Outlines of Orthopaedic Pathology and Imaging [Team-IRA] [1 ed.] 1527507319, 9781527507319

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Outlines of Orthopaedic Pathology and Imaging

Outlines of Orthopaedic Pathology and Imaging: A Review By

Dariusz Borys and Adam Greenspan

Outlines of Orthopaedic Pathology and Imaging: A Review By Dariusz Borys and Adam Greenspan This book first published 2023 Cambridge Scholars Publishing Lady Stephenson Library, Newcastle upon Tyne, NE6 2PA, UK British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Copyright © 2023 by Dariusz Borys and Adam Greenspan All rights for this book reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the copyright owner. ISBN (10): 1-5275-0731-9 ISBN (13): 978-1-5275-0731-9

TABLE OF CONTENTS

CHAPTER 1 . ............................................................................................ 1 METABOLIC BONE ABNORMALITIES Osteoporosis. ........................................................................................ 1 Osteomalacia . ........................................................................................ 6 Hyperparathyroidism . ........................................................................... 9 Alkaptonuria – ochronosis . ................................................................. 17 Paget disease . ...................................................................................... 22 CHAPTER 2 . .......................................................................................... 29 INFECTIOUS BONE ABNORMALITIES Acute osteomyelitis. ............................................................................ 29 Chronic osteomyelitis . ........................................................................ 36 CHAPTER 3 . .......................................................................................... 41 ARTHRITIDES AND ARTHROPATHIES Rheumatoid arthritis (RA) . ................................................................. 41 Osteoarthritis (OA) . ............................................................................ 47 Gout . ................................................................................................... 53 Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease . .......................................................................................... 59 Ankylosing spondylitis (AS). .............................................................. 65 Diffuse idiopathic skeletal hyperostosis (DISH) syndrome ................ 71 Sarcoidosis . ......................................................................................... 74 CHAPTER 4 . .......................................................................................... 79 TRAUMATIC BONE ABNORMALITIES Bone fractures . .................................................................................... 79 Osteonecrosis (ischemic necrosis, avascular necrosis) ....................... 86 Myositis ossificans (MO) . ................................................................... 91 Posttraumatic intraarticular osteochondral body(bodies) – Osteochondritis dissecans (OD); Osteochondral fracture.............. 97

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CHAPTER 5 . ........................................................................................ 103 TUMORS AND TUMOR-LIKE LESIONS (A) BONE FORMING (OSTEOGENIC) TUMORS .......................... 103 Osteoma . ........................................................................................... 103 Osteoid osteoma . ............................................................................... 108 Osteoblastoma. .................................................................................. 113 Osteosarcomas . ................................................................................. 118 Conventional osteosarcoma . ....................................................... 118 Osteoblastic ................................................................................. 124 Chondroblastic ............................................................................. 126 Fibroblastic .................................................................................. 127 Telangiectatic osteosarcoma . ...................................................... 130 Small cell osteosarcoma . ............................................................. 137 Low grade central osteosarcoma . ............................................... 139 Surface osteosarcomas . ............................................................... 144 Parosteal osteosarcoma ................................................................ 144 Periosteal osteosarcoma ............................................................... 150 High grade surface osteosarcoma . .............................................. 155 Secondary osteosarcomas . .......................................................... 159 Post-radiation osteosarcoma .................................................. 159 Osteosarcoma arising in Paget disease of bone ..................... 161 Osteosarcoma associated with fibrous dysplasia ................... 164 (B) CARTILAGE FORMING (CHONDROGENIC) TUMORS ......... 165 Enchondroma (chondroma), enchondromatosis................................ 165 Osteochondroma and multiple hereditary osteochondromas ............ 175 Bizarre parosteal osteochondromatous proliferation (BPOP, Nora lesion) . ................................................................................ 181 Periosteal (juxtacortical) chondroma ................................................ 186 Chondroblastoma . ............................................................................. 190 Chondromyxoid fibroma. .................................................................. 195 Synovial chondromatosis (osteochondromatosis) ............................. 200 Chondrosarcomas. ............................................................................. 206 Conventional chondrosarcoma . .................................................. 206 Clear cell chondrosarcoma . ........................................................ 215 Mesenchymal chondrosarcoma . .................................................. 220 Dedifferentiated chondrosarcoma . .............................................. 225 Periosteal (juxtacortical) chondrosarcoma ................................ 230

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(C) FIBROUS (FIBROGENIC) LESIONS ....................................... 234 Nonossifying fibroma (NOF) . ........................................................... 234 Desmoplastic fibroma . ...................................................................... 238 Fibrous dysplasia (monostotic, polyostotic) ..................................... 243 Osteofibrous dysplasia . ..................................................................... 248 (D) CYSTIC LESIONS . ..................................................................... 253 Simple bone cyst (SBC) . ................................................................... 253 Aneurysmal bone cyst (ABC) . .......................................................... 258 (E) GIANT CELL-RICH LESIONS . .................................................. 265 Giant cell tumor (GCT) . .................................................................... 265 Giant cell reparative granuloma (solid variant of ABC) ................... 273 Tenosynovial giant cell tumor, localized type (Localized pigmented villonodular synovitis). ................................................................ 277 Tenosynovial giant cell tumor, diffuse type (Pigmented villonodular synovitis – PVNS) . ...................................................................... 284 (F) VASCULAR LESIONS . ............................................................... 290 Intraosseous haemangioma . .............................................................. 290 Epithelioid haemangioma . ................................................................ 296 Synovial haemangioma . .................................................................... 300 Epithelioid haemangioendothelioma of bone.................................... 304 Intraosseous angiosarcoma . .............................................................. 309 (G) HEMATOPOIETIC LESIONS . .................................................. 314 Langerhans cell histiocytosis (Eosinophilic granuloma)................... 314 Plasmacytoma (multiple myeloma) . ................................................. 320 Primary lymphoma of bone . ............................................................. 327 (H) MISCELLANEOUS TUMORS AND TUMOR-LIKE LESIONS .. 332 Intraosseous lipoma . ......................................................................... 332 Angiomatoid fibrous histiocytoma of bone....................................... 336 Chordoma . ........................................................................................ 339 Adamantinoma . ................................................................................. 344 Ewing sarcoma . ................................................................................. 349 Leiomyosarcoma of bone . ................................................................. 355 Undifferentiated pleomorphic sarcoma (UPS) of bone ..................... 360 (I) OSSEOUS METASTASES . ........................................................... 363

