CBCT.  Both modalities are subject to the same restrictions with regard to radiation safety.

Ultrasonography Diagnostic ultrasonography of the head and neck is mainly used to assess organs and lesions that lie near the surface, including the salivary glands, the thyroid gland, the major vessels, enlarged superficial lymph nodes, and other superficial pathologic lesions. Superficial palpable masses of the head and neck are also common in the pediatric population, with the vast majority of the lesions ultimately proven to be benign. Duplex ultrasonography (US) is the first-line imaging modality for the evaluation of superficial pediatric masses. Without utilizing radiation, iodinated contrast material, or sedation and/or anesthesia, US provides a means for quick and cost-effective acquisition of information, including the location, size, shape, internal content, and vascularity of the lesion. US is usually performed in an array of common and uncommon pediatric head and neck masses that include neonatal scalp hematoma, craniosynostosis, dermoid and epidermoid cysts, Langerhans cell histiocytosis, lymph nodes and their complications, fibromatosis colli, thyroglossal duct cyst, branchial cleft cyst, cervical thymus, congenital goiter, thyroid papillary carcinoma, parathyroid adenoma, hemangioma, lymphangioma, jugular vein phlebectasia, Lemierre syndrome, acute parotitis and parotid abscess, leukemia and/or lymphoma, neurogenic tumor, and rhabdomyosarcoma. Finally,

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in situations where the head or neck mass is too large and deep, or if it is hyperechoic to be fully assessed within the US field of view, or if malignant or a high-flow vascular lesion is suspected, then further evaluation with cross-­ sectional imaging becomes necessary [8].

Computed Tomography CT is the most commonly used imaging modality for all indications in the head and neck region. The spiral CT mode currently involves the acquisition of only one thin-section axial volume data set. From this data set, tomographic images in all of the required planes can be computed without any further radiation exposure or loss of image quality. Intravenously administered contrast media improve the delineation of soft-tissue pathologies and are in-dispensable in the diagnosis of malignant tumors and inflammatory complications. Low-dose CT is the imaging modality of choice for chronic rhinosinusitis. The preoperative CT reveals the site and extent of chronic inflammatory changes that have not responded to conservative treatment; it also documents any anatomical variants that may have contributed to the causation of sinusitis or that might be danger areas for the current state-of-the-art, minimally invasive, endoscopic surgical approach. The imaging modality of choice for trauma involving the orbit, midface, and skull base is again thin-section CT.  Multiplanar and three-dimensional reconstructions of the CT data set yield the details that are needed for the comprehensive assessment of complex fractures affecting the entire midface or any part of it. The proper imaging study to evaluate visual disturbances is an MRI or CT of the whole cranium, orbits included. CT is the preferred modality for the assessment of trauma, aggressive inflammatory diseases and other extracranial processes, and conductive or mixed hearing loss, as well as for the planning of cochlear implantation and other surgical procedures in the temporal region.

Cone Beam CT CBCT is a sectional imaging modality similar to CT that was used initially only for dental diagnosis because of the restriction to small volumes. Technical advances have made CBCT applicable in larger volumes, and it can now be used as an alternative to CT for evaluation of the craniofacial and temporal high-contrast structures. The advantages of CBCT are high spatial resolution, low radiation exposure (in the same range as low-dose CT), and decreased metal artefact. It is unsuitable for soft-tissue diag-

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nosis as the image-noise is too high. Apart from clinical use in the diagnosis of high-contrast structures like teeth and jaws, a definite judgment, mainly as an alternative method to CT, is not possible as yet. Therefore, the current guidelines designate CBCT as a possible alternative to CT in individual cases but provide no specific recommendations regarding its use.

Magnetic Resonance Imaging MRI is currently the imaging modality that yields the most detailed view of the soft tissues. Its main advantage, in comparison to CT, is the absence of ionizing radiation; its main disadvantage is the much longer time during which the patient must keep still during the study. Patients who cannot cooperate may need sedation or even general anesthesia. In the head and neck, MRI is mainly used for pre- and postoperative tumor imaging and to evaluate suspected intracranial complications of sinusitis. MRI is the imaging study of first choice for the evaluation of orbital tumors or endocrine orbitopathy, after ultrasonographic examination by an ophthalmologist. CT can be particularly useful for the demonstration of calcifications or bony changes. MRI is the method of choice to assess anomalies of the inner ear, sensorineural hearing loss/deafness, dizziness, and intracranial processes. Other rare indications include congenital anomalies of the temporal bone, as well as the preoperative assessment for cochlear implants. MRI can be used instead of CT as the primary imaging modality whenever ionizing radiation is to be avoided, for example, in children who need imaging of the paranasal sinuses before surgery.

Nuclear Isotope Imaging Nuclear isotope imaging plays a key role in the evaluation of thyroid disease. Bone scanning can be used to evaluate craniofacial or other skeletal involvement by chronic inflammatory or neoplastic entities. Positron emission tomography (PET) gives the details of whole-body functional imaging with good spatial resolution. [18F] Fluorodeoxyglucose ([18F] FDG) PET has a wide range of applications in staging oncological disease and monitoring response to treatment. Moreover, the increasing availability of PET-CT allows improved localization and definition of disease activity. The role of PET and PET-CT in childhood malignancies continues to evolve, but it is widely used in the staging and followup of lymphoma and also have a role in soft tissue ­ sarcomas.

S. Palasamudram and M. Shroff

Contrast Media in Children We address specific areas in which pediatric use of contrast material differs from adult use.

Iodinated Intravascular Contrast Media Unique Considerations in Children Contrast Agent Osmolality Osmolality is an important physical property of contrast media. A variety of adverse effects attributed to intravascularly administered iodinated contrast agents seem to be related, at least in part, to this physical property, including physiologic side effects, allergic-like reactions, complications following contrast medium extravasation, and fluid shifts. Contrast media osmolality is of particular importance in neonates and small children. These patients are thought to be especially susceptible to fluid shifts and have a lower tolerance for intravascular osmotic loads when compared to adults. Intravascular administration of hyperosmolar contrast medium may result in migration of fluid from extravascular soft tissues into blood vessels, consequently expanding blood volume [9, 10]. If the fluid shift is large, cardiac failure and pulmonary edema can result; children with significant preexisting cardiac dysfunction may be at particular risk. Contrast Media Viscosity Viscosity, a measure of fluid resistance to stress, is another important physical property of contrast media. As viscosity increases, the pressure associated with an intravascular contrast medium injection increases. This physical property is especially important for pediatric patients due to the use of small gauge angiocatheters in tiny blood vessels. Contrast medium viscosity and angiocatheter size are important factors in determining maximum injection rates. If a rapid injection rate is desired through a small angiocatheter and if contrast medium viscosity is high, two problems can potentially result: First, the desired injection flow rate may not be achieved. Second, high pressure may cause catheter failure and/or vessel injury. Additionally, contrast medium viscosity is not directly proportional to the concentration of iodine iscosity of contrast media is affected by temperature. As temperature increases, viscosity decreases, allowing for increased flow rates at lower pressures. A study by Vergara and Seguel [11] that included both adult and pediatric patients showed that warming contrast media resulted in fewer adverse events following injection when compared to contrast media adminis-

2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases

tered at room temperature. In another study of 24,826 intravenous (IV) contrast material administration in children and adults [12], warming of iopamidol-370 to body temperature reduced the extravasation rate, but warming of iopamidol-­ 300 to body temperature had no effect. The authors concluded that higher viscosity agents may benefit more from warming than lower viscosity agents.

 ther Unique Concerns in Children O Several additional issues complicate the administration of intravascular contrast media to neonates and children, including the use of small volumes of contrast medium, the use of small gauge angiocatheters, and unusual vascular access sites. First, very small volumes of contrast media are typically administered to neonates and infants (typically 1.5–2 mL/kg) [13]. As a result, timing of image acquisition with regard to contrast medium administration may be important when performing certain imaging studies, such as CT angiography. In some instances, a slower injection rate (compared to that used in older children and adults) may be useful to prolong intravascular enhancement. Second, small-­ gauge angiocatheters (e.g., 24-gauge) located in tiny peripheral veins (e.g., in the hand or foot) are commonly utilized in neonates and infants. A study by Amaral et al [14] showed that 24-gauge angiocatheters in a peripheral location can be safely power injected using a maximum flow rate of approximately 1.5 mL/sec and a maximum pressure of 150 psi. When access is thought to be tenuous, hand injection of contrast medium should be strongly considered to minimize the risk of vessel injury and extravasation. Since many currently used central venous catheters are not approved for power injection, one should always verify in advance that any catheter to be utilized for bolus contrast material instillation can tolerate the anticipated injection. It is also important to ensure that the pressure used does not exceed the catheter’s pressure rating. Particular attention should be paid to the injection sites of neonates and infants, as such individuals cannot effectively communicate the possibility of an injection site complications. Extravasation rates in children appear to be similar to those of the adult population. An extravasation rate of 0.3% was documented in a study of 554 children in which a power injector was used to administer iodinated contrast medium [14]. Most extravasations in the pediatric population resolve without untoward sequelae. A study by Wang et  al [15] showed that 15 of the 17 cases of contrast-medium extravasation in children were mild in severity with minimal or no adverse effects.  hysiologic Side Effects in Children P Although most minor physiologic side effects to IV contrast medium administration in adults are of minimal significance, such events are often of increased importance in

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children. For example, local warmth at the injection site and nausea, generally regarded as physiologic side effects to contrast medium administration, may cause a child to move or cry. Such a response to contrast medium injection may result in the acquisition of a nondiagnostic imaging study, necessitating repeat imaging and additional exposure to contrast medium and radiation. There may be differences between the various nonionic low-osmolality iodinated contrast agents with regard to the incidence of injectionrelated side effects [16].

I ncidence of Allergic-Like Reactions There are several difficulties in interpreting the available literature on the incidence of allergic-like reactions to IV iodinated contrast media in children. First, many studies have failed to discriminate between physiologic side effects and allergic-like reactions and have used heterogeneous definitions of what constitutes mild, moderate, or severe reactions. Second, there is a lack of controlled prospective pediatric studies on the topic. Prospective investigations are difficult to perform because allergic-like reactions to contrast media in children are rare, and large numbers of patients would be needed to acquire statistically meaningful results. Also, much of the existing literature is retrospective in nature, for which it is difficult to ensure that all adverse reactions are appropriately documented. It is generally agreed, however, that the incidence of allergic-­like reactions in children is lower than that in adults [11, 16, 17]. A very large retrospective study by Katayama et al of more than 100,000 contrast medium administrations [17], when stratified by age and the use of non-ionic iodinated contrast media, showed that patients less than 10 years of age and the elderly have the lowest rates of adverse reactions. A study by Dillman et al. [18] retrospectively reviewed more than 11,000 IV injections of low-osmolality nonionic iodinated contrast media in children and neonates and documented an allergic-like reaction rate of 0.18%. Of the 20 reactions documented in their study, 16 were mild, one was moderate, and three were severe [17]. A similarly performed study by Wang et  al. [19] in adult patients from the same institution over a similar time period revealed an adult reaction rate of approximately 0.6%. A study by Callahan et al. [20] of 12,494 consecutive patients up to 21  years of age revealed a 0.46% incidence of adverse reactions to ioversol, the majority of which were mild. A smaller study by Fjelldal et al. [21] documented five allergic-like reactions to iohexol following a total of 547 injections, for a rate of reaction of 0.9%. Although fatal reactions to contrast media in children are extremely rare (and may be due to co-morbid conditions in some cases), infants and young children require close observation during and immediately following IV contrast medium administration, as they are unable to verbalize reaction-­related discomfort or symptoms.

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 revention of Allergic-Like Reactions P General guidelines for the prevention of allergic-like reactions in children are similar to those used for adult patients. Allergic-like reactions following premedication may still occur, although the frequency of such reactions is unknown [18]. It should be noted that there has been no prospective, controlled investigation performed to assess the efficacy of premedication for the prevention of allergic-like reactions to iodinated contrast media in children.  reatment of Allergic-Like Reactions T General guidelines for the treatment of allergic-like reactions in children are similar to those used for adult patients. Pediatric medication dosages are significantly different from adult dosages used in the management of such reactions. It can be helpful to have a pediatric medication chart with weight-based dosages placed on the emergency cart or posted in the rooms where intravascular contrast media is to be injected into children. Dedicated pediatric emergency resuscitation equipment (including various sizes of supplemental oxygen face masks) also should be available in all such locations. A separate box of pediatric airway equipment attached to the emergency cart may be useful in areas where both children and adults receive contrast media.

S. Palasamudram and M. Shroff

clinically significant and suggest some degree of renal impairment, even though both measurements may be within acceptable limits for patient age. Serum creatinine concentration may not become abnormal until glomerular filtration has decreased substantially. Second, it may take several days in the setting of acute renal failure for serum creatinine concentration to rise. A patient, therefore, may have impaired renal function and a normal serum creatinine concentration. Measurement of blood urea nitrogen (BUN) concentration is a poor indicator of renal function. BUN concentration depends on numerous variables in addition to renal function, including daily dietary protein intake, hepatic function, and patient hydration. A popular manner by which to express renal function in children is the estimated glomerular filtration rate (eGFR). It is important to note that the formula used to calculate pediatric eGFR (see below) is different from that used in adults. eGFR calculation in children requires knowledge of patient serum creatinine concentration and height. In addition, the assay used to measure serum creatinine concentration must be known.

GFR Calculator for Children There is no perfect manner of estimating the GFR in children. The National Kidney Disease Education Program, an initiative of the National Institutes of Health, provides an Contrast-Induced Nephrotoxicity in Children online calculator for estimating purposes and has published There has been no large prospective investigation dealing the following information regarding the estimation of GFR with the possible nephrotoxic effects of intravascular low-­ in children. Currently, the best equation for estimating GFR osmolality iodinated contrast agents in children. from serum creatinine in children is the Bedside Schwartz Consequently, the effects of contrast media on the kidneys equation. This formula is for use with creatinine methods are generally assumed to be similar between children and with calibration traceable to isotope dilution mass spectrosadults. A few key differences are mentioned below. copy (IDMS). Using the Original Schwartz equation (which is no longer recommended) with a serum creatinine value Measurement of Renal Function in Children from a method with calibration traceable to IDMS will overSerum creatinine concentration reflects the balance between estimate GFR by 20–40%. creatinine production and excretion. Creatinine is a breakEquation: Bedside Schwartz Equation down product of skeletal muscle, and its rate of production is  0.41 height  proportional to muscle mass. Muscle mass depends on a GFR mL / min/ 1.73 m 2  serum creatinine variety of factors, including patient age, gender, and level of physical activity. Normal serum creatinine concentrations, thus, are quite variable in pediatric patients, even in the pres- • Height in cm ence of preserved renal function. It is important to recognize • Serum creatinine in mg/dL that normal adult creatinine concentrations cannot be applied to the pediatric population. Normal pediatric serum creatiAlthough other methods of estimating GFR exist (such as nine concentrations increase with age, with the upper limits cystatin C measurement or nuclear medicine GFR study), the of normal always less than adult values. Age-based normal Bedside Schwartz equation remains the most readily availserum creatinine concentrations may vary slightly from labo- able and easiest to use in pediatric patients. ratory to laboratory. There are problems with using serum creatinine concen- Prevention of Contrast-Induced Nephrotoxicity tration as the sole marker of renal function. First, a normal in At-Risk Children serum creatinine value does not mean that renal function is Risk factors for contrast-induced nephrotoxicity (CIN) in preserved. For example, an increase in creatinine from children are thought to be similar to those in adults. 0.4 mg/dL to 0.8 mg/dL in a 10-year-old patient would be Unfortunately, there are no established evidence-based





2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases

guidelines for the prevention of CIN in children with impaired renal function. As no pediatric-specific measures for the prevention of CIN have been established in the literature, strategies described in adults should be considered when using IV iodinated contrast media in children with renal dysfunction. A noncontrast imaging examination should be performed if the clinical question can be answered without IV iodinated contrast media. In addition, the use of alternative imaging modalities, such as ultrasound and MR (with or without gadolinium-based contrast medium, depending on the exact degree of renal impairment and the clinical question to be answered), should be considered.

 adolinium-Based IV Contrast Agents G There are only a few published studies that address adverse reactions to gadolinium-based IV contrast media in children. The guidelines for IV use of gadolinium-based contrast agents are generally similar in both the pediatric and adult populations. A few pediatric-specific issues regarding these contrast agents are discussed below. Osmolality and Viscosity As with iodinated contrast media, there is a significant range in osmolality and viscosity of gadolinium-based MRI contrast agents. These physical properties, however, potentially are less important when using gadolinium-based contrast agents in children compared to iodinated contrast agents. The much smaller volumes of gadolinium-based contrast agents typically administered to pediatric patients likely result in only minimal fluid shifts. The slower injection flow rates generally used for gadolinium-based contrast agents result in lower injection-related pressures and decreased risk for vessel injury and extravasation. Allergic-Like Reactions and Other Adverse Events Though rare, allergic-like reactions to IV gadolinium-based contrast media in children do occur. A study by Dillman et al [22] documented a 0.04% (48 reactions/13,344 injections) allergic-like reaction rate for these contrast agents in children. A more recent study by Davenport et al that included 15,706 administrations of gadolinium-based contrast media in children (under the age of 18  years) documented only eight allergic-like reactions, for a reaction rate of 0.05% [23]. Although mild reactions are most common, more significant reactions that require urgent medical management may also occur [23]. Pediatric allergic-like reactions to gadolinium-­ based contrast media are treated similarly to those reactions to iodinated contrast agents. While no investigation has studied the efficacy of corticosteroid and antihistamine premedication regimens for the prevention of allergic-like reactions to gadolinium-based contrast agents in children or adults, regimens, such as those

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presented in Table A below, are thought to provide some protective benefit. A variety of physiologic side effects may also occur following administration of gadolinium-based contrast media, including coldness at the injection site, nausea, headache, and dizziness. There is no evidence for pediatric renal toxicity from gadolinium-based contrast media at approved doses. Extravasation of gadolinium-based contrast media is usually of minimal clinical significance because of the small volumes injected.

 ephrogenic Systemic Fibrosis N and Asymptomatic Gadolinium Deposition in Tissues There are only a small number of reported cases of nephrogenic systemic fibrosis (NSF) in children. As of September 2012, there were 23 unique pediatric NSF cases, and all patients were 6 years of age or older [23]. Seventeen of these children had documented exposure to gadolinium-based contrast material. Thirteen of 13 children with available clinical data pertaining to renal disease had substantial renal dysfunction (acute kidney injury and/or chronic kidney disease), and 10 were on hemodialysis or peritoneal dialysis (or both). In 10 children, renal status was unknown. A few early cases were described prior to this condition’s known apparent association with gadolinium-based contrast media (24–30). Only 10 children (all older than 8  years of age) with biopsy-­confirmed NSF have been reported to the Yale Registry, with no new cases reported between 2007 and 2013 after guidelines were published in 2007 limiting the use of gadolinium-­based contrast media in children with impaired renal function [24]. As there are no evidence-based guidelines for the prevention of NSF in children in particular, adult guidelines are to be followed for identifying at-risk patients and administering gadolinium-based contrast media in the presence of impaired renal function [25]. Children at risk for renal impairment should be identified (chronic kidney disease or acute kidney injury) and screened for impaired renal function. As in adults, gadolinium-based contrast media should be avoided in the setting of acute kidney injury or chronic kidney disease with an eGFR. High-osmolality iodinated contrast agents should be avoided in children who are at risk for aspiration. Aspirated hyper osmolality contrast medium may cause fluid shifts at the alveolar level and chemical pneumonitis with resultant pulmonary edema (33–36). Aspiration of large volumes of both barium-based and iodinated oral contrast agents rarely may be fatal [26]. Gadolinium deposition has been observed in pediatric patients [27]. The gadolinium deposition is seen in patients with normal renal function. Multiple studies have confirmed increased signal intensity in the dentate nucleus and globus

18

pallidus on unenhanced T1-weighted image that was correlated with previous exposure to GBCAs (Gadolinium-based contrast agents). It was also confirmed that the hyperintensity noted in brain nuclei was caused by gadolinium deposition on autopsy studies [27]. Similar to NSF, gadolinium deposition is dose-dependent and increases with number of doses. Also, the hyperintensity of brain nuclei was predominantly seen with linear agents though some degree of gadolinium deposition in brain was seen with all agents on pathology. The chemical form deposited and the mechanism of deposition is still unknown. Since the deposition is predominantly seen with linear agents that have less stability, de-chelation is proposed as one of the predisposing factors for gadolinium deposition in tissues. Gadolinium deposition has also been noted in other tissues including skin and bones. However, these depositions including in the brain, have not shown any clinical effects and are largely asymptomatic [27]. Premedication Dosing Guidelines Corticosteroid Dosage Prednisone 0.5–0.7 mg/kg PO (Up to 50 mg) Timing 13, 7, and 1 hr prior to contrast injection AND Antihistmine Diphenhydramine 1.25 mg/kg PO (Up to 50 mg) Timing 1 hr prior to contrast injection OR Methylprednisolone 1  mg/kg PO or IV at 12  h and 2  h before contrast injection (maximum: 32 mg/dose) AND Antihistamine Diphenhydramine 1–2 mg/kg IV or PO (maximum dosage 50  mg/dose, 300  mg/day), I hour before contrast injection

Head and Neck Pathologies (Table 2.1) In pediatric population, congenital and inflammatory pathologies constitute 80% of the head and neck pathologies. The ten subsets of pathologies are discussed below.

Normal Variations It is important to understand the appearance of the developing anterior skull base to avoid interpretive errors in this complex region. Studies demonstrated that the ethmoidal labyrinth and turbinates (derived from the primitive nasal

S. Palasamudram and M. Shroff Table 2.1  Ten subsets of pediatric head and neck pathologies Pathologies Examples Normal variations Mineralization patterns of bones at different ages 2 Emergencies Ludwig’s angina, Lemierre syndrome 3 Epithelial Dermoid, epidermoid, teratoma inclusion cysts 4 Cephaloceles Frontoethmoidal encephalocele, nasal glial heterotopia 5 Vascular Hemangioma, venolymphatic malformation anomalies and venous malformations 6 Branchial cleft Type I, Type II, Type III, and Type IV cysts cysts 7 Trauma Dissection, pseudoaneurysms 8 Benign neoplasms Juvenile nasopharyngeal angiofibroma, pilomatrixoma, nerve sheath tumors 9 Malignant Rhabdomyosarcoma, lymphoma, leukemia, neoplasms Retinoblastoma, papillary thyroid cancer, & metastases 10 “Touch me not” Fibromatosis colli, ectopic thymus lesions 1

capsule) serve as the nidus for ossification of the anterior skull base [28]. Ossification continues from this area toward the midline over the first few months of life, accounting for the midline gaps normally seen on coronal CT scans. As the child matures, ossification of the anterior skull base proceeds in a fairly constant manner, with fusion of the cribriform plate and lateral ethmoid bone masses beginning as early as 2 months of age (Fig. 2.2). Similarly, nonossified portion of C2 vertebra may appear as focal hypodensity in infants often causing errors in interpretation. Arrested pneumatization of sphenoid sinus is another normal variant, which mimics a lesion (Fig. 2.3). These findings are eventually stable in the follow-up imaging.

Non-Traumatic Emergencies Computed tomography (CT) is the first-line imaging modality in the acute setting and subsequently, magnetic resonance (MR) imaging for further assessment. Awareness of these conditions is important not only to provide an accurate diagnosis but also to assess the extent of disease, evaluate for potential complications, and recommend definitive subspecialty evaluation. These can occur in the oral cavity (Ludwig angina), oropharynx (peritonsillar abscess), retropharynx (retropharyngeal abscess), hypopharynx (epiglottitis), salivary gland (sialadenitis, parotiditis), spine (discitis, septic facet arthritis), vascular space (Lemierre syndrome), orbits and sinuses (cellulitis, dacryocystitis, and invasive sinusitis) [29]. Ludwig angina is a serious life-threatening infection of the floor of the mouth that rapidly spreads bilaterally to the soft tissues of the oral cavity [29]. Ludwig angina is a type of cellulitis and not a focal abscess. It is caused by an infection

2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases

a

b

Fig. 2.2  CT of the anterior skull base showing progress of mineralization in infants, toddlers, and older children (a, b, and c). (a) In an infant, there is no ossification of the anterior skull base between the orbital plates of the frontal bones (F), although the turbinates are ossified

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c

(arrows). (b) In a toddler, ossification begins in the roof of the ethmoidal labyrinth laterally and spreads toward the midline (arrows). (c) In an older child, the entire anterior skull base is well ossified

Fig. 2.3  Arrested pneumatization of sphenoid sinus. Sagittal T1  W image showing a focal hyperintense area within the left sphenoid sinus (arrow) that is due to arrested pneumatization of sphenoid sinus

of the third mandibular molar tooth or pericoronitis (an infection of the gums surrounding the partially erupted lower third molar tooth), both of which are caused by Streptococcus organisms. As the soft-tissue swelling extends in Ludwig’s angina, it displaces the tongue into the pharyngeal airway and causes difficulty in breathing (Fig.  2.4). Treatment includes airway management and antibiotics. Imaging is performed to evaluate airway patency and determine if gas-­ forming organisms, assess presence of underlying dental infection, or a drainable abscess.

Fig. 2.4  Ludwig’s angina. Coronal CT neck showing edema in the right submandibular space and base of tongue with adjacent subcutaneous fat stranding

Lemierre syndrome is a rare and potentially life-­ threatening complication of acute respiratory tract infection. It can occur in healthy adolescents and young adults. In Lemierre syndrome, there is presence of septic thrombophlebitis of the internal jugular vein and disseminated abscesses, as well as septic pulmonary emboli. The causative organism

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S. Palasamudram and M. Shroff

is Fusobacterium necrophorum, an anaerobe present in normal oropharyngeal flora [29]. An ingested foreign body could be an important cause of retropharyngeal abscess in children (Fig. 2.5).

Epithelial Inclusion Cysts

Fig. 2.5  Retropharyngeal abscess secondary to foreign body ingestion. Lateral cervical spine radiograph demonstrating prevertebral soft tissue swelling and dense linear foreign body which is a fish bone (arrow)

a

Epithelial cysts are benign lesions which are histologically characterized by cystic spaces lined by simple squamous epithelium (epidermoid cyst) (Figs.  2.6 and 2.7), which contain skin adnexa (“true” dermoid cyst) (Figs.  2.8 and 2.9) or tissues of all three germ layers, like muscle, teeth, bone, cartilage, etc. (teratoid cyst) (Fig. 2.10). They commonly occur at areas of embryonic fusion and constitute 1.6–6.9% of all cysts in the head–neck region [30]. They may also result from abnormal invagination of surface ectoderm along the embryologic sites of dermal fusion that form the eyes, ears, and face. Computed tomography (CT) scan would demonstrate a unilocular cyst with homogeneous, hypo-attenuating (0–18 HU) fluid or fat material that has multiple hypo-­attenuating fat density nodules giving a “sack of marbles” appearance; this imaging appearance is pathognomonic for a dermoid cyst. Magnetic resonance imaging (MRI) shows fluid signal due to high protein content, and areas of fat component will show low signal on fat suppressed images. MRI helps in visualization

b

Fig. 2.6  Epidermoid. T2 (a), postcontrast T1 W (b), FLAIR (c), and diffusion weighted (d) MRI images showing a nonenhancing cystic lesion (arrow) located in the left mastoid that shows restriction on diffusion image (d)

2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases

c

d

Fig. 2.6 (continued)

a

b

Fig. 2.7  Epidermoid. Axial T1, T2 W MR images (a and b) showing a cystic lesion in the midline of the floor of the oral cavity (arrow)

21

22

Fig. 2.8  Dermoid. Coronal CT showing hypodense lesion of fat attenuation involving left fronto zygomatic suture (arrow)

a

S. Palasamudram and M. Shroff

Fig. 2.10  Teratoma in the neck. CT neck showing a large lesion with foci of fat and calcification (arrow)

b

Fig. 2.9  Nasal dermoid. Axial and coronal CT images (a and b) at the level of anterior cranial fossa showing widened foramen caecum (horizontal arrow) with bifid crista galli (vertical arrow)

of the exact location and extent of cystic lesions in the floor of the mouth and is useful for determining their relationship to the surrounding muscles. These cysts carry relatively higher risk of recurrence as compared to lipomas and certain other benign lesions that mimic these cysts.