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CHAPTER 6 . ........................................................................................ 368 MISCELLANEOUS BONE LESIONS Osteopetrosis. .................................................................................... 368 Erdheim-Chester disease . .................................................................. 374 Rosai-Dorfman disease . .................................................................... 379 REFERENCES . .................................................................................... 382

CHAPTER 1 METABOLIC BONE ABNORMALITIES Osteoporosis Definition: x Generalized metabolic bone disease characterized by insufficient formation or increased resorption of bone matrix that results in a decreased bone mass and microarchitectural deterioration of bone, leading to an increased risk of bone fractures. Although there is a reduction in bone tissue, the tissue is fully mineralized (the bone is quantitatively deficient but qualitatively normal). Epidemiology: x Metabolic bone disease mostly affects patients older than 50 years. x Commonly seen in postmenopausal women due to estrogen deficiency. x Risk factors include poor nutrition (low calcium diet), aging, family history, medication, and immobilization. x Major health problem affecting more than forty-four million Americans, with about two million fractures annually. Clinical presentation: x Most commonly affects the spine and pelvis. x Vertebral fractures present with back pain, loss of height, and thoracic kyphosis. Imaging: x Diffuse osteopenia of bones (Figure 1). x Thinning of the cortices of the long and short tubular bones. x Dual-photon absorptiometry, Single X-ray absorptiometry, and Dualenergy X-ray absorptiometry (DEXA) are diagnostic. x Occasionally, other methods are used, such as Digital computer-assisted X-ray radiogrammetry (DXR) or Quantitative ultrasound (QUS) techniques.

Chapter 1

2

A

B

C

D

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E Figure 1. Anteroposterior (A) and lateral (B) radiographs of the knee show increased radiolucency of bones, thinning of the cortices, and sparse trabecular pattern. These changes are more effectively demonstrated on axial computed tomography sections obtained through the proximal tibia and fibula (C) and distal femur (D), as well as on the reformatted coronal image of the distal femur (E). (Reprinted with permission of the Authors and Publisher from Greenspan A, Beltran J. Orthopaedic imaging – A practical approach. 7th ed., Philadelphia 2021, Wolters Kluwer, figure 27.2, p.1285).

Pathology: Gross. x Prominent loss of trabecular bone. x Kyphosis of the thoracic spine. Histopathology. x Decrease of cortical and trabecular bone (Figure 2). x Trabecular bone is more affected by prominent trabecular thinning, discontinuation, and separation (Figures 3 and 4). x Bone cortex is thinning with widened Haversian channels.

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Chapter 1

Figure 2. Decrease in cortical and trabecular bone.

Figure 3. Trabecular bone thinning, discontinuation, and separation.

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Figure 4. Thinning of bone trabeculae.

Prognosis and therapy: x Pathologic fractures correlate with increased mortality. x The therapeutic goal is to prevent bone loss and fractures with proper nutrition (vitamin D and calcium supplementation), exercise, and medication (bisphosphonates, estrogen receptor modulators such as raloxifene). Differential diagnosis: x Osteomalacia. x Osteogenesis imperfecta. x Hyperparathyroidism.

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Chapter 1

Osteomalacia Definition: x Defective skeletal mineralization (calcification) of a bone matrix with an accumulation of unmineralized bone caused most often by faulty absorption of fat-soluble vitamin D from the gastrointestinal tract secondary to malabsorption syndrome. Epidemiology: x Associated with bone and soft tissue tumors such as phosphaturic mesenchymal tumors. x Deficiencies or disorders of phosphorus, calcium, and vitamin D metabolism. Clinical presentation: x Musculoskeletal weakness and bone pain are common features. x Bone fractures of vertebral bodies and femoral neck are common findings. x Low levels of vitamin D and increased alkaline phosphatase. x Milkman syndrome, a condition with numerous pseudo fractures. x Association with neurofibromatosis, fibrous dysplasia, and Wilson disease. x Oncogenic osteomalacia (also known as tumor-induced osteomalacia – TIO) is a paraneoplastic syndrome characterized by hypophosphatemia, hyperphosphaturia, and low plasma levels 1,25-dihydroxy vitamin D, caused by bone and soft-tissue tumors or tumor-like lesions. Imaging: x Multiple, bilateral, and often symmetrical radiolucent lines in the cortex, perpendicular to the long axis of the bone, referred to as pseudo fractures or Looser zones. x Generalized osteopenia. x Total decrease in bone mineral density on DEXA studies. x Areas of unmineralized bones caused by fast bone resorption and slow mineralization.