Cephaloceles Intracranial tissue may herniate through a defect in the cranium that leads to an encephalocele. They occur in one of every 4000 live births and are most often occipital in location

2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases

(75%). Lesions are frontoethmoidal in 15% of cases and basal in 10%. There are often significant associated intracranial anomalies. Occipital encephaloceles may be associated with Chiari or Dandy Walker malformations and callosal or migrational anomalies [31]. Frontoethmoidal lesions are not typically associated with these types of anomalies. Frontoethmoidal encephaloceles are also known as sincipital encephaloceles and are further divided into nasofrontal, nasoethmoidal, and naso-orbital types. These are more common in South and Southeast Asian populations [31]. They track along the nasal bridge between the nasofrontal sutures into the glabella (nasofrontal region) (Fig. 2.11), under the nasal bones and above the nasal septum (nasoethmoidal region), or along the medial side of the orbit at the level of the frontal process of the maxilla and the ethmoid-lacrimal bone junction (naso-orbital region). Frontoethmoidal encephaloceles (Fig.  2.12) present as a clinically visible mass along the nose. The intracranial root of most frontoethmoidal encephaloceles is located at the foramen cecum, which is a small ostium located at the bottom of a small depression anterior to the crista galli and is formed by the closure of the frontal and ethmoid bones. Basal encephaloceles are internal and do not manifest externally, although they may present as a lump or bump in the oropharynx or nasopharynx. Basal encephaloceles include transethmoidal, sphenoethmoidal, transsphenoidal, and frontosphenoidal types [31]. Trans sphenoidal and transethmoidal encephaloceles are the common varieties. In the former, there is a defect in the floor of the sella and into the nasal cavity, and in the latter, they present through a midline or cribriform plate defect into the nasal cavity. Transsphenoidal encephaloceles may be associated with a cleft palate and could also project into the oral cavity. Affected children may present with nasal obstruction. Surgery is the treatment for encephaloceles, and MR imag-

a

b

23

ing is the imaging modality of choice for identifying the contents of an encephalocele prior to surgery. High-resolution CT may also be used to display the bone anatomy, but the intracranial connection is best depicted with MR imaging. Occipital encephaloceles commonly involve the cerebellar or cerebral hemispheres with involvement of the dural venous sinuses. MR venography is used to demonstrate venous involvement in these lesions. Nasal glial heterotopia (nasal glioma) occur near the root of the nose (where the cranial portion of the nose joins the forehead). These are composed of dysplastic glial tissue and are basically congenital nonneoplastic lesions best categorized as heterotopia (Fig. 2.13). Nasal gliomas are intranasal in 30% of cases, extra nasal in 60%, and mixed in 10% [31].

Fig. 2.12  Nasal glial heterotopia (nasal glioma). Coronal T2W MRI showing a linear hyperintense stalk connecting the right nasal mass to the intracranaial cavity (arrow)

c

Fig. 2.11  Midline frontoethmoidal cephalocele. 3D CT reconstructions (a, b) showing a midline defect (arrow) and a nasal mass (arrow). Coronal T2 W MRI (c) showing brain and CSF herniating through the cribriform plate (arrows)

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S. Palasamudram and M. Shroff

They are treated by surgical resection. MRI is the imaging of choice and they appear isointense relative to normal brain.

Vascular Anomalies Vascular anomalies of the head and neck region constitute approximately 60% of vascular anomalies diagnosed in children and affect approximately 1 in 22 children [32]. These lesions broadly fall into two categoriesvascular tumors and vascular malformationsand both have physical and psychological implications for both the patient and their family, particularly if visibly disfiguring. Imaging with ultrasound (US) and/or magnetic resonance imaging (MRI) offers exquisite soft tissue detail with delineation of blood vessel architecture and flow patterns. For a diverse group of lesions presenting in complex anatomical locations, a multidisciplinary approach is essential with ­representation from specialists in pediatrics, dermatology, plastic surgery, orthopedic, and craniofacial surgery, otorhinolaryngology, oncology, neurosurgery, interventional radiology, and neuro-radiology, as well as supportive input from psychology, physiotherapy, and occupational therapy when needed. Treatment strategies for vascular malformations include conservative management, drug treatment, minimally invasive interventions by interventional radiology, laser therapy and open surgery. A combination of these therapies is often required [32]. a

b

Hemangiomas and vascular malformations are endothelial disorders divided into two pathological groups: vascular tumors (including hemangiomas) and vascular malformations as mentioned below. They were initially categorized in this way by Mulliken and Glowacki in 1982, based on the natural history, histology, and cellular activity of these lesions [33]. Currently, the ISSVA classification is used [34]. Vascular tumors are composed of rapidly proliferating cells and incomplete blood vessels. Infantile hemangioma (IH) (Fig. 2.14) constitutes to the large majority of the lesions in the vascular tumors category. There is spontaneous involution noted in these lesions (Fig. 2.15). Vascular malformations on the other hand are present at birth and grow proportionately with the child. They are composed of dysplastic arterial, venous, and/or lymphatic vessels. Unlike IH, spontaneous involution does not occur. They are further categorized according to the predominant vessel type and are further classified as “high-flow” and “low-flow” lesions, as mentioned below. Lesions that demonstrate arteriovenous shunting such as arteriovenous malformations (AVMs) and arteriovenous fistulae (AVF) are described as high flow, whereas venous malformations (VMs) (Fig.  2.16), lymphatic malformations (LMs), or combined lympho-­ venous/veno-lymphatic malformations (VLMs) (Fig. 2.17), together with CMs are labeled as low flow lesions. ISSVA classification [34] for vascular anomalies c

Fig. 2.13  Infantile hemangioma. Axial T2, T1, and postcontrast T1 W images (a, b, and c) showing an intensely enhancing mass in the right parotid space with flow voids (arrows)

2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases Vascular tumors Benign  • Infantile hemangioma/Hemangioma of infancy  •  Congenital hemangioma  •  Rapidly involuting (RICH)  •  Noninvoluting (NICH)  •  Partially involuting (PICH)  •  Tufted angioma  •  Spindle-cell hemangioma  •  Epithelioid hemangioma  • Pyogenic granuloma (also known as lobular capillary hemangioma) Locally aggressive  • Kaposiform hemangioendothelioma  •  Retiform hemangioendothelioma  • Papillary intralymphatic angioendothelioma (PILA), Dabska tumor  •  Composite hemangioendothelioma  • Pseudomyogenic Hemangioendothelioma  • Polymorphous hemangioendothelioma  • Hemangioendothelioma not otherwise specified  •  Kaposi sarcoma

Vascular malformations Simple Combined

 • Capillary malformations  • Lymphatic malformations  • Venous malformations  • Arteriovenous malformations  • Arteriovenous fistula

Capillary-venous malformation, capillary lymphatic malformation, capillary-­ arteriovenous malformation, lymphatic-venous malformation, capillary-lymphatic-­ venous malformation, capillary-lymphatic-­ arteriovenous malformation, capillary-venous-­ arteriovenous malformation

25

Of major named vessels

Associated with other anomalies

Affect: Lymphatics, veins, arteries Anomalies of:  •  Origin  •  Course  •  Number  •  Length  • Diameter (aplasia, hypoplasia, stenosis, ectasia/aneurysm)  •  Valves  •  Communication (AVF)  • Persistence (of embryonal vessel)

Klippel-­Trenaunay syndrome, Parkes Weber syndrome, Servelle–Martorell syndrome, Sturge–Weber syndrome, Maffucci syndrome, CLOVES syndrome, Proteus syndrome, CLAPO syndrome

Malignant  •  Angiosarcoma  •  Epithelioid hemangioendothelioma

Fig. 2.14  Infantile hemangioma. Axial T1  W MRI showing fatty replacement of stroma within the lesion (arrow) located in right parotid space

Fig. 2.15  Cervico facial venous malformation. Contrast-enhanced CT showing an enhancing mass on the left side of the neck with phleboliths (arrows) within the lesion

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S. Palasamudram and M. Shroff

Branchial Cleft Cysts Branchial anomalies are the commonest embryological anomalies of the head and neck in pediatric population. They can present in the form of sinuses, fistulae, and cysts. The clinical history and symptoms help in raising a suspicion of branchial cleft cysts. The commonly used imaging modalities are computed tomography, magnetic resonance imaging, ultrasonography, and fine-needle aspiration [35]. The mainstay of management is usually by surgical excision. They are subdivided depending on their embryological origin First Branchial Cleft Cysts [35] Their occurrence is uncommon and comprise only 7% of all recorded cases of branchial cysts. On examination, it appears as a round or oval cystic mass, which can be located either within, superficial, or deep to the parotid gland or along the external auditory canal. It is a possible differential for cystic lesions observed in the parotid or peri-parotid regions. These cysts are further classified as: Fig. 2.16  Craniofacial venolymphatic malformation. Coronal T2W MRI showing a large lesion with fluid-levels (arrow) involving the left side of the face and neck in a neonate

a

• Type 1: These are located close to the external auditory meatus. In a large number of cases, they are present infe-

b

Fig. 2.17  Type 2 branchial cleft cyst. Axial T1, coronal T2 W MR images (a and b) showing a cystic lesion (arrow) deep to the sternocleidomastoid and lateral to the carotid space

2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases

rior and posterior to the tragus. However, they can also be present in the parotid gland or at the angle of the mandible. • Type 2: These correspond to the submandibular gland and are found in the anterior triangle of the neck. They open into the external auditory canal. Treatment is by surgery and surgical method is unique for every case of this anomaly in keeping with the integrity and patency of the tract for complete excision. Second Branchial Cleft Cysts [35] This subtype of branchial cleft cysts makes up approximately 95% of all branchial anomalies. These are further classified into four subtypes, as follows: • Type 1: Situated anterior to the sternocleidomastoid, just deep to the platysma. • Type 2: The most common variant of the four subtypes, found deep to the sternocleidomastoid, lateral to the carotid space (Fig. 2.18). • Type 3: These extend medially between the bifurcation of internal and external carotid arteries up to the lateral pharyngeal wall. • Type 4: Located in the pharyngeal mucosal space, medial to the carotid sheath.

27

In the case of fistula or sinus, the internal opening may be found in the region of the palatine tonsillar fossa. The external opening here is along the intersection of the middle and distal portions of the anterior border of the sternocleidomastoid. There is a possibility of secondary infection (Fig. 2.19); hence, the preferred management strategy is surgical excision. It is normally delayed until the age of two to three years. In cases of isolated type 4 second branchial cleft cyst, an intraoral approach can be considered. Third Branchial Cleft Cysts [35] Third branchial cleft cysts are rare in occurrence. However, they have been found to be the second most common congenital lesions of the posterior cervical area after thyroglossal cysts. They are often located deep to the sternocleidomastoid. They are found to be more commonly situated on the left side. Management is by surgical excision. Visualization of the pyriform sinus is necessary before surgery, and the preferred approach is along the sternocleidomastoid muscle. Fourth Branchial Cleft Cysts [33] Fourth branchial cleft cysts are very rarely prevalent and comprise 1−4% of all branchial cleft anomalies. These are common on the left side and are situated in the thyroid gland and mediastinum. These occur in early childhood, frequently after a recurrent abscess or a preceding thyroiditis (which can be superimposed, acute, and suppurative). Due to their rare occurrence, there are no precise established procedures outlined for their management. The definitive treatment is surgical excision combined with partial thyroidectomy.

Trauma

Fig. 2.18  Infected Type 2 branchial cleft cyst. Postcontrast CT shows rim enhancing cystic lesion (arrow) on the right side, lateral to carotid space

Carotid artery dissection (CAD) and vertebral artery dissection (VAD) are uncommon but in children, traumatic dissections that appear to be more common than nontraumatic dissections. The incidence of traumatic dissection for carotid and vertebral artery is 0.08–0.4% of the entire trauma population [36]. These are underdiagnosed because of the lack of early warning symptoms, and traumatic pseudoaneurysms may be misdiagnosed as saccular aneurysms, or vasospasm following subarachnoid hemorrhage. CAD can lead to thrombosis and occlusion of the vessel [36] and is one of the major causes of stroke in children. The most common mechanism in traumatic CADs is direct blows to the neck/head or hyperextension. Motor vehicle accidents, sporting events, fights, and falls can cause arterial d­ issections. Although angiogram continues to be the gold standard for diagnosis, CTA is equally popular, as their specificity and sensitivity is approaching that of cerebral angiograms (Fig. 2.20). Because of its invasive nature and the radiation

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S. Palasamudram and M. Shroff

a

b

Fig. 2.19  Pseudoaneurysm of right ICA secondary to trauma in a 4-year-old boy who was stabbed with a pencil in the right side of the neck. Axial and sagittal CT angiography (a and b) showing mild irregu-

a

b

larity of the right ICA (arrow) with a small pseudoaneurysm in the same location on sagittal CTA image (arrow)

c

Fig. 2.20 Juvenile nasopharyngeal angiofibroma (JNA). Axial contrast-­enhanced CT (a), axial contrast-enhanced MRI (b), and catheter angiography (c) show an avidly enhancing lesion (arrow) in the left

pterygopalatine fossa that extends to posterolateral wall of the nasal cavity with an intense tumor blush (arrows) on angiography

concerns, angiography and CTA are commonly avoided in children, and instead, MRA is often performed [36]. Treatment is directed to limit the propagation of thrombus formation and reducing embolization and occlusion, while the dissection is being endothelialized over time [36]. There

is still debate on which treatment option should be employed. Some authors suggest surgical therapy [37] and endovascular treatment [38], whereas others have recommended conservative options such as close observation in asymptomatic patients.

2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases

29

Benign Neoplasms

including lymphoma is believed to be multifactorial, related to both immunosuppressive therapy and ongoing antigenic Figure 2.21 stimulation. Infectious agents that are associated with NHL include: human immunodeficiency virus, EBV, human T-cell lymphotropic virus-1, human herpesvirus 8, Helicobacter Malignant Neoplasms pylori, and Chlamydia psittaci [39]. On CT, the involved nodal tissue does not enhance as Lymphoma (approximately 50% of cases) and rhabdomyo- avidly as infectious lymphadenitis, and stranding of the sursarcoma (approximately 20% of cases) constitute for the rounding fat is usually absent. On MRI, lymphomatous majority of malignant pediatric head and neck tumors [39]. involvement tends to produce enlargement of lymphoid tisThyroid, nasopharyngeal, and salivary gland carcinomas are sue that is homogeneous and of lower signal intensity than the most frequently noted pediatric head and neck carcino- reactive adenopathy. There is again variable enhancement mas [39]. that is less marked than reactive adenopathy. Whole-body Lymphoma is the most common head and neck malig- imaging can be performed using nuclear medicine imaging nancy in children. Hodgkin lymphoma (HL) is primarily with F-18 FDG PET for diagnosis, staging, and follow-up of seen in early adolescence and is more common than non-­ disease [37]. Hodgkin lymphoma (NHL), which occurs throughout childRhabdomyosarcoma (RMS) is the most common soft-­ hood. HL presents as nodal disease with a firm, nontender tissue sarcoma and the second most frequent head and neck unilateral neck mass, or less commonly bilateral neck malignancy after lymphoma. Approximately 36% of cases of masses, with disease involving contiguous lymph nodes. RMS occur in the head and neck [39]. The disease has a Associated mediastinal involvement may be seen in approxi- bimodal distribution with one peak occurring during the first mately 40% of HL patients, and 80% of patients with cervi- decade of life and the second peak during adolescence. The cal HL have disease outside of the head and neck [39]. common anatomic locations for RMS are the masticator NHL, on the other hand, presents as painless unilateral space and orbit (Fig. 2.22). RMS is typically an aggressive adenopathy. Approximately 30% of cases present with extra neoplasm that erodes bone. Imaging of RMS shows a soft-­ nodal disease in the head and neck and about 70% of patients tissue tumor, commonly with lytic bone destruction or occahave disease outside of the head and neck (65). Extra nodal sionally bony remodeling. The tumor is usually NHL disease could involve the lymphoid tissue of the heterogeneous, at times necrotic, and has relatively well-­ Waldeyer ring, or the Sino nasal, thyroid, or orbital regions. circumscribed borders. On contrast-enhanced CT or MRI, Histological subtypes of NHL in children include Burkitt there is variable tumor enhancement noted. The signal intenlymphoma, lymphoblastic lymphoma, diffuse large B-cell sity of tumors on T2-weighted images is variable but usually lymphoma, and anaplastic large cell lymphoma. relatively iso to hypointense compared with brain reflecting Increased incidence of NHL is noted in children with the cellular nature of the tumor. When it involves the orbit it hereditary immunodeficiencies. In immunosuppressed chil- may resemble a hemangioma on imaging. However, dren, the development of lymphoproliferative disorders restricted diffusion on MRI due to hypercellularity favors a

a

b

Fig. 2.21  Rhabdomyosarcoma. Axial T2 W MRI, diffusion (DW) and pparent diffusion coefficient (ADC) MR images (a, b, and c) showing a mass in the superomedial location of right orbit (arrow). There is

c

restricted diffusion within the lesion on diffusion (arrow) and ADC images (arrow)

30

malignant lesion. Hemangiomas are benign lesions and do not show restricted diffusion on diffusion weighted MRI. Coronal contrast-enhanced fat-suppressed T1-weighted images are useful for detecting a parameningeal tumor. An assessment of the cervical lymph node chain is performed to detect metastatic adenopathy. Treatment of RMS constitutes surgery, radiation, and chemotherapy. The most frequently occurring carcinomas of the head and neck are thyroid carcinoma and nasopharyngeal carcinoma (NPC) [39]. Thyroid carcinoma manifests as a thyroid mass with or without cervical adenopathy. The most common histological subtype is papillary carcinoma. NPC occurs in adolescents with presenting symptoms of nasopharyngeal mass, cervical lymphadenopathy, unilateral otitis media, rhinorrhea, and nasal obstruction. On imaging NPC is visualized as a nasopharyngeal mass with cervical lymphadenopathy and aggressive characteristics including bony destruction of the paranasal sinuses and central skull base and intracranial extension. Nuclear protein of the testis (NUT) midline carcinoma is a rare, aggressive, and fatal carcinoma that most commonly occurs in the midline of the body, which includes the head, neck, and mediastinum. It is a rare subtype of squamous cell carcinoma and is characterized by undifferentiated morphological features immunoreactive to NUT and defined by NUT rearrangement. There is a unique chromosomal rearrangement involving the NUT gene on chromosome 15 [39]. This cytogenetic abnormality is a harbinger of a poor prognosis and generally death occurs in months due to metastatic disease in spite of aggressive treatment. In the head and neck location, these tumors involve the Sino nasal region, the epiglottis or larynx. The low signal intensity on T2-weighted MR images is consistent with a cellular neoplasm; however, imaging findings are otherwise indistinguishable from other high-grade neoplasms such as lymphoma or sarcoma that are also associated with aggressive bone destruction and metastatic adenopathy. Carcinoma involving the salivary glands is commonly mucoepidermoid in nature [39]. These tumors can be difficult to distinguish based on imaging characteristics from other parotid tumors, the most common of which is pleomorphic adenoma. The signal and enhancement characteristics of mucoepidermoid carcinoma are variable like the histological grade. Retinoblastoma (RB) is the most common ocular malignancy in children [39]. The peak incidence occurs in first 3 years of life. Children with bilateral RB have a significant predisposition to the development of other tumors like osteogenic sarcoma, both related and unrelated to prior irradiation. Ultrasound and CT findings of RB includes an intraocular calcified mass, sometimes with associated retinal detachment. Usually the globe is normal in size or enlarged, which helps distinguish RB from other calcified lesions such

S. Palasamudram and M. Shroff

as prior infection or retinopathy of prematurity. MRI is reserved for cases of bilateral retinoblastoma for evaluating for suspected extraocular extension and for the development of synchronous or metachronous tumors in the hypothalamic and pineal regions. Children with unilateral RB undergo surgical enucleation. Bilateral RB is treated with a combination of chemotherapy and focal radiotherapy to the globe. Metastatic disease involving the pediatric head and neck commonly involves the bony skeleton with variable involvement of cervical lymph nodes. During the first decade of life, especially in children less than 2 years, neuroblastoma is the most common [39]. Leukemic disease also causes metastases, usually in older patients, and sometimes indistinguishable in imaging appearance. Solitary and multiple facial and calvarial lesions also occur as a manifestation of metastatic disease caused by a wide variety of other tumor types, often sarcomatous, usually in older children [39]. CT demonstrates lytic, permeative bony destruction, spiculated periosteal reaction, and enhancing soft-tissue masses. On MRI, lesions are of relatively low signal on T2-weighted images with moderate to intense enhancement. Neuroblastoma causes diffuse expansion of the diploic space because of marrow involvement [39].

“Do Not Touch” Lesions These are the lesions which mimic tumors or other pathologies on imaging but require no intervention. These include fibromatosis colli and ectopic thymus. Fibromatosis colli is a muscular lesion which is found in newborn children (about 3 weeks after birth). It presents as swelling of sternocleidomastoid muscle, usually associated with torticollis [40]. It is assumed to be caused

Fig. 2.22  Fibromatosis colli. Longitudinal ultrasound of neck showing an enlarged sternocleidomastoid muscle with heterogeneous echotexture

2  Principles and Practice of Radiological Investigations for the Diagnosis of Pediatric Head and Neck Diseases

a

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b

Fig. 2.23  Ectopic thymus. Coronal contrast-enhanced T1-weighted magnetic resonance (MR) image and ultrasound of the neck (a and b) showing a mild enhancing parapharyngeal mass on the left side (arrow),

which is isointense relative to the mediastinal thymus on MRI. This was also confirmed on ultrasound (b) as this mass has same echogenicity as that of mediastinal thymus

by muscle trauma during birth. Ultrasound is the imaging modality of choice and shows swollen, fusiform sternocleidomastoid muscle in the mid portion (Fig.  2.23a), with alteration of the normal structure [40]. It may appear hypo or hyperechoic with one or both heads of the muscle being involved. The swelling usually regresses in a few months. There are various locations and extensions of the thymus described by several studies [41]. Familiarity with these variations is essential in distinguishing thymic tissue from other pathologic masses to minimize unnecessary intervention. The cervical component of the thymus, which is occasionally detected with US, shows distinct hyperechoic foci that resembles a starry sky (Fig. 2.23b). The thymus is very pliable and hence does not cause compression or displacement of the adjacent structures [41]. This finding can be a particularly important part of a real-time sonographic examination because cardiac pulsations and respiratory motions may affect the shape of the thymus. In contrast, solid tumors or diffuse infiltrative processes are less malleable and are more rigid.

4. Khong P, Ringertz H, Donoghue V, Frush D, Rehani M, Applegate K, et  al. ICRP publication 121: radiological protection in paediatric diagnostic and interventional radiology. Ann ICRP. 2013;42(2):1–63. 5. Nagayama Y, Oda S, Nakaura T, Tsuji A, Urata J, Furusawa M, et  al. Radiation dose reduction at pediatric CT: use of low tube voltage and iterative reconstruction. Radiographics. 2018;38(5):1421–40. 6. Dammann F, Bootz F, Cohnen M, Hassfeld S, Tatagiba M, Kösling S. Diagnostic imaging modalities in head and neck disease. Dtsch Arztebl Int. 2014 Jun 9;111(23–24):417–23. 7. Jend HH, Helkenberg G. Über den Wert der konventionellen Schädelaufnahmen nach Kopfverletzungen. RöFo. 1995;162:7–12. 8. Bansal AG, Oudsema R, Masseaux JA, Rosenberg HK.  US of Pediatric Superficial Masses of the Head and Neck. Radiographics. 2018 Jul–Aug;38(4):1239–63. 9. Standen JR, Nogrady MB, Dunbar JS, Goldbloom RB.  The Osmotic Effects of Methylglucamine Diatrizoate (Renografin 60) in Intravenous Urography in Infants. Am J Roentgenol Radium Therapy, Nucl Med. 1965;93:473–9. 10. Morris TWHP, Reece K, Katzberg RW. Tissue fluid shifts during renal arteriography with conventional and low osmolality agents. Investig Radiol. 1983;18:335–40. 11. Vergara M, Seguel S.  Adverse reactions to contrast media in CT: effects of temperature and ionic property. Radiology. 1996;199(8668779):363–6. 12. Davenport MS, Wang CL, Bashir MR, Neville AM, Paulson EK.  Rate of contrast material extravasations and allergiclike reactions: effect of extrinsic warming of low-osmolality iodinated CT contrast material to 37 degrees C.  Radiology. 2012;262(22106356):475–84. 13. Trout AT, Dillman JR, Ellis JH, Cohan RH, Strouse PJ.  Patterns of intravenous contrast material use and corticosteroid premedication in children—a survey of Society of Chairs of Radiology in Children’s Hospitals (SCORCH) member institutions. Pediatr Radiol. 2011;41(21594547):1272–83. 14. Amaral JG, Traubici J, BenDavid G, Reintamm G, Daneman A.  Safety of power injector use in children as measured

References 1. Thukral BB. Problems and preferences in pediatric imaging. Indian J Radiol Imaging. 2015 Oct–Dec;25(4):359–64. 2. Ditchfield M. 3T MRI in paediatrics: Challenges and clinical applications. Eur J Radiol. 2008;68:309–19. 3. Gold JI, Kim SH, Kant AJ, Joseph MH, Rizzo AS. Effectiveness of virtual reality for pediatric pain distraction during I. V placement. Cyberpsychol Behav. 2006 Apr;9(2):207–12.

32 by incidence of extravasation. AJR Am J Roentgenol. 2006;187(16861567):580–3. 15. Wang CLCR, Ellis JH, Adusumilli S, Dunnick NR.  Frequency, management, and outcome of extravasation of nonionic iodinated contrast medium in 69,657 intravenous injections. Radiology. 2007;243:80–7. 16. Cohen MD, Herman E, Herron D, White SJ, Smith JA. Comparison of intravenous contrast agents for CT studies in children. Acta Radiol. 1992;33(1449887):592–5. 17. Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K.  Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology. 1990;175(2343107):621–8. 18. Dillman JR, Strouse PJ, Ellis JH, Cohan RH, Jan SC.  Incidence and severity of acute allergic-like reactions to i.v. nonionic iodinated contrast material in children. AJR Am J Roentgenol. 2007;188(17515388):1643–7. 19. Wang CL, Cohan RH, Ellis JH, Caoili EM, Wang G, Francis IR. Frequency, outcome, and appropriateness of treatment of nonionic iodinated contrast media reactions. AJR Am J Roentgenol. 2008;191(18647910):409–15. 20. Callahan MJPL, Zurakowski D, Taylor GA.  Nonionic iodinated intravenous contrast material-related reactions: incidence in large urban children’s hospital—retrospective analysis of data in 12,494 patients. Radiology. 2009;250:674–81. 21. Fjelldal ANT, Eriksson J. Experiences with iohexol (Omnipaque) at urography. Pediatr Radiol. 1987;17:491–2. 22. Dillman JR, Ellis JH, Cohan RH, Strouse PJ, Jan SC.  Frequency and severity of acute allergic-like reactions to gadolinium- containing i.v. contrast media in children and adults. AJR Am J Roentgenol. 2007;189(18029897):1533–8. 23. Davenport MS, Dillman JR, Cohan RH, et  al. Effect of abrupt substitution of gadobenate dimeglumine for gadopentetate dimeglumine on rate of allergic-like reactions. Radiology. 2013;266(23238152):773–82. 24. Sanchez-Ross MSR, Colome-Grimmer MI, Blumberg M, Huttenbach Y.  Raimer S2007. Nephrogenic fibrosing dermopathy in a patient with systemic lupus erythematosus and acute lupus nephriti. Pediatr Dermatol. 2007;24:E36–9. 25. Thomsen HS.  How to avoid nephrogenic systemic fibrosis: current guidelines in Europe and the United States. Radiol Clin N Am. 2009;47(5):871–5. vii 26. McAlister WH, Siegel MJ. Fatal aspirations in infancy during gastrointestinal series. Pediatr Radiol. 1984;14(2):81–3. 27. Holowka S, Shroff M, Chavhan GB. Use and safety of gadolinium based contrast agents in pediatric MR imaging. Indian J Pediatr.

S. Palasamudram and M. Shroff 2019 Feb 22; https://doi.org/10.1007/s12098-­019-­02891-­x. [Epub ahead of print] 28. Belden CJ, Mancuso AA, Kotzur IM. The developing anterior skull base: CT appearance from birth to 2 years of age. AJNR Am J Neuroradiol. 1997 May;18(5):811–8. 29. Capps EF, Kinsella JJ, Gupta M, Bhatki AM, Opatowsky MJ. Emergency imaging assessment of acute, nontraumatic conditions of the head and neck. Radiographics. 2010;30(5):1335–52. 30. Dutta M, Saha J, Biswas G, Chattopadhyay S, Sen I, Sinha R.  Epidermoid cysts in head and neck: our experiences, with review of literature. Indian J Otolaryngol Head Neck Surg. 2013 Jul;65(Supp 1):14–21. 31. Morón FE, Morriss MC, Jones JJ, Hunter JV.  Lumps and bumps on the head in children: use of CT and MR imaging in solving the clinical diagnostic dilemma. Radiographics. 2004 Nov–Dec;24(6):1655–74. 32. Mahady K, Thust S, Berkeley R, et  al. Vascular anomalies of the head and neck in children. Quant Imaging Med Surg. 2015;5(6):886–97. 33. Mulliken JB, Glowacki J.  Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69:412–22. 34. ISSVA Classification of Vascular Anomalies ©2018 International Society for the Study of Vascular Anomalies. Available at “issva. org/classification”. Accessed July 2019. 35. Bagchi A, Hira P, Mittal K, Priyamvara A, Dey AK. Branchial cleft cysts: a pictorial review. Pol J Radiol. 2018;83:e204–9. 36. Mortazavi MM, Verma K, Tubbs RS, Harrigan M. Pediatric traumatic carotid, vertebral and cerebral artery dissections: a review. Childs Nerv Syst. 2011 Dec;27(12):2045–56. 37. Hardin CA, Snodgrass RG.  Dissecting aneurysm of the inter nal carotid artery treated by fenestration and graft. Surgery. 1964;55:207–9. 38. Ramgren B, Cronqvist M, Romner B, Brandt L, Holtås S, Larsson EM. Vertebrobasilar dissection with subarachnoid hemorrhage: a retrospective study of 29 patients. Neuroradiology. 2005;47:97–104. 39. Robson CD.  Imaging of head and neck neoplasms in children. Pediatr Radiol. 2010 April;40(4):499–509. 40. Smiti S, Kulkarni NM, Singh J. Case Report: Fibromatosis colli in a neonate. Indian J Radiol Imaging. 2010;20(1):45–6. 41. Nasseri F, Eftekhari F.  Clinical and radiologic review of the normal and abnormal thymus: pearls and pitfalls. Radiographics. 2010;30(2):413–28.