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Figure 1. A looser zone, also called insufficiency-type stress fracture, represented by a radiolucent defect in the cortical bone, reflects the accumulation of non-mineralized osteoid tissue and is a characteristic feature of osteomalacia. (Reprinted with permission of the Authors and Publishers from Greenspan A, Beltran J. Orthopedic imaging. A practical approach. 7th Ed. Philadelphia, 2021, Wolters Kluwer, Fig. 26.5, p. 1276).

Pathology: Gross. x Soft unmineralized bone, easy to fracture.

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Chapter 1

Histopathology. x Excessive quantities of inadequate mineralized bone matrix (osteoid) coating the surface of trabeculae in spongy bone and lining the Haversian canals in the cortex. x Decreased mineralization and calcification of the bone. x Von Kossa stain highlights an unmineralized portion of the bone trabeculae (eosinophilic) and a mineralized portion (dark grey or black) (Figure 2).

Figure 2. Von Kossa stain highlights an eosinophilic unmineralized portion of the bone at the surface of the bone. (Courtesy of Michael Klein, M.D., New York).

Prognosis and therapy: x Main cause of bone fractures in elderly patients. x Correction of vitamin D deficiency or underlying medical condition as treatment. Differential diagnosis: x Osteopenia. x Osteoporosis. x Hyperparathyroidism.

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Hyperparathyroidism Definition: x Hyperparathyroidism is a disease occurring because of overactivity of parathormone-producing parathyroid glands resulting in excessive secretion of parathyroid hormone – PTH (which regulates calcium metabolism and has an impact on osteoclasts and osteoblasts activity) either secondary to gland adenoma (90% of cases), gland hyperplasia (9% of cases) or carcinoma (1% of cases). In addition, increased secretion of PTH causes secondary hyperparathyroidism in response to a sustained hypocalcemic state associated with renal disease or malnutrition (severe calcium or vitamin D deficiency). Brown tumors commonly occur in primary and secondary hyperparathyroidism. Epidemiology: x Mostly seen in 50-year-old patients and menopausal women. x In patients with multiple endocrine neoplasias, type I, and type IIA. Clinical presentation: x Bone and joint pain with pathologic fractures due to osteopenia. x Weakness, muscular hypotonia, nausea, anorexia, constipation, polyuria, and thirst. x Nephrocalcinosis. x Depression and forgetfulness. x Laboratory studies show increased levels of calcium and decreased levels of phosphorus. x Long-standing form results in forming multiple large cystic lesions in bones (osteitis fibrosa cystica).

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Chapter 1

Imaging: x General osteopenia. x In the skull, the characteristic mottling of the vault yields a “salt-andpepper” appearance. x Subperiosteal, subchondral, and intracortical (tunneling) bone resorption (Figure 1). x Resorption of acromial ends of the clavicles. x Loss of lamina dura around the tooth socket. x Brown tumors (also known as osteoclastomas) present circumscribed lytic lesions resulting from massive bone resorption due to osteoclast activity, associated with hemorrhage and hemosiderin deposition (brown color). They may be solitary or multifocal, resembling metastases. Commonly they involve facial bones, ribs, pelvic bones, and long and short tubular bones (Figures 2 and 3). They can occur in primary and secondary hyperparathyroidism and renal osteodystrophy. x In secondary hyperparathyroidism, soft tissue and cartilage calcifications, bone density increase, and the spine have a characteristic sandwich-like appearance (rugger-jersey spine).

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Figure 1. The radiograph of the finger shows subchondral resorption at the head of the second metacarpal bone (arrow) and subperiosteal resorption at the proximal and distal phalanges (open arrows).

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Chapter 1

Figure 2. A radiograph of the ilium shows well-circumscribed lytic lesions representing brown tumors.

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Figure 3. A coronal reformatted CT image of the pelvis shows a sizeable lowattenuation lesion within the left ilium representing a brown tumor.

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Chapter 1

Pathology: Gross. x Fragments of friable brown tissue. Histopathology. x Uniform spindle histiocytic cell proliferation with aggregates of osteoclast-like giant cells and hemosiderin deposition (Figure 4). x Increased osteoclastic activity with intertrabecular tunneling (dissecting resorption) and bone resorption (Figure 5). x Abundant fibrosis, hyalinization, and bone sclerosis can be found (Figure 6). x Histopathology of the brown tumor may resemble giant cell reparative granuloma.

Figure 4. Uniform spindle histiocytic cell proliferation with aggregates of osteoclast-like giant cells and hemosiderin deposition.

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Figure 5. Increased osteoclastic activity with intertrabecular tunneling and bone resorption.

Figure 6. Stromal fibrosis and hyalinization.

Chapter 1

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Prognosis: x Surgical removal of the hyperfunctioning parathyroid gland is curative. Differential diagnosis: x x x x x

Myelofibrosis. Giant cell tumor of bone. Giant cell reparative granuloma. Lytic metastases. Osteomalacia.

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Alkaptonuria - ochronosis Definition: x A rare autosomal recessive inherited disease characterized by the presence of homogentisic acid in the urine, which turns black when oxidized (alkaptonuria), and deposition of dark pigment in cartilage or fibroconnective synovial tissue (ochronosis) caused by lack of the enzyme homogenous acid oxidase which plays a part in the normal degradation process of the aromatic amino acids tyrosine and phenylalanine. Epidemiology: x Affects males and females equally. x More common in certain areas in Slovakia, Dominican Republic, Jordan, and India. x Most affected are large joints, including knees, shoulders, and hips. Clinical presentation: x x x x x x x

In general, affected individuals are asymptomatic until adult life. Mild pain and decreased range of motion in the affected joints. Osteoarthritis of large joints and spine. Gray to brown pigmentation in the sclera of eyes. Thickened and darkened cartilage in the ears. Discoloration of the skin, particularly around sweat glands. Dark-colored urine and kidney stones.