3

Principles and Practice of Surgical Pathology for the Diagnosis of Pediatric Head and Neck Diseases Bo-Yee Ngan

The most frequent tissue samples submitted to the Pediatric Surgical Pathology Laboratory for analyses and diagnosis are associated with three major categories of diseases: abnormal tissue growths or lesions that may or may not be neoplastic, inflamed or infectious disease tissues, and tissues removed from surgical correction of developmental anomalies or inflammatory conditions. Light microscopy analysis of tissues (Histopathology) currently is the method of choice for routine diagnosis of surgical biopsies or excisions. For the diagnosis of complex diseases such as infections or neoplasms, microscopic evaluation is also an important initiating step to be followed with one or several adjunct analytical procedures (such as cytogenetic, flow cytometry, immunohistochemistry, and molecular testing) that may be necessary to establish an accurate diagnosis. To ensure an efficient time-line in making a final diagnosis for patient treatment and management, surgical pathology laboratories adopt standardized guidelines to implement the essential procedures to process the tissues submitted for examination, followed by the types of analysis according to the hospital environment (primary care centers versus academic health science centers) and the type(s) of information to be incorporated in the pathology report. Both principles and practice of these procedures are explained in this chapter.

 ractical Guides for the Submission P of Tissues to the Pathology Laboratory An appropriate tissue preparation is crucial in rendering the particular type of diagnostic testing. This is important to know and to plan ahead of any procurement of disease tissues to be sent to the pathology laboratory. This is of particular importance regardless of whether the tissue is submitted B.-Y. Ngan (*)

Division of Pathology, Paediatric Laboratory, Hospital for Sick Children Division of Pathology, Toronto, ON, Canada e-mail: [email protected]

to pathology laboratory as a biopsy with a diagnostic intent or after performing surgical excision with both a diagnostic and a curative intent. Tissue biopsy for diagnosis of complex diseases, for example, neoplasms that require microscopic analysis followed by the appropriate adjunct diagnostic procedures, requires fresh tissues without fixation additives. For these samples, they must be submitted fresh. To prevent dehydration, the tissue wedges or cores should be wrapped gently with sterile physiological saline-soaked gauze or small amounts of sterile tissue culture fluids in an airtight container and delivered to the pathology laboratory. If the lesion requires microbiology or virology analyses, a separate sample should be obtained in the operation room under a sterile surgical field and submitted fresh to the microbiology/virology laboratory. For surgical resections of the mass lesion, the surfaces of the tissue mass should be left intact. Appropriate marking sutures should be placed by the surgery team to denote the anatomical orientation of the tissue excised. In addition, if a particular region contains an important resection margin to be analyzed, this region should also be identified with a marking suture. If these tissues do not require complex analyses, formalin fixative can be added into the tissue container and then send to the pathology laboratory. If an intra-­ operative diagnosis is needed to guide surgical management with regards to the adequacy or completion of tumor resection, a fresh sample of the resection margin can be submitted to the pathology laboratory for a frozen section analysis. For malformations (non-syndromic types), corrective surgeries for developmental anomalies, simple cysts, granulation tissues, nevi, tragus, and localized tissue growths associated with hyperplasia where malignancy is not clinically suspected or tissue debridement where microbiological cultures are not required, these resected tissues should be deposited in toto in formalin fixative, and send to the ­pathology laboratory for further analyses. For tissues that are submitted from patients with infectious agent, pathology laboratory should be informed of

© Springer Nature Switzerland AG 2021 P. Campisi et al. (eds.), Pediatric Head and Neck Textbook, https://doi.org/10.1007/978-3-030-59265-3_3

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their biohazard potentials. Appropriate labels should be attached to the specimen container. For fine-needle aspirate samples, these should be fixed in cytolyte fixative (alcohol-based) and for aspirates of crystalline material, these aspirates should be fixed in alcohol (100% ethanol). For skin biopsies where bullous diseases of autoimmune diseases are suspected, an additional fresh piece should be submitted to be frozen for immunofluorescence stains. For samples that electron microscopy is needed, tissues should be fixed rapidly in glutaraldehyde/cacodylate buffer and stored cold (+4C). The pathology laboratory will further divide the tissue into small pieces.

 valuation Procedures and Methods Used E in the Pathology Laboratory Tissue Examination Upon arrival of surgical resection tissues/tissue masses in the pathology laboratory, the specimen must be weighed and recorded. The external dimensions must be taken and recorded. If a tissue mass is visible, dimensions of the lesion in these aspects: superior/inferior distance; anterior/posterior distance; and medial/lateral distance should be taken and recorded. Photo-documentation: Surgical resections/excisions that involve an organ or part of an organ should be photographed always with a coded identifier and a measuring scale. The specimen should be laid out reflecting the anatomical position of the patient capturing the coronal or sagittal plane. Thereafter, the external surfaces of the tissue should be painted with special ink/dyes that are resistant to tissue processing fluids during the subsequent paraffin embedding and tissue sectioning procedures for microscopy. Ideally, multiple ink colors are used to mark the orientation of the tissue; for example, using different colors for the superior or inferior poles, the anterior/posterior surfaces, and the medial and lateral surfaces. The ink can be immobilized with exposure to a fixative of formalacetic acid alcohol (a mixture of 25 ml formalin that contains 37% formaldehyde, 25 ml of glacial acetic acid, and 450 ml of alcohol). Pending on the type of organ resected, and ideally, the specimen is cut open along the coronal, or sagittal or anterior/posterior plane or along the midline only, to allow the best visualization of the relationship of the

B.-Y. Ngan

lesion within the organ to its nearest resection margin for photo documentation. Note that for thyroidectomies where preservation of the capsule are required, they should not be cut open in the fresh state and opening the specimen by cutting should be delayed until after formalin fixation. Similarly, for enucleated tumor masses that have a thin veil surface covering, opening of the specimen may best be delayed until it has been hardened after formalin fixation. For small biopsies other than core tissue biopsies, frequently such as those from the skin or a small single piece of nodular mass, marking the resection surface with surgical ink is mandatory. For tumor lesions that are not visible until the specimen is cut open, dimensions of the lesion(s) similar to those visible externally must be taken. At least two photos should be taken (with calibrated scale placed adjacent to the lesion) where one of them will be used to provide a tissue sampling blocking template to aid in the completion of a documentation of the locations of where tissue samples have been taken later for paraffin block embedding for microscopy. In addition, the distance between the edge of the lesion to its nearest resection margin or any other surface margins must be taken and recorded. For small tissue specimens such as oral odontogenic specimens that are submitted with cystic tissues and teeth, photo documentation is also important. After formalin fixation, all calcified tissues need to have the minerals removed (solutions containing dilutions of glacial acetic acid or EDTA) prior to sectioning.

General Guidelines for Tissue Sampling For all practical purposes, all tissue requires fixation in buffered formalin (10% phosphate-buffered formalin contains a final concentration of 4% formaldehyde) for at least 24 h. For larger tissues, they will require longer fixation time. Large tissue sample may need to be sectioned serially into 1 cm thick slices to ensure adequate penetration of the formalin fixative. For the subsequent sampling of the tissue, 1 tissue block per 1 cm of tumor size that is representative of the abnormal gross appearance of the tissue is the routine recommendation. However, if the tumor exhibits unusual and unexpected appearances on gross examination, sampling in additional tissue blocks is recommended. The standard t­issue cassettes size accommodates a maximum 3  ×  2.5  ×  0.4  cm piece of tissue sample.

3  Principles and Practice of Surgical Pathology for the Diagnosis of Pediatric Head and Neck Diseases

 pecific Guidelines for Tissue Sampling S and Analytical Procedures for Neoplastic Surgical Specimens Pediatric Head and Neck Neoplasms Introduction Pediatric Head and Neck malignancies unlike those in the adults are rare. A brief world-wide literature search was performed on the surveillance of Pediatric Head and Neck malignancy published after 2013. Qaisi M. and Eid I. from the United States in 2016 reported that pediatric H&N malignancies represent 12% of all pediatric malignancies and have an incidence of 1.49 cases per 1 million person-years [1]. They reported that the most common types are lymphoma (27%), neurotumors, including primitive neuroectoderm tumors (23%), thyroid malignancies (21%), and sarcomas (including rhabdomyosarcoma) (12%). Less common are nasopharyngeal carcinomas, skeletal/bone, and odontogenic malignancies, including osteosarcoma, Ewing, Langerhans histiocytosis, and ameloblastic carcinoma [1]. Another review published in 2018 from Brazil reported that pediatric H&N malignancies represent 5.1% of all of the 7181 pediatric cancers (registered between 1986 and 2016) and the mean age of diagnosis was 9.35  years [2]. Burkitt lymphoma (16.62%), nodular sclerosis Hodgkin lymphoma (13.08%), nasopharyngeal carcinoma (12.81%), and rhabdomyosarcoma (12.81%) were observed [2].

 ead and Neck Epithelial Neoplasms H Carcinomas in children and adolescents in the head and neck region are rare. In the largest review of pediatric H&N non-­ nasopharyngeal squamous cell carcinomas, 159 patients we registered between 2004 and 2013 in the US National Cancer Database [3]. 6% of these patients were 0–4 years old, 9% were 5–10 years old, 22% were 11–15 years old, and 63% were 16–19 years old [3]. 55% involved the oral cavity, 14% in the larynx, 13% in the nasal cavity, 17% in the salivary gland, and 10% in the oropharynx. The most common stage group was Stage IV (33%). 72% were without HPV data status. 16% were unknown. 7% were registered as negative, 1% was positive for low-risk type, and 4% were of high-risk type. A National study from Denmark (1980–2014) reported 32 pediatric patients with H&N squamous cell carcinomas [4]. The most common location was in the oral cavity, accounting for 43%. None of their laryngeal carcinomas occurred in the age group between 0 and 17 years. All six cases of laryngeal carcinomas were 18–24 years old [4]. This review also pointed out that when pediatric H&N squamous cell carcinoma was observed, there was an association to predisposing factors such as DNA repair defects (Fanconi anemia, Bloom syndrome), prior irradiation of H&N among cancer survivors, oral graft versus host disease, or oncogenic

35

viral infections (such as EBV in nasopharyngeal carcinomas). Sporadic case reports of rare pediatric H&N carcinomas in the current literature included a case of HPV+ve laryngeal carcinoma in a Fanconi anemia patient with additional NOTCH 1 mutation [5]; extremely rare sites such as the thyroglossal duct cyst [6, 7]; vocal cord [8]; lip [9]; branchial cleft cyst [10]; external auditory canal [11], and a large cell neuroendocrine carcinoma of the nasopharynx in a 9-year-old child [12]. Newly recognized highly aggressive malignant carcinoma such as NUT carcinoma of the facial midline [13–15] and mammary analog secretory carcinomas of the salivary gland [16] also emerged from the recent clinical and pathology literature. As surgical resections are essential of the treatment for many of these conditions, even for their rarity, pediatric pathologist will encounter resections for examination and tissue evaluations, a discussion on specific examination protocols for cancer staging in this section is warranted. Lymph nodes for staging of H&N neoplasms are methodically examined and if they appear abnormal, they are excised and identified to the pathology laboratory according to the origin of their anatomical domain. The identifier comprises the uniform denotation terminology of Level I to VII, modified from the contents of Tables 5.1 and 5.2 AJCC [17]; also see Fig 3.1, from Fig 5.1, Chap. 5 AJCC [17]. Level I is further

Fig. 3.1  Diagram indicating the location of lymph nodes in the neck. Used with permission of AJCC Cancer Staging Manual. 8th Edition, 2017. Amin MB.  Editor in chief. Springer; Springer International Publishing, AG Switzerland

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divided into Level Ia and Level I b. The anatomical boundaries of Level Ia are: Superior: Symphysis of the mandible; Inferior: Body of the hyoid; Anterior/medial: Anterior belly of the contra-lateral digastric muscle; Posterior/lateral: Anterior belly of the ipsilateral digastric muscle. Lymph nodes in this region are at risk of metastases from cancers arising from the floor of the mouth, anterior oral tongue, anterior mandibular alveolar ridge, and lower lip. For Level Ib, the anatomical boundaries are: Superior: Body of the mandible; Inferior: Posterior belly of the digastric muscle; Anterior/mandible: Anterior belly of the digastric muscle; Posterior/lateral: Stylohyoid muscle. The submandibular gland is usually removed with the lymph nodes within this triangle. Lymph nodes in this region are at risk of metastases from cancers arising from the oral cavity, anterior nasal cavity, skin and soft tissue structures of the midface, and the submandibular gland. Level II is also further subdivided into IIa and IIb. The anatomical boundaries of Level IIa are: Superior: Skull base; Inferior: Horizontal plane defined by the Inferior border of the hyoid bone; Anterior/medial: Stylohyoid muscle and Posterior: Vertical plane defined by the spinal accessory nerve. The anatomical boundaries of Level IIb are: Superior: Skull base; Inferior: Horizontal plane defined by the Inferior body of the hyoid bone; Anterior/medial: Vertical plane defined by the Spinal accessory nerve; and Posterior/lateral: Lateral border of the Sternocleidomastoid muscle. Lymph nodes in this region are at risk of metastases from cancers arising from the oral cavity, nasal cavity, nasopharynx, oropharynx, larynx, and parotid gland. The anatomical boundaries of Level III are: Superior: Horizontal plane defined by the inferior body of the hyoid; Inferior: Horizontal plane defined by the inferior border of the cricoid cartilage; Anterior/medial: Lateral border of the sternohyoid muscle; Posterior/lateral: Lateral body of the sternocleidomastoid or sensory branches of the cervical plexus. Lymph nodes in this region are at risk of metastases from cancers arising from the oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx. The anatomical boundaries of Level IV are: Superior: Horizontal plane defined by the inferior border of the cricoid cartilage; Inferior: Clavicle; Anterior/medial: Lateral border of the sternohyoid muscle; Posterior/lateral: Lateral border of the sternocleidomastoid or sensory branches of the cervical plexus. Lymph nodes in this region are at risk of metastases from cancers arising from the hypopharynx, thyroid, cervical esophagus, and larynx. Level V is further divided into Va and Vb. The anatomical boundaries of Level Va are: Apex of the convergence of the sternocleidomastoid muscle and trapezius muscles; Inferior: Horizontal plane defined by the lower border of the cricoid cartilage; Anterior/medial: Posterior border of the sternocleidomastoid muscle or sensory branches of the cervical plexus; Posterior/lateral: Anterior border of the trapezius muscle. The anatomical boundaries

B.-Y. Ngan

of Level Vb are: Horizontal plane of the lower border of the cricoid cartilage; Inferior: Clavicle; Anterior/medial: Posterior border of the sternocleidomastoid muscle; Posterior/lateral: Anterior border of the trapezius muscle. Lymph nodes in this posterior triangle region are at risk of metastases from cancers arising from the nasopharynx, oropharynx, and cutaneous structures of the posterior scalp and neck. The anatomical boundaries of Level VI are: Superior: Hyoid bone; Inferior Suprasternal notch; Anterior/medial: Common carotid; Posterior/lateral: Common Carotid artery. Lymph nodes in this region are at risk of metastases from cancers arising from the thyroid glands, glottis and subglottic larynx, apex of the piriform sinus, and cervical esophagus. The anatomical boundaries of Level VII are: Superior: Suprasternal notch; Inferior: Innominate artery; Anterior/ medial: Sternum; Posterior/lateral: Trachea, esophagus, and prevertebral fascia. Lymph nodes in this region are at risk of metastases from cancers arising from the thyroid and the esophagus. In addition to the Lymph node groups described above, other lymph node sites pertinent to assessment in H&N neoplasm include sub-occipital, retropharyngeal, para-­ pharyngeal, buccinators (facial), pre-auricular and peri-parotid and intra-parotid. Examination of the resected tissues and lymph nodes is essential to capture the pertinent data that are needed to be entered into the final pathology report to fulfill the TMN categorization of these tumors according to the recommendation of the ACC [17]. The histopathology information is useful to guide post-operative treatment and prognosis of the tumor.

Pediatric Sarcoma Unique to most of the malignant pediatric sarcomas, the neoplastic cells are primitive and display very little light microscopic features indicative of their cell of origin. Under the routine hematoxylin and eosin (H&E) stain of the tissue section, the neoplastic cells characteristically show small hyperchromatic (blue-stained) nuclei with scant amounts of pale eosinophilic cytoplasm. The term “small round blue cell tumors” are frequently used to describe them. Other revealing histopathology features may be the frequency of mitosis, apoptosis, and the abundance of nuclear anaplasia (defined by the presence of tumor cells that have nucleus 4× larger than the adjacent tumor cells with or without abnormal large atypical mitotic figures). Final diagnosis requires utilization of a comprehensive set of adjunct analysis that includes histochemistry, immunohistochemistry, cytogenetics, and molecular analyses [18]. For cytogenetic analyses and ­complex molecular procedures, submission of fresh tumor tissues to the pathology laboratory is required. Use of frozen section analysis currently plays a very minor role in providing a diagnosis.

3  Principles and Practice of Surgical Pathology for the Diagnosis of Pediatric Head and Neck Diseases

 ediatric Lymphoma and Lymphoproliferative P Diseases Microscopic examination of sections of well-fixed lymphoid tissue is an important initial step toward a diagnosis. Similar to pediatric sarcoma, final diagnosis requires extensive analysis with adjunct analytical procedures. They include immunohistochemistry, flow-cytometry, cytogenetics, and molecular analysis [19]. As a result, all lymphoma samples require fresh tissue submitted to the pathology laboratory for adjunct analysis. Use of frozen section analysis currently plays a very minor role in providing a diagnosis.

Adjunct Diagnostic Procedures  nalysis for Abnormal Tissue Components or A Infectious Agents with Histochemistry Histochemistry stains are useful to detect the presence of abnormal tissues matrix (e.g., sulfated proteoglycans; mucin; elastin, collagen, basement membrane proteins or amyloid) deposits of unusual substances extrinsic to the natural environment of normal tissue (e.g., iron, or copper), or unusual accumulation of granules, metabolites within cytoplasm of the abnormal cells (e.g., melanin, glycogen, lysosomes, myeloperoxidase, argentaffin, and argyrophil granules (exclusively for endocrine cells); or cytoplasmic mucin). The menu of histochemistry stains available for the specific detection of these substances is as follows: The most frequent usages are hematoxylin and eosin for all tissue slides; Elastic trichrome to demonstrate elastin fibers and collagen; Movat pentachrome stain for vascular tissues or Snooks reticulin, they can demonstrate elastin fibers and the Movat pentachrome stain also identifies collagen in yellow and cells in red; Periodic acid-Schiff (PAS) and PAS with diastase treatment—PASD to distinguish glycoprotein from glycogen; Oil red O to demonstrate fat/cytoplasmic lipid; Mucicarmine or Alcian Blue(for acid mucin) or Hale stain to demonstrate mucin or proteoglycans (by the latter); and Fontanna-Masson for melanin. Other less common stains are: iron stain, copper stain, Congo red for amyloid, Von Kossa calcium stain; Phospho-tungstic acid hematoxylin (Mallory PTAH) for neuro lesions and muscle differentiation. For hematological cells and tissues, Giemsa for lymphoid/myeloid cell cytology and for granules in mast cells. Toluidine blue for mast cells, Chloroacetate for myeloid leukemia cells in tissues; Wright stain for blood smears. Similarly, a limited numbers of histochemistry are also available to detect microbial pathogens in tissues. These stains include gram stain for bacteria; Grocott-­ methenamine-­silver nitrate (GMS) stain for fungi, Ziehl-­ Neelson (ZN) stain for mycobacteria Warthin Starry stain for Spirocheles or Bartonelle species, Steiner stain for bacteria and spirochetes, Dieterle stain for Spirochetes, and mucicar-

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mine to detect Cryptococcus. Further identification, subtyping, and identifying the antibiotic sensitivities of these pathogens are best analyzed by microbiologist via the further application of culture and or molecular procedures (e.g., polymerase chain reaction (PCR)-mediated DNA amplification techniques). For histological samples, Epstein–Barr virus (EBV) can be detected by in-situ hybridization of the EBV-encoded RNA.  Similarly, in-situ hybridization procedures are applicable to HPV subtyping. Immunostains are available for the detection of cytomegalovirus, adenovirus, herpes virus, or HHV6.

Immunohistochemistry As most of the antibodies from commercial sources now are produced to formalin-treated antigen epitopes, immunohistochemistry stains today can be done on formalin-fixed paraffin-­embedded tissue sections. Application of immunohistological stain is most useful to analyze tumor. For most of the diagnoses made for non-neoplastic tissues, with the exception of lymphoproliferative diseases or some dermopathies, immunohistochemistry may not provide additional diagnostic advantages. When applied to pediatric small round blue cell tumors, it can provide evidence of the histogenic origin of the neoplastic tissue and together with the knowledge of some of their association with unique expression of certain proteins, these primitive neoplasms can be subclassified with accuracy. Based on my experience, with few exceptions, only a few tumors have association with a unique/specific protein expression (e.g., NUT midline carcinomas with expression of nuclear protein of testes) [14]. In a majority of tumor screening analyses, a customized panel of multiple antibodies is required. Listed below are examples of several useful customized panels of antibodies that are useful to screen pediatric tumors in order to group them into a particular tissue tumor domain and to narrow the pathological differential diagnosis. Specific immunopathology details that best define each individual type of pediatric tumor are discussed in their respective chapters. Useful Antibody Panels Customized to Screen Pediatric Soft Tissue Neoplasm and Some Cutaneous Lesions Use of CD99, myogenin, desmin, smooth muscle actin, actin, vimentin, S100, pan-cytokeratin, epithelial membrane antigen, and CD45 in this panel would be a reasonable first start. Pending on the results, a second panel comprising a few selected from some of these antibodies will further narrow the differential diagnosis within the soft tissue tumor, or pediatric small round blue cell tumors: beta-catenin, TLE-1, Bcl2, CD56, CD57, neuron-specific enolase, synaptophysin, neurofilament, CD117, SOX 10 and ALK-1; for malignant bone lesions, SATB2 or CD207, S100 and CD1a for Langerhans cell histiocytosis; for cutaneous lesions, Factor

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XIIIa CD34, CD68, CD163, S100, CD207, SOX 10, Mel A, or HMB45. For vascular lesions, smooth muscle actin, Factor VIII, CD31, CD34, D2-40, and Glut-1 are helpful. For rarer pediatric sarcoma, the additional third panel of antibodies that comprise BAF47, CCNB3, MiTF, or TFE3 may further define a rare/smaller subset of sarcomas such as undifferentiated sarcoma, Ewing sarcoma-like tumors or poorly differentiated synovial sarcoma with BCOR–CCNB3 fusion or alveolar soft part sarcoma respectively, as examples. For further details of immunophenotypes of each type of sarcoma, please see the chapter on sarcoma.

 seful Antibody Panel Customized to Screen U Lymphoid Neoplasm Lymphoma comprises two distinct entities: Hodgkin and non-Hodgkin lymphoma. Both have distinct immunopathological characteristics. Hodgkin lymphoma is associated with the presence of Reed Sternberg cells and a subtype of Hodgkin lymphoma: Nodular lymphocyte predominant Hodgkin lymphoma has atypical lymphohistiocytic cells. The immunostain expression of Reed Sternberg cells are: CD15+, CD30+, CD45-ve, PAX 5 weak +; CD20-ve in a majority of cases; ALK1-ve and T-cell antigen negative in a vast majority of cases. The immunostain panel results for nodular lymphocyte predominant Hodgkin lymphoma are CD30+, CD20+, CD45+, PAX 5 weak +; CD15+/− and T-cell antigen negative. A collarette of PD1+ or CD57+ small lymphocytes surrounding the atypical lymphohistiocytic cells can be present [19]. The nomenclature of Hodgkin lymphoma is currently designated according to the origin of lymphocyte subsets within various domains of the normal lymph node. A large number of lymphocyte markers are needed for the identification of neoplastic cells. Not infrequently, lymph nodes are abnormal in size due to the presence of leukemia cells rather than lymphoma. Application of immunohistochemistry using myeloperoxidase immunostain can be useful to identify the presence of myeloid malignancy. As lymphomas can arise from immature or mature B cells or T cells, the use of TdT immunostains can identify immature lymphomas which show positive nuclear staining. For the initial screening of non-Hodgkin lymphoma (in the absence of leukemia), a panel of B-cell and T-cell-specific antibodies that include CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD20, CD30, CD43, CD45, CD45RO, CD79a, TdT, and ALK1 should be adequate. Detailed association of additional markers with specific lymphoma subtypes can be found in the lymphoma chapter. For the assessment of post-transplant lymphoproliferative disease, detection of EBV by in situ hybridization should be included. For assessment of primary immunodeficiencies, immunohistological assessment of the thymus can be helpful, a panel of antibodies that includes CD1a, CD2, CD3, CD4, CD5, CD7,

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CD8, S100, T-reg (i.e., FOX P3), S100, CD68, pan-­ cytokeratin, and CK8 are important. A portion of fresh thymic tissues should be sent to clinical immunology lab for in vitro lymphocyte functional testing and further testing for the expression of other T-cell functional antigens by flow cytometry. Flow cytometric analysis is performed from cell suspension of the mononuclear cells population retrieved from teasing the fresh lymph node in vitro in the laboratory. The flow cytometer is equipped with cell surface staining with a number of antibodies tagged by fluorescent markers. The staining results are quantitated via a detector. It is rapid and for pediatric hematological neoplasms, it is applicable to detection of leukemia, and B-cell lymphomas. However, for the analyses of Hodgkin lymphoma and T-cell lymphomas, the use of immunohistopathology is more reliable. Useful Antibody Panel Customized to Screen Pediatric Epithelial Neoplasm Pan-cytokeratin, CAM 5.2, vimentin, epithelial membrane antigen, carcinoembryonic antigen (CEA), S100, actin, desmin, and smooth muscle actin  are initially applied. Then according to the histopathological differential diagnosis, additional antibodies are used to guide in determination of  the final diagnosis, as discussed in the following examples. For thyroid tumors inclusion of TTF1, CK5/6, CK7, CK20, 34betaE12, and p63 are useful. Calcitonin to be added for medullary thyroid carcinoma and CK19, calcitonin, p27, chromogranin, synaptophysin, Rb protein for parathyroid tumors. For some salivary gland tumors, addition of CK5/6, CK7, CK20, 34betaE12, and p63 are important. For mammary analogue carcinoma of salivary glands, inclusion of mammaglobin with cytokeratin is important. For immunostains of mediastinal germ cell tumors, a combination of pan-cytokeratin, Sox2, Oct-4, alpha fetoprotein, PLAP, Beta-HCG, and Sall4 will be useful. The results from this antibody panel are not entirely foolproof. For example, sarcoma known as epithelioid sarcoma will express some of these markers. This highlights the importance of not relying completely on the application of immune-histopathology alone for diagnosis. Any final diagnosis cannot be made without the context of pathological information from histopathology as well as other testing results such as cytogenetic and or molecular procedures described in the following paragraphs. Recently, immunostain of some types of pediatric tumors offers an additional role in determining the eligibility of patients to enroll in phase 2 or phase 3 clinical trial of targeted therapy with bio-active small synthetic molecule agents or immune checkpoint blockade modifiers at major academic health science centers. One example in Pediatric

3  Principles and Practice of Surgical Pathology for the Diagnosis of Pediatric Head and Neck Diseases

Pathology is the frequent request to perform BRAF-v600 immunostain of thyroid carcinoma, systemic Langerhans cell histiocytosis (infrequently, for Erdheim-Chester disease, due to its rarity in children and adolescents), and melanoma. Positive immunostain of this BRAF-V600 corresponds to the presence of BRAF gene mutation. In thyroid carcinomas presence of this mutation has been correlated with more aggressive and iodine-resistant phenotypes [20]. In the case studies of Langerhans cell histiocytosis, BRAF activating mutation (50% prevalence) or in frame deletion of its exon 12 (6% prevalence) or somatic MAP 2K1 mutation 20% prevalence) results showed all exhibited a central role in ERK phosphorylation/activation of the MAP-Kinase pathway and currently, clinical response has been reported by the administration of pharmacologically active ERK1/2phosphorylation inhibitors such as vemurafenib, dabrafenib or upon failing this, with PLX8394 and trametinib [21]. Similar example is the use of vemurafenib and cobimetinib for the treatment of metastatic melanoma [22]. Another example of new therapeutic approaches is to target the blockade of the PD1-PDL1 for Hodgkin and non-­ Hodgkin B-cell lymphoma [23]. In such therapeutic trials treatment  with the addition of  PD1 inhibitors (monoclonal antibody to PD1 ligand Nivolumab)  were  evaluated [24]. Immunostain of lymphoma cells using PDL1 plays a vital role in patient selection for these trials.