Imaging: x Dystrophic calcifications in the intervertebral disk spaces, articular cartilage, tendons, and ligaments. x Degenerative changes of the hip, spine, and knee joints with joint and disk space narrowing. x Calcification and fusion of disk spaces (Figure 1). x Imaging appearance may mimic osteoarthritis and CPPD crystal deposition arthropathy.

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Chapter 1

Figure 1. A lumbar spine radiograph demonstrates the narrowing of several intervertebral disk spaces associated with characteristic calcifications. (Reprinted with permission of the Author and Publisher from Greenspan A, Gershwin ME. Imaging in rheumatology. A clinical approach. 1st ed. Philadelphia, 2018, Wolters Kluwer, Fig. 7.42, p.298).

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Pathology: Gross. x Black pigmentation of skin, cartilage, tendons, and ligaments. x Cartilage is brittle and fragmented.

Figure 2. The sagittally sectioned spine specimen shows black pigmentation within the narrowed intervertebral disks. (Reprinted with permission of the Author and Publisher from Greenspan A, Gershwin ME. Imaging in rheumatology. A clinical approach. 1st ed. Philadelphia, 2018, Wolters Kluwer, Fig. 7.41, p.298).

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Chapter 1

Histopathology. x Dark pigmentation of cartilage and fibroconnective synovial tissue.

Figure 3. Dark pigmentation of cartilage and synovial tissue.

Figure 4. Dark pigmentation of the cartilage.

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Genetics: x The disease is caused by a mutation in the HGO gene located in the arm of chromosome 3q1, responsible for the enzyme homogentisate 1,2dioxygenase, which leads to the accumulation of homogentisic acid (dark pigment) in various organs, with a predilection for connective tissue. Differential diagnosis: x Medication-induced hyperpigmentation (e.g., minocycline). x Osteoarthritis. x CPPD crystal deposition arthropathy.

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Chapter 1

Paget disease Definition: x Chronic, progressive disturbance in bone metabolism affects normal bone remodeling due to an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts, leading to bone enlargement of bones and weakness followed by stress and frank fractures. Epidemiology: x Most patients are older than 55 years old, rare in patients younger than 40. x Familial occurrences were reported. x More common occurrence was reported in North America, Australia, New Zealand, Europe, and people of Anglo-Saxon descent. Clinical presentation: x x x x x

Commonly involves the pelvis, spine, skull, and lower extremities. Frequently asymptomatic, particularly in early stages. Periosteal tenderness, bone pain, and arthritis. Neural compression. Long-standing disease can cause an increase in head size (headaches and deafness), bowing deformities of the limbs, and curvature of the spine (spinal stenosis). x Elevated serum alkaline phosphatase levels with normal serum calcium and phosphorus levels.

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Imaging: x Early phase of the disease (osteolytic or hot phase) shows prominently bone resorption, manifesting by radiolucent wedge or elongated area with sharp borders termed advancing wedge, candle flame, and blade of grass (Figure 1). x Early changes in the skull may be destructive and radiolucent, known as osteoporosis circumscripta. x In the intermediate or mixed phase, bone destruction is accompanied by new bone formation, manifesting by the thickening of the cortex and coarse trabeculation of cancellous bone. The spine “picture frame” around the vertebral body is characteristic (Figure 2). In the skull, a “cotton ball” appearance is characteristic. x In the cool or sclerotic phase, a diffuse bone density increase occurs together with the bone's enlargement and widening and marked cortical thickening. Loss of demarcation between cortex and spongiosa. Bowing deformities of long bones and the pelvis (Figure 3) are striking features. In the skull, there is the obliteration of the diploic space. x Radionuclide bone scan shows a marked increase in the uptake of radiopharmaceutical agents in affected bones. x Stress and frank fractures may be present in long bones.

Chapter 1

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A

B

Figure 1. Anteroposterior (A) and lateral (B) radiographs of the leg show the acute stage of the disease with the characteristic blade of grass appearance (arrows).

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Figure 2. Picture frame appearance of the vertebral body marks the intermediate phase of the disease.

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Chapter 1

Figure 3. Anteroposterior pelvis radiograph shows increased bone density and deformity and triangular appearance of the pelvic cavity, the characteristic features of the cool phase of the disease.

Pathology: Gross. x Hyperemic bone with distortion of the standard structure and disorganized trabecular pattern. Histopathology. x Early osteolytic stage shows increased osteoclastic activity with increased bone resorption (Figure 4). x Mixed phases show increased osteoclastic and osteoblastic activity with remodeling, fibrosis, and osteoid formation (Figure 5). x Late sclerotic stage shows an increased number of reversal cement lines, which creates a characteristic mosaic pattern (wavy cement lines) of bone remodeling (Figure 6).

Metabolic Bone Abnormalities

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Figure 4. The early osteolytic stage shows increased osteoclastic activity with increased bone resorption. (Courtesy of Michael Klein, M.D., New York).

Figure 5. The mixed phase of the disease shows increased osteoclastic and osteoblastic activity with remodeling, fibrosis, and osteoid formation. (Courtesy of Michael Klein, M.D., New York).

Chapter 1

28

Figure 6. The late sclerotic stage of the disease shows an increased number of reversal cement lines, which creates a characteristic mosaic pattern (wavy cement lines) of bone remodeling. (Courtesy of Michael Klein, M.D., New York).

Genetics: x The gene SQSTM1, which encodes a protein p62 involved in regulating osteoclast functioning, has been identified in familial cases. x Mutations at the CSF1, OPTN, and TNFRSF11A genes have been linked with a higher risk for Paget disease. Complications: x x x

Pathologic fractures. Formation of benign or malignant giant cell tumors. Development of bone sarcoma (less than 1%).

Differential diagnosis: x x x x

Monostotic and polyostotic fibrous dysplasia. Hyperparathyroidism. Familial idiopathic hyperphosphatasia (“juvenile Paget disease”). Chronic osteomyelitis.

CHAPTER 2 INFECTIOUS BONE ABNORMALITIES

Acute osteomyelitis Definition: x Acute inflammatory process of bone resulting from bacterial, mycobacterial, viral, or fungal infection. x Pathogens may enter the bone through the bloodstream (hematogenous spread), from nearby infected soft tissue (contiguous spread), or through direct invasion (e.g., via open fracture or surgery). Epidemiology: x Most common pathogens include Staphylococcus aureus, Streptococcus pyogenes, and Salmonella. The latter is associated with complications in patients with sickle cell disease. x Hematogenous spread is most common in children and favors the long bone metaphysis. x Neonatal hematogenous osteomyelitis is frequently polyostotic. x Streptococci A and B are common pathogens among immunocompromised patients. x Hematogenous spread in adults is commonly sourced from indwelling catheters, chronic infections, and intravenous drug use. x Contiguous spread may begin at decubitus ulcers, where bacteria enter bone through the periosteum or articular cartilage. x Direct invasion associated with an open fracture, orthopedic implants, or orthopedic surgery is typically due to Staphylococcus, Streptococcus, or Pseudomonas aeruginosa.

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Chapter 2

Clinical presentation: x Pain, high fever, leukocytosis x In most cases, solitary involvement of any bone x Blood cultures may be negative; bone biopsy with tissue culture may provide the diagnosis. Imaging: x Early infection may not show appreciable osseous abnormalities; however, surrounding soft tissue may exhibit swelling, loss of fascial planes, and gas as early as 24 to 48 hours from the onset of infection. x The earliest bony changes are destructive lytic lesions. They can usually be detected by radionucleotide bone scan or MRI within 7 to 10 days after infection onset. x After 2 to 6 weeks, the infection progresses to cortical and medullary bone destruction, followed by endosteal sclerosis indicated by the reactive new bone formation and periosteal reaction (Figure 1). x At 6 to 8 weeks, sequestra indicating areas of necrotic bone become apparent. They are surrounded by dense involucrum, representing a sheath of periosteal new bone. (Figure 2). x Later, a draining sinus tract often forms. Small sequestra are gradually resorbed or extruded through the sinus tract.

Infectious Bone Abnormalities

A

31

B

Figure 1. Antero-posterior (A) and lateral (B) radiographs of the knee of an 8-yearold boy show destruction of the cortical and medullary portions of the metaphysis and diaphysis of the distal femur, as well as periosteal reaction. There is also a pathologic fracture present (arrows). On the lateral view, a large periosteal abscess is evident (arrowheads). (Reprinted with permission of the Authors and Publisher from Greenspan A, Beltran J. Orthopaedic Imaging: A practical approach, 7th ed., Philadelphia, Wolters Kluwer, 2021, Fig. 25.2 A, B, p. 1237).

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Chapter 2

Figure 2. Sequestra surrounded by involucrum within the fibula of a 2-year-od child is a feature of advanced acute osteomyelitis usually apparent after 6 to 8 weeks of infection. (Reprinted with permission of the Authors and Publisher from Greenspan A, Beltran J. Orthopaedic Imaging: A practical approach, 7th ed. Philadelphia, Walters Kluwer, 2021, Fig. 25.3, p. 1237).

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Histopathology: x Early changes show accumulation of polymorphonuclear leukocytes (neutrophils), edema, hemorrhage, osteoclastic bone resorption (Figure 3), “bitten” or “chewed” bone, ischemic necrosis of bone trabeculae and bone marrow, and vascular thrombosis (Figure 4). x With time, bone necrosis progresses and demonstrates empty lacunae. x Acute inflammation may evolve into chronic inflammation composed of lymphocytes, plasma cells, macrophages, and fibrovascular tissue (Figure 5). x Colonies of bacteria or fungal organisms may be found (Figure 6)

Figure 3. Accumulation of neutrophils, edema, hemorrhage, osteoclastic bone resorption, "bitten" (chewed) bone, and marrow infarction.

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Chapter 2

Figure 4. Acute inflammation with necrosis, edema, hemorrhage, and osteoclastic bone resorption.

Figure 5. Chronic inflammation with lymphocytes, plasma cells, macrophages, and fibrovascular tissue.

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Ancillary tests: x Microbiology culture (part of the submitted fresh tissue should go to microbiology to grow organisms) x Gram stain for bacterial organisms x Grocott’s methenamine silver stain (GMS) positivity indicates the presence of fungal organisms (Figure 7)

Figure 6. GMS stain is positive for fungal organisms.

Differential diagnosis: x x x x

Early stage of bone fracture Langerhans cell histiocytosis Chronic osteomyelitis Ewing sarcoma

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Chapter 2

Chronic osteomyelitis Definition: x Chronic osteomyelitis extends acute osteomyelitis and lasts more than six weeks. Epidemiology: x Many cases of untreated acute osteomyelitis may progress to chronic osteomyelitis. x May be caused by non-pyogenic bacteria such as Mycobacteria tuberculosis (tuberculous osteomyelitis) or Treponema pallidum (syphilitic osteomyelitis). x Fungal granulomatous osteomyelitis caused by Candida, Cryptococcus, Blastomyces, and Coccidioidomycosis species. Clinical presentation: x May present as swelling, erythema, and pain around the affected bone. x Systemic signs of low-grade fever and weight loss. Imaging: x Lytic destructive bone lesion with sclerosis, sequestra, and sinus tract formation (Figures 1 and 2). x Periosteal reaction. x Involvement of soft tissue.

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Figure 1. Draining sinus tract formation within the bone is a characteristic feature of chronic osteomyelitis.

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Chapter 2

Figure 2. Coronal and sagittal reformatted CT images show the intraosseous sinus containing several sequestra.

Infectious Bone Abnormalities

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Pathology: Gross. x Infected bone may be white-yellow-grey and look necrotic. Histopathology. x Necrotizing or non-necrotizing granulomatous inflammation (fungal osteomyelitis) (Figures 3 and 4). x Lymphoplasmacytic or histiocytic inflammation (Treponema, Mycobacteria). x Bone necrosis with osteoclastic activity and bone resorption. x Fibrosis of the bone marrow cavity. x Reactive bone formation and periosteal reaction. x Identified organisms are diagnostic.

Figure 3. Granulomatous inflammation with visualized fungal organisms (arrow, H&E stain).

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Chapter 2

Ancillary studies: x Grocott’s methenamine silver stain (GMS) highlights fungal organisms (Figure 4). x Warthin-Starry highlights Treponema species. x Acid-fast bacteria (AFB) stain highlights Mycobacteria species.

Figure 4. GMS stain highlights fungal organisms (arrow).

Differential diagnosis: x Hematopoietic malignancies. x Langerhans cell histiocytosis. x Sarcoidosis. x Plasmacytoma/myeloma.

CHAPTER 3 ARTHRITIDES AND ARTHROPATHIES

Rheumatoid arthritis (RA) Definition: x Rheumatoid arthritis is a progressive, chronic, systemic autoimmune inflammatory disease affecting the synovial lining of joints, bursae, and tendon sheaths, leading to loss of articular cartilage and erosions of subchondral bone. Epidemiology: x More common in females than males, with a ratio of 3:1. x Patient’s age may range between 30- 55 years. x Commonly affects small joints of the hands, wrists, and feet. Clinical presentation: x May present as joint swelling, tenderness to palpation, decreased range of motion, morning stiffness, and warmth in multiple joints. x Rheumatoid nodules. x Systemic symptoms may include malaise, fatigue, anorexia, weight loss, low-grade fever, anemia, and occasionally interstitial lung disease. x Laboratory tests: Rheumatoid factor (RF) and anti-citrullinated protein antibody (ANTI-CCP or APCA) tests are diagnostic for the disease.

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Chapter 3

Imaging: x Diffuse, usually a multicompartmental symmetric narrowing of the joint spaces associated with marginal or central erosions, periarticular osteoporosis, periarticular soft tissue swelling., and joint effusion (Figure 1). x In a later stage, deformities of the joints and ankylosis (are more common in the juvenile form of RA (JIA). x Commonly affected are the hand's intercarpal, carpometacarpal, metacarpophalangeal, and proximal interphalangeal joints. However, the distal interphalangeal joints are most of the time preserved (Figure 2).

Figure 1. Anteroposterior (A) and lateral (B) radiographs of the knee show concentric narrowing of all three joint compartments, periarticular osteoporosis, and joint effusion.

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Figure 2. A hand radiograph shows severe osteoporosis, narrowing, and erosions of metacarpophalangeal and proximal interphalangeal joints associated with radial deviation in the radiocarpal joint and ulnar deviation of the fingers. Observe that the distal interphalangeal joints are not affected.

Pathology: Gross. x Joint deformities and destruction. x Hyperplastic, thick, and edematous synovium. Histopathology. x Hyperplastic change of synovium (Figure 3). x Synovium is involved with chronic inflammation, lymphoid follicles, and aggregates (Figure 4). x Fibrinoid exudate and chronic inflammation on the surface of the synovium. x Reactive synovium may cover the articular surface and destroy underlying cartilage.

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Chapter 3

x Subchondral bone may be involved with chronic inflammation. x Rheumatoid subcutaneous nodules were identified in one-fourth of the cases. x Rheumatoid nodule shows central fibrinoid necrosis rimmed by palisaded histiocytes and giant cells.

Figure 3. Hyperplastic change of synovium with lymphoid aggregates.

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Figure 4. Synovium is involved with chronic inflammation and lymphoid follicles and aggregates.

Chapter 3

46

Genetics: x Association with the susceptibility loci of HLA-DRB1 and PTPN22 genes. x Link to this arthritis was also associated with the 18q21 chromosome region of the TNFRSR11A gene, which encodes the receptor activator of nuclear factor-kB. x A common genetic variant at the TRAF1-C5 locus on chromosome nine is associated with an increased risk of anticitrullinated protein (CCP)positive RA. Prognosis: x Clinical course may be variable and unfavorable prognostic factors, including HLA-DR4 genotype, elevated level of RF antibodies, extraarticular manifestation, number of involved joints, patients younger than 30 years of age, women, and patients with systemic manifestations. Differential diagnosis: x x x x x x

Osteoarthritis. Erosive osteoarthritis. Juvenile inflammatory arthritis (JIA). Psoriatic arthritis. Septic arthritis. Crystal-induced arthropathies.

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Osteoarthritis (OA) Definition: x Also known as degenerative joint disease, OA is characterized by progressive cartilage and subchondral bone destruction associated with aging, trauma, or familial predisposition. Epidemiology: x It can be idiopathic or secondary to trauma, systemic diseases, or other underlying conditions. x There is no gender predisposition. x The risk of developing osteoarthritis increases with age; up to 80% of cases are in patients older than 65. x Most affected joints: knee, hip, interphalangeal of the hand, cervical, and lumbar spine. x Less common affected joints: shoulder, wrist, and elbow, usually secondary osteoarthritis. x Most cases are limited to one joint (monoarticular), bilateral involvement of the same joint, or multiple joints (polyarticular). Clinical presentation: x Joint pain, exacerbated by activity, joint stiffness, decreased range of motion, tenderness to palpation. x Focal swelling of joints, cracking, and locking the joints. Imaging: x With considerable joint involvement, radiography shows joint space narrowing, subchondral sclerosis, osteophytes, and cystic changes in the subchondral bone (Figure 1). x In the hand, narrowing and osteophyte formation in the distal interphalangeal joints (Heberden nodes) and the proximal interphalangeal joints (Bouchard nodes) (Figure 2). x MRI shows cartilage loss, degenerative meniscal tears, subchondral edema, and synovitis.

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A

B Figure 1. Anteroposterior (A) and lateral (B) radiographs of the knee show narrowing of the medial and femoropatellar joint compartments associated with subchondral sclerosis and osteophyte formation.

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Figure 2. A hand radiograph shows degenerative changes in the distal interphalangeal joints in the form of Heberden nodes and the proximal interphalangeal joints in the form of Bouchard nodes. The arrow points to degenerative changes in the first carpometacarpal joint, a common site of hand OA.

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Pathology: Gross. x x x x

Degeneration of cartilaginous surface (thinning, fragmentation). Eburnation (exposed subchondral ivory-like dense bone). Sclerotic bone changes underlying cartilage eroding. Severe degenerative changes may show cystic spaces lined by fibrous tissue filled with clear fluid, microfractures, and avascular necrosis. x Osteophytes (bony outgrowths at joint periphery). Histopathology. x Thinning and loss of articular cartilage (Figure 3). x Irregular thickening interface between cartilage and bone (reduplicated tidemark) (Figure 4). x Sclerosis of underlying cartilage bone with microfractures and cystic formation in long-standing cases. (Figure 5). x Synovial hypertrophy and hyperplasia. x Most cases do not show any inflammation; however, lymphocytic infiltration and lymphoid aggregates in synovium may be present.

Figure 3. Thinning and loss of articular cartilage.

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Figure 4. Irregular thickening of the interface between cartilage and bone (reduplicated tidemark).

Figure 5. Sclerosis of underlying cartilage bone with microfractures and cystic changes in long-standing cases.

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Genetics: x Several studies showed chromosomes 2q, 9q, 11q, and 16p linked to OA. x Implicated genes include VDR, AGC1, IGF-1, and TGF beta. x Most recent studies suggested that mutations in the gene GDF5 (cartilage-derived morphogenetic protein 1) can be linked with the etiology of OA of the hip and knee. Differential diagnosis: x Rheumatoid arthritis. x Septic arthritis. x Crystal-induced arthritis.

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Gout Definition: x Painful arthritis resulting from a disorder of purine metabolism, associated with the presence of monosodium urate monohydrate crystals in the synovial fluid leukocytes and, in many cases, gross deposits of sodium urate (tophi) in periarticular soft tissues. Epidemiology: x x x x x x x

x

Affects about 1–2% of the Western population. Mostly affects patients between 40 and 50 years of age. Male predominance. Most cases are associated with a genetic defect in the synthesis or excretion of purines, e.g., Lesh Nyhan Syndrome (hypoxanthineguanine phosphoribosyl transferase defect). Deposition of monosodium urate crystals is associated with alcohol, meat, or seafood consumption. Commonly seen in patients with obesity, hypertension, diabetes mellitus, and high lipid levels. Recent data from genome-wide association studies (GWAS) shows that genetic variants of SLC2A9/GLUT9 were associated with lower serum uric acid levels, and the values were higher among women. Conversely, genetic variants of protein ABCG2 were associated with higher serum uric acid levels, and the values were higher among men. Use of diuretics, niacin, ACE inhibitors, and beta blockers may be associated with gouty attacks.

Clinical presentation: x Painful attacks of acute arthritis (red, tender, and swollen joint), usually monoarticular, commonly affecting the great toe (podagra). x Other affected sites include ankles, knees, elbows, wrists, and fingers. x Deposition of tophi (sodium urate deposits) in the soft tissues around the joints. x Uric acid kidney stone formation and urate nephropathy.

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Imaging: x Periarticular erosions, sharply marginated, with characteristic “overhanging edge” feature, sparing part of the joint (Figure 1). x Periarticular erosions are asymmetric in distribution. x Soft tissue mass adjacent to the erosion (tophus) with an area of mineralization. x Minimal reactive sclerosis may be seen. x Dual-energy, color-coded CT images can accurately depict gouty tophi (Figure 2).

Figure 1. A radiograph of the great toe shows a para-articular erosion exhibiting an overhanging edge (arrows) with preservation of part of the joint (open arrow) and formation of soft tissue tophus (arrowheads). (Reprinted with permission of the Authors and Publishers from Greenspan A, Gershwin ME. Imaging in rheumatology. A clinical approach. 1st edition. Philadelphia, Wolters Kluwer, 2018, Fig. 7.5B, p. 273).

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Figure 2. Three dimensional reconstructed dual-energy CT color-coded image of the foot shows several urate tophi (green color).

Pathology: Gross. x Deposition of chalky-white tophi (uric acid crystals) in periarticular soft tissue and joints. x Destruction of adjacent bone and articular cartilage may be seen.

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Histopathology. x Accumulation of various-sized eosinophilic material rimmed by fibrous tissue, macrophages, and giant cells (Figures 3 and 4). x Crystals may be seen on H&E stain, but most of the time are dissolved during processing (it is essential to submit a gout specimen in alcohol). x Sodium urate crystals are needle-shaped (Figure 5) with negative birefringence (bright yellow under polarized light) (Figure 6). x The synovium shows villous hyperplasia and hypertrophy and hyperplasia of synoviocytes. x Synovial fluid cytology may show inflammatory exudate of polymorphonuclear leukocytes, macrophages, neutrophils, and lymphocytes and may be mistaken for septic inflammation.

Figure 3. Accumulation of various-sized eosinophilic material rimmed by fibrous tissue.

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Figure 4. Accumulation of various-sized eosinophilic material rimmed by fibrous tissue, macrophages, and giant cells.

Figure 5. Needle shaped monosodium urate crystals (H&E stain).

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Figure 6. Needle-shaped monosodium urate crystals under polarized light (bright yellow).

Differential diagnosis: x x x x

Pseudogout. Rheumatoid arthritis. Septic arthritis. Psoriatic arthritis.

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Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease Definition: x A condition characterized by the accumulation of CPPD crystals in intraarticular and periarticular tissues, most commonly within fibrocartilage and hyaline cartilage (chondrocalcinosis), frequently symptomatic (pseudogout syndrome), and leading to structural damage to the articular cartilage (calcium pyrophosphate arthropathy). Epidemiology: x Primary: hereditary or sporadic (most common) disorder. x Progressive ankylosis protein homolog encoded by the ANKH gene might be responsible for the disease. x Secondary: may be associated with hypothyroidism, hyperparathyroidism, hemochromatosis, or gout. x No gender predilection. x Most commonly, the patients are middle-aged and older. Clinical presentation: x The condition may be asymptomatic. x When symptomatic, acute joint pain is similar to one seen in gout (pseudogout syndrome). x Any joint in the body may be affected, including the spine, but the most common sites are the knee and metacarpophalangeal joints. Imaging: x Deposits of calcium in menisci fibrocartilage are most common (chondrocalcinosis) (Figure 1 A). x Punctate calcium deposits in synovial tissue may be identified. x Changes in the joints similar to osteoarthritis; however, the femoropatellar joint compartment is most severely affected (Figure 1 B), and in the hands – metacarpophalangeal joints (most commonly the second and third).

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(A)

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(B) Figure 1. Anteroposterior radiograph of the knee (A) shows calcifications of the medial and lateral menisci (chondrocalcinosis). A lateral radiograph (B) Lateral radiograph shows severe narrowing of the femoropatellar joint compartment, a characteristic feature of this condition.

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Pathology: Gross. x Small chalky-white deposits in affected tissue. Histopathology. x Deposition of calcium pyrophosphate rhomboid crystals ranging up to ten micromillimeters in length with weak positive birefringence (dim blue appearance) (Figure 2). x To preserve crystals for examination, they should be placed in ethanol fixative or evaluated fresh. x Inflammatory changes around crystal deposits may not be seen in neovascularized tissue (Figures 3 and 4). x In vascularized tissue, inflammation and foreign body giant cells around crystal deposits are seen. x Deposition of calcium pyrophosphate crystals in fibrocartilaginous menisci is commonly seen (Figure 5)

Figure 2. Accumulation of calcium pyrophosphate crystals deposits in synovial tissue with inflammatory changes at the periphery (mostly histiocytes).

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Figure 3. Accumulation of calcium pyrophosphate crystals in synovial tissue without an inflammatory response.

Figure 4. The higher power view shows the accumulation of calcium pyrophosphate dihydrate crystals (blue dye on H&E stain).

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Figure 5. Accumulation of calcium pyrophosphate dihydrate crystals in menisci fibrocartilage (blue dye on H&E stain).

Differential diagnosis: x x x x

Gout. Osteoarthritis. Neuropathic arthropathy. Hemochromatosis.

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Ankylosing spondylitis (AS) Definition: x Chronic, progressive, inflammatory arthritis principally affecting the synovial joints of the spine and sacroiliac joints. Epidemiology: x Begins in early adulthood. x Strong familial association. x Male to female ratio 7:1. Clinical presentation: x x x x

Back pain and stiffness. Sacroiliitis, bilateral and symmetric. Low-grade fever, anorexia, fatigue, and weight loss. Iritis, pulmonary fibrosis, cardiac conduction defects, aortic incompetence, spinal cord compression, amyloidosis. x Negative rheumatoid factor. x High percentage of patients (up to 95%) possess histocompatibility antigen HLA-B27. Imaging: x Shiny corners (Romanus lesion) at the anterosuperior and anteroinferior corners of the vertebral bodies. x Early findings of squaring off the vertebral bodies. x Formation of delicate, vertically oriented syndesmophytes bridging the anterior aspects of the vertebral bodies (Figure 1). x Fusion of the facet joints. x Paravertebral ossifications. x Ossifications of the supraspinous and interspinous ligaments (dagger sign) (Figure