Cytogenetic Analyses Cytogenetic abnormalities have been observed in a limited number of pediatric conditions. These range from abnormalities associated with some syndromic conditions, to some benign tumors as well as several malignant neoplasms. Examples of abnormal genetic findings found in syndromic conditions are germline mutations in RET, MEN2A, and MEN2B associated with multiple tumors manifesting as medullary carcinoma of the thyroid, or paraganglioma; germline P53 mutations in patients with Li-Fraumeni syndrome that develop soft tissue tumors. NF2 germline mutations in neurofibromas, vestibular schwannoma; alterations/ inactivating mutations in the PTCH1 gene in the odontogenic keratocysts of both syndromic (Gorlin–Goltz/nevoid basal cell carcinoma syndrome) [25, 26] and sporadic odontogenic keratocysts as well as sporadic developmental cysts including dentigerous cysts [27, 28]. Some cytogenetic abnormalities are seen in benign lesions such as dentigerous cysts that exhibit loss of heterozygosity in the PTCH1 gene, USP6 fusions in 50% cases of aneurysmal bone cysts [29], and similar genetic findings in some cases of nodular fasciitis. PLAG gene alteration in lipoblastoma as well as in smaller number of cases of lipomas [30]. In some conditions, the same abnormality can be associated with different diseases. Such examples are the ETV6– NTRK3 fusion in infantile fibrosarcoma [31], mammary

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analogue carcinoma of the salivary gland [32]  or  the presence of USP6 fusions in bone cyst or nodular fasciitis [29]. This non-specificity feature highlights the importance of the necessity of integrating the cytogenetic findings together with other diagnostic parameters. In the analysis of malignant neoplasms, the most benefits of the cytogenetic information are the important role it has in the refinement of diagnosis of pediatric soft tissue tumors and lymphomas, especially in the diagnosis of small round blue cell tumors. In addition, for pediatric rhabdomyosarcoma, not only does the presence of PAX3 or PAX5 gene translocation to FOXO-1(FKHR) associated with t(2;13) (q35;q14) or t(1;13)(p36;q14) respectively defines the diagnosis of alveolar rhabdomyosarcoma, the type of fusion gene partner is specifically associated with the prognosis within this tumor (i.e., PAX3–FKHR fusion is unfavorable with marked inferior outcome than tumors with PAX5–FKHR fusion). Many other gene fusion anomalies which have important diagnostic values have been associated with various types of sarcomas and lymphomas. These are described in the corresponding chapters. A few cytogenetic abnormalities have also been found in other non-soft tissue tumors. For example: t(3;8)(p21;q12); CTNNB1–PLAG1 fusion in >50% pleomorphic adenoma the t(8q12); PLAG1 fusion in 80% lipoblastoma [30]. Other examples of cytogenetic anomalies are described in the corresponding chapter.

 nalyses with Molecular Procedures A Molecular diagnosis can be performed with several technological platforms and I would like to group them and discuss their application to surgical pathology samples in two broad categories. The first category are the molecular tests that are designed to detect specific DNA alterations or sequence abnormalities that can be completed with a reasonable turnaround time in frame with the expected time taken to issue a surgical pathology report for diagnosis and management. The second category are the molecular genome analyses with analytical platforms that generate a huge volume of data with an overwhelming complexity that require lengthy analyses by bioinformaticians for proper interpretations. The level of equipment and laboratory manpower support has limited the application of these analyses to major academic health science centers. These analyses are performed on specimens from patients who consent to participate and enroll in clinical treatment trials for the evaluation of the efficacy of personalized or targeted cancer therapy. Some of the molecular analyses may discover previously unknown disease mechanisms that could a specific hallmark feature of

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that disease. Such information could be proven to be essential in the diagnosis of that disease entity. As future technology improvements in the speed of analyses of big data via the additional implementation of artificial intelligence for interpretation, and when the cost of these analyses becomes lower, and together with positive evidences of benefits from these clinical treatment trials, it is our hope that the molecular tests within this category will become available as part of an adjunct analysis to enrich the information within the diagnostic reports. Molecular Tests that Have Positive Value to the Disease Diagnosis Gene amplification procedures (polymerase chain reaction, PCR) are rapid analytical procedures that can be designed to analyze specific single gene locus such as the antigen receptor gene of lymphocytes to determine the presence or absence of clonal lymphoproliferations [34]. It can also be designed to detect known abnormal gene fusion abnormalities by using primers that have DNA sequences that are homologous to the flanking regions around specific gene fusion breakpoints provided the fusion regions are tightly clustered [35]. This single gene detection procedure broadens the detection to more than one type of gene fusions by expanding the primer repertoire that recognizes and binds to flanking regions of different types of gene fusion known to specific types of tumors. This multiple primer panel design permits to scale down the number of procedures needed for rapid diagnosis. Recently, other ultra-sensitive rapid screenings for nucleic acid abnormalities in tumors are available by the use of gene hybridization platforms by directly capturing, imaging, and counting fluorescent barcoded DNA primers, designed to recognize and hybridize multiple sequences present in known genes present in specific abnormal DNA molecules specific to each of numerous types of tumors incorporated in the reaction mixture, as much as 800 gene targets can be screen in each run of the assay (e.g., NanoString procedures) [36]. This is done without amplification or reverse transcription and circumvent the deleterious effects on this assay due to nucleic acid degradation. This assay is capable of sensitive and precise quantification of mRNA, miRNA, or DNA (for copy number variation or ChIP-Seq screening) as well as the characterization of gene fusions, splice variants [37, 38]. Challenges common to all of these nucleic acid detection platforms lie in the integrity of the source of DNA or RNA from the lesional tissues (fresh, frozen, or post formalin-­ fixed paraffin-embedded tissues). In general, gene hybridization platforms are less vulnerable to nucleic acid degradation but are less sensitive and gene amplification platforms are more prone to the effects of poor nucleic acid quality but are more sensitive in detection.

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Polymerase Chain Reaction (PCR), for Qualitative Assessment These DNA tests are based on using DNA (or reverse transcriptase generated c-DNA) amplification procedures known as polymerase chain reaction (PCR) to detect the presence of abnormal gene fusions (in specific types of soft tissue neoplasms). The design of this type of DNA analysis is based on the known structural gene abnormalities observed by cytogenetic analyses, followed by the subsequent cloning studies to obtain the specific DNA sequence at the gene fusion junction and thus the finding is complementary to the cytogenetic results. The sensitivity of this PCR analysis is however remarkably enhanced. It can detect an abnormal DNA fusion motiff within a tumor cell within one million normal cells. This test is applicable to tumor cell diagnosis as well as the assessment of minimum residual disease. This assay technique has also been expanded to screen for multiple tumor types by the introduction of various sets of oligonucleotide primers (amplimers) with specificities to each type of gene fusions (multiplex PCR). This procedure has also been applied to detect the presence of clonal lymphocytes (a hallmark pathological feature of lymphoma cells) by designing amplification DNA primers that target and hybridize to the known invariable DNA sequences that flank the variable regions of antigen receptor genes of lymphocytes. qPCR for Relative Quantitation By using the same cyclical DNA amplification procedure principle in the presence of thermostable DNA polymerase with an addition of a synthetic reporter probe which is tagged by mutually quenching fluors at each end that can hybridize to the specific abnormal DNA sequence to the DNA amplification probe mixture, and as the DNA synthesis progresses to completion during this procedure, one of the quenching fluor will be released and the newly synthesized DNA products become detectable and measurable in a real-time PCR machine. The geometric increase which corresponds to an exponential increase of the product can be used to determine the quantification cycle in each reaction. By performing the same amplification kinetics using primers specific to normal house-keeping genes, one can compare the relative quantity of normal versus the abnormal DNA templates or in the case of analyzing the relative differences in the expressed genes between normal and abnormal samples by using c-DNA as the initiating templates for the PCR. Droplet Digital PCR for Absolute Quantification Target-specific amplification of nucleic acid for detection remains the design backbone of this analytical platform. The main distinction is that the reaction mixture is separated into thousands to millions of partitions which is followed by a real-time or an endpoint detection of the amplified products.

3  Principles and Practice of Surgical Pathology for the Diagnosis of Pediatric Head and Neck Diseases

The distribution of target sequences into these partitions typically would follow the Poisson distribution. This would allow an accurate and absolute quantification of the target from the ratio of positive against all partitions at the end of the amplification reaction. This procedure has the added advantage that reference materials with known target concentrations are not needed and it also has increased accuracy of quantification at low target concentrations compared to qPCR. This procedure is also more resilient to the presence of inhibitors in different types of samples [39]. Applications of this procedure to detect copy number variations in genes have been described [40].

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and structural/copy number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. An unambiguous predisposing germline variant was observed in 7–8% of the children in this study and 50% of the neoplasms harbor a potentially druggable event. These results are relevant for the design of clinical trials in the future [43]. The time required for targeted NGS analysis of neoplastic tissues is costly and lengthy and exceeds the turnaround time for the practice of surgical pathology. By scaling the types of targeted genes to a specific type of malignancy and selecting only genes that are prevalent in certain types of Molecular Tests That are Valuable to Clinical Research malignancies to be targeted (e.g., pediatric sarcomas and or and are Beneficial to Support Clinical Trials myeloid malignancies) as seen in one example of NGS of Targeted Therapies using OncoKids (a custom-designed NGS platform)  or Currently in the field of medical oncology, developing more TruSight sequencing panels from Illumina, key driver specific and less damaging therapies especially for children mutations (such as SMARCB1 in Rhabdoid tumors, Alk with malignancies based on the identification of tumor-­ point mutations in neuroblastomas), or gene fusions results associated so-called “driver genes” to be targeted with can be obtained for purpose of diagnostic, prognostic, and custom-­made agents has become the central rationale of con- therapeutic applications [44]. ducting gene targeting clinical trials. Next-generation sequencing (NGS) procedures have demonstrated to have the ability to identify specific gene alterations as key oncogenic Formulation of the Diagnostic Pathology drivers as novel actionable drug target(s) from tumor nucleic Report acids. The results of these types of analyses may be used to guide clinical treatment decisions in clinical trials. Advances The Basic Essentials to Enter into a Pathology in bioengineering toward automated DNA sequencing led to Report in a Free Text Format the development of rapid massive parallel DNA sequencing Surgical pathology reports for non-neoplastic tissues are platforms for human genes. Several major commercially structured in a free text format that preferably include gross available platforms, such as the fluorescent imaging-based specimen information, microscopic description pertinent to Illumina NGS system and the Pacific Biosciences Single the applicable diagnostic criteria, results of other studies, for Molecule real Time (SMRT) NGS platform; Ion Torrent and example, microbiological stain results, connective tissue the Nanopore technology (Oxford Nanopore and Genia stain results or other histochemistry stain results, immunos[Roche]) are available. The details of the sequencing tech- tain results, electron microscopy results, and/or genetic/cytonology behind them will not be described here, please see genetic results if applicable along with the final diagnosis. reference [41]. NGS procedures used to support these oncolFree text surgical pathology reports for neoplasia diagnoogy trials are modified not to engage in seeking casual vari- sis should include the surgical procedure, the site of origin ants (which is extremely time-consuming) but to screen for classification of the tumor, tumor size (e.g., maximum diamthe presence of single nucleotide variants, short insertions eter), and the status of the tumor resection margin (gross and deletions (indels), copy number variations (CNVs), and measurements or microscopic status) (as in appropriate situother structural variants of a panel of known tumor onco- ations). In the microscopic description, pertinent cytological genes and tumor suppressor genes. Hence this procedure is features, the degree of differentiation, that is grade (with the known as targeted NGS. The huge volume of DNA sequences exception of lymphomas), presence or absence of necrosis obtained have to be subjected to bioinformatics tools (no less and apoptosis, the presence of absence of metastasis, vascuthan 26 currently available) to conduct analyses and the qual- lar, neuroinvasion, and status of tumor capsule with regard to ity of data is critically dependent on the type of algorithms the tumor growth should be reported. The number of lymph engaged to create consensus and accuracy in the identifica- nodes, and the number of lymph nodes with tumor metastation of true Cancer driver Genes [42]. sis and the pathological stage should be examined. In the Recent comprehensive genome analyses of 961 tumors microscopic description, for sarcomas, tumor grade and from childhood cancers discovered 24 distinct molecular mitoses should be included [45]. For melanomas, the depth types of cancer. There were 149 putative cancer driver genes of lesion from the epidermis is important to report. Results of that separate these tumors into two classes: small mutation other studies, for example, connective tissue stain results or

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other histochemistry stain results, immunostain results, electron microscopy results and/or genetic/cytogenetic results if applicable should be included  along with the final diagnosis.

 he Essentials of a Specialized Pathology Report T for Pediatric H&N Resection for Neoplasms Over the past decades, cancer staging has been shown to play a central role in the improvement of cancer care. It has provided benchmarks and standards to define cancer prognosis and for the determination of best treatment for the specific type of cancer. Since 1997, The American Joint Committee on Cancer (AJCC) published a manual for cancer staging. This manual has since been periodically updated. The summary of part of the guideline for capturing the pertinent pathology aspects of cancers at specific H&N sites listed for the fulfillment of pathologist’s role in cancer staging is based on the current 8th edition of AJCC Cancer Staging Manual published in 2017 [16]. Moreover, pathology reports for childhood neoplasms have a role to support ongoing multicenter international oncology trials in providing essential data that are important for the clinical and pathological evaluation of these trials with respect to the evaluation of pathology-­related prognostic factors [45].  he Synoptic Pathology Report for Pediatric T Head and Neck Neoplasms Based on the original and primary source of information in the AJCC Cancer Staging Manual, Eighth Edition (2016) published by Spinger, Science+Business Media, The College of American Pathologists (CAP) posted revised Cancer Protocols (February 27, 2019) that are accessible from their website at www.cap.org/cancerprotocols. The CAP authorizes use of these protocols by physicians and other health care providers in reporting on surgical specimens, in teaching, and in carrying out medical research for non-profit purposes. Protocols for that are pertinent to this book that include: Thyroid carcinoma, thyroid biomarker reporting; head and neck protocols that include the larynx, lip, and oral cavity, major salivary glands, nasal cavity and paranasal sinuses, pharynx, squamous cell carcinomas, head and neck biomarker reporting; hematologic neoplasms protocols that include bone marrow, Hodgkin lymphoma, non-Hodgkin lymphoma, ocular adnexal lymphoma; pediatric neoplasm protocols that include Ewing, germ cell tumor, neuroblastoma, rhabdomyosarcoma; skin protocols that include melanoma; and others such as soft tissue tumor and the thymus. With the initiative of introducing these protocols, free text reporting of neoplasms such as the ones described in the previous section would eventually be replaced as free text reporting usually lack diagnostic parameters and hence is regarded as incomplete. CAP permits the use of these proto-

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cols for the purpose of issuing pathology reports for cancer diagnosis.

References 1. Qaisi M, Eid I.  Pediatric head and neck malignancies. Oral Maxillofac Surg Clin North Am. 2016;28:11–9. 2. Arboleda LPA, Hoffmann IL, Cadinalli IA, Santos-Silva AR, de Mendoca RMH.  Demographic and clinicopathologic distribution of head and neck malignant tumors in pediatric patients from a Brazilian population: a retrospective study. J Oral Pathol Med. 2018;47:696–705. 3. Modh A, Gayar OH, Elahaikh MA, Paulino AC, Sidiqui F. Pediatric head and neck squamous cell carcinoma: patient demographics, treatment trends and outcomes. Int J Ped Otolaryngol. 2018;106:21–5. 4. Jensen JS, Grohoj C, Mirian C, Hjuler T.  Incidence and survival of head and neck squamous cell carcinoma in children and young adults in Denmark: a nationwide study from 1980 to 2014. Acta Oncol. 2018;57:1152–8. 5. D’Souza AM, Mark J, Demarcocantonio M, Leino D, Sisson R, Geller JI. Pediatric laryngeal carcinoma in a heterozygous carrier of Fanconi anemia. Pediatr Blood Cancer. 2017;64:e26463. 6. Rayess HM, Monk I, Svider PF, Gupta A, Raza SN, Lin HS.  Thyroglossal duct cyst carcinoma: a systematic review of clinical features and outcomes. Otolaryngol Head Neck Surg. 2017;156:794–802. 7. Tahr A, Sankar V, Makura Z. Thyroglossal duct cyst carcinoma in child. J Surg Case Rep. 2015;4:1–2. 8. Balakrishnan R, Chowdhury Q, Hussain MA, Arup MMH, Haque N, Sharmeen F, et al. Early glottis squamous cell carcinoma in a 16 year old. Case report, review of the literature and pediatric head and neck radiotherapy guidelines. Case rep Oncol. 2015;8:363–8. 9. Tomo S, da Silva Santos I, Stefanini AR, de Oliveira Cucolicchio G, Miyahara GI, Simonato LE. Uncommon occurrence of lip squamous cell carcinoma in a pediatric patient. J Dentistry Children. 2017;84:86–9. 10. Strassen U, Hofauer B, Matsuba Y, Becker K, Mansour N. Knopf a. Bronchogenic cancer: It still exists. Laryngoscope. 2016;12:638–42. 11. Snietura M, Chelmecka-Wiktorcyk L, Pakulo S, Kopec A, Piglowski W, Drabik G, et  al. Vertically transmitted HPV-dependent squamous cell carcinoma of the external auditory canal. Case report of a child. Strahlenther Onkol. 2017;193:156–61. 12. Dumars C, Thebaud E, Joubert M, Renaudin K, Canou-Patron G, Heyman MF. Large cell neuroendocrine carcinoma of the nasopharynx: a pediatric case. J Paediatr Hematol Oncol. 2015;37:474–6. 13. French CA.  The importance of diagnosing NUT midline carcinoma. Head Neck Pathol. 2013;7:11–6. 14. Hellquist H, French CA, Bishop JA, Coca-Pelaz A, Propst EJ, Correia P, et  al. NUT midline carcinoma of the larynx: an international series and review of the literature. Histopathology. 2017;70:861–8. 15. Lemelle L, Pierron G, Freneaux P, Huybrechts S, Spiegel A. Plantaz D et. Al. NUT carcinoma in children and adults: a multicenter retrospective study. Pediatr Blood Cancer. 2017;64:e26693. 16. Ngouajio AL, Drejet SM, Phillips DR, Summerlin DJ, Dahl JP. A systematic review including an additional pediatric case report: Pediatric cases of mammary analogue secretory carcinoma. Int J Paediatr Otorhinolaryngol. 2017;100:187–93. 17. AJCC Cancer Staging Manual. 8th Edition, 2017. Amin MB.  Editor in chief. Springer; Springer International Publishing, AG Switzerland.

3  Principles and Practice of Surgical Pathology for the Diagnosis of Pediatric Head and Neck Diseases 18. Allagio R, Coffin CM.  The evolution of pediatric soft tissue sarcoma classification in the last 50 years. Pediatr Dev Pathol. 2015;18:481–94. 19. Ngan B, Vergilio J, Lim M. Lymph nodes, bone marrow and immunodeficiencies. In: Cohen M, Scheimberg I, editors. Essentials of surgical pediatric pathology: Cambridge University Press; 2000. p. 228–74. 20. Li DD, Zhang YF, Xu HX, Zhang XP.  The role of BRAF in the pathogenesis of thyroid carcinoma. Front Biosci (Landmark Ed). 2015;20:1068–78. 21. Chakraborty R, Burke TM, Hampton OA, Zinn DJ, Lim KPH, Abhyakar H, et al. Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis. Blood. 2016;128:2533–7. 22. Hauschild A, Larkin J, Ribas A, Dreno B, Flaherty KT, Ascierto PA, et al. Modeled prognostic subgroups and treatment outcomes in BRAF V600-mutated metastatic melanoma: pooled analysis of 4 randomized clinical trials. JAMA Oncol. 2018;4:1382–8. 23. Merryman RW, Armand P, Wright KT, Rodig SJ.  Check point blockade in Hodgkin and non-Hodgkin lymphoma. Blood Adv. 2017;1(26):2643–54. 24. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with novolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9. 25. Li TJ. The odontogenic keratocyst. A cyst or a cystic neoplasm? J Dent Res. 2011;90:133–42. 26. Qu J, Yu F, Hong Y, Sun L, Li X, Zhang J, et al. Underestimating PTCH1 mutation rate in sporadic keratocystic odontogenic tumors. Oral Oncol. 2015;51:40–5. 27. Levanet S, Pavelic’ B, Cmic’ I, Oreskovic S, Manojiov S. Involvement of PTCH1 gene in various non-inflammatory cysts. J Mol Med. 2000;78:140–6. 28. Pavelic’ B, Levanat S, Cmic’ I, Kobler P, Anic I, Manojiovic E, Sutalo J. PTCH gene altered in dentigerous cysts. J Oral Pathol Med. 2001;30:569–76. 29. Oliveira AM, Chou MM. USP6-induced neoplasms: the biological spectrum of aneurysmal bone cyst and nodular fasciitis. Hum Pathol. 2014;45:1–11. 30. Dadone B, Refae S, Lemarie’-Delauney C, Bianchini L, Pedeutour F.  Molecular cytogenetics of pediatric adipocytic tumors. Cancer Genet. 2015;208:469–81. 31. Davis JL, Lockwood CM, Albert CM, Tsuchiya K, Hawkins DS, Rudzinski ER.  Infantile-associated mesenchymal tumors. Pediatr Dev Pathol. 2018;21:68–78. 32. Majewska H, Ska’lova’ A, Stodulski D, Kimkova’ A, Steiner P, Stankiewicz C, Biernat W.  Mammary analogue secretory carcinoma of salivary glands: a new entity associated with ETV6 gene rearrangement. Virchows Arch. 2015;466:245–54.

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33. Rito M, Fonseca I. Salivary gland neoplasms: does morphological diversity reflect tumor heterogeneity. Pathobiology. 2018;85:85–95. 34. Boone E, Heezen KC, Groenen PJTA, Lanerak AW.  Euro clonality consortium. PCR gene scan and heteroduplex analysis of rearranged immunoglobulin or T-cell receptor genes for clonality diagnostics in suspect lymphoproliferations. Methods Mol Biol. 2019;1956:77–103. 35. Ngan BY, Nourse J, Cleary ML. Detection of chromosomal translocation t(14;18) within the minor cluster region of BCL2 by polymerase chain reaction and direct genomic sequencing of the enzymatically amplified DNA in follicular lymphomas. Blood. 1989;73:1759–62. 36. Karlsson A, Staal J. Clinical application of fusion gene detection using next-generation sequencing and the nanostring technology. Methods Mol Biol. 2019;1908:139–52. 37. Chang KTE, Goytain A, Tucker T, Karsan A, Lee CH, Nielson TO, et  al. Development and evaluation of a pan-sarcoma fusion gene detection assay using the NanoString nCounter Platform. J Mol Diagn. 2018;20:63–77. 38. Denaro M, Navan E, Ugolini C, Seccia V, Donati V, Casani AP, et al. A microRNA signature for the differential diagnosis of salivary gland tumors. PLoS One. 2019;14:e0212968. 39. Gutierrez-Aguirre I, Racki N, Dreo T, Ravdnikar M. Droplet digital PCR for absolute quantification of pathogens. Methods Mol Biol. 2015;1302:331–47. 40. Harmala SK, Butcher R, Roberts CH. Copy number variation analysis by droplet digital PCR. Methods Mol Biol. 2017;1654:135–49. 41. Di Stefano JK, Kingsley CB. Identification of disease susceptibility alleles in the next generation sequencing era. Methods and protocols. Methods Mol Biol. 2018;1706:3–16. 42. Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasingle A, et  al. Comprehensive characterization of cancer drive genes and mutations. Cell. 2018;173:371–85. 43. Grobner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, et  al. The landscape of genomic alterations across childhood cancers. Nature. 2018; https://doi.org/10.1038/ nature25480. 44. Hiemenz MC, Ostrow DG, Busse TM, Buckley J, Maglinte DT, Bootwalla M, et  al. OncoKids. A comprehensive next-­generation sequencing panel for pediatric malignancies. J Mol Diagn. 2018;20:765–76. 45. Black JO, Coffin CM, Parham DM, Hawkins DS, Speights RA, Spunt SL. Opportunities for improvement in pathology reporting of childhood non-rhabdomyosarcoma soft tissue sarcomas. A report from the Children’s Oncology Group (COG) Study ARST0332. Am J Clin Pathol. 2016;146:328–38.

Part II Pediatric Surgical Diseases of the Ear and Temporal Bone

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Clinical and Surgical Management of Pediatric Diseases of the Ear and Temporal Bone Adrian James

Introduction As is well known, the external ear is comprised of the pinna and ear canal which is separated from the air containing middle ear cleft by the tympanic membrane. For the purpose of hearing, energy from sound waves impacting the tympanic membrane is transmitted across the middle ear space by the ossicular chain into the cochlea. The temporal bone provides the bony framework for these structures and functions. It is situated on the lateral aspect of the skull base and comprises four parts. The largest is the squamous part, which makes up the part of the calvarium above the ear canal. The petrous part of the temporal bone contains the sensory apparatus of the cochlea and vestibular system. It is approximately conical with the apex pointing toward the center of the skull base. The mastoid part forms the bony prominence behind the ear canal. The tympanic ring is the smallest part of the temporal bone and makes up most of the bony part of the external ear canal. The internal carotid artery, jugular vein and facial, cochlear and vestibular nerves pass through the temporal bone. The trigeminal, abducens, and bulbar nerves all lie in close proximity. Dysfunction of any of these structures may be caused by temporal bone pathology. A variety of benign and malignant pathologies can affect the temporal bone in childhood. Clinical features of these disorders overlap: hearing loss and otorrhea, even bleeding from the ear from an aural polyp, are very nonspecific symptoms that can be caused by many different pathologies. Otalgia, swelling around the ear, and facial nerve or other cranial nerve palsy are more strongly suggestive, but not diagnostic, of malignant disorders. However, as is described below, neoplastic disorders of the temporal bone are excep-

A. James (*) Hospital for Sick Children, Department of Otolaryngology—Head and Neck Surgery, University of Toronto, Toronto, ON, Canada e-mail: [email protected]

tionally rare in childhood. Published experience of many such disorders is limited to small series or even case reports, and experience at the Hospital for Sick Children over the last 15 years is often limited to individual cases. In comparison, cholesteatoma is relatively common with many hundred cases being seen over this time period. Although the histology of cholesteatoma may provide little challenge for the pathologist, cholesteatoma is covered in some depth in this chapter because of its prevalence and challenging behavior. Although the pathology of cholesteatoma is benign, the disease is proliferative, locally invasive, and destructive with high propensity to recidivism. It is the commonest cause of permanent conductive hearing loss in children and carries the risk of facial palsy and life-­ threatening suppurative complications.

Tympanosclerosis Definition Tympanosclerosis is a condition in which hard white plaques form within the middle layer of the tympanic membrane or elsewhere in the middle ear cleft. It is most commonly confined to the tympanic membrane alone, in which location it is more correctly referred to as myringosclerosis. Although the term tympanosclerosis is often used to describe lesions confined to the tympanic membrane, for the sake of clarity in this chapter, “tympanosclerosis” is used to describe the condition within the middle ear, and “myringosclerosis” lesions confined to the tympanic membrane. The severity of tympanosclerosis has been categorized into clinically relevant stages based on the extent of ossicular involvement as, for example, by Wielinga and Kerr [1]: • Type I: tympanic membrane involvement (i.e., myringosclerosis). • Type II: attic fixation of the malleus-incus complex with a mobile stapes.

© Springer Nature Switzerland AG 2021 P. Campisi et al. (eds.), Pediatric Head and Neck Textbook, https://doi.org/10.1007/978-3-030-59265-3_4

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• Type III: isolated stapes footplate fixation. tone audiometry are clues to the presence of tympanosclero• Type IV: fixation of the stapes footplate and the malleus-­ sis, especially if the child is known to have had normal hearincus complex. ing previously (e.g., on newborn hearing screening), has no history of temporal bone trauma and no evidence of an effuThe pathogenesis is thought to begin with invasion of sion, tympanic membrane retraction, or cholesteatoma. fibroblasts into the submucosal plane, followed by condensation of collagen fibers within which calcium deposits collect. This process is also referred to as hyalinization. It is Radiological Features rarely seen without a history of prior ear disease. Randomized controlled trials of children with otitis media CT scan may reveal larger plaques of tympanosclerosis with with effusion show that myringosclerosis occurs in around a density between that of bone and soft tissues (Fig. 4.1d). one-third of ears after tympanostomy tube insertion compared with 15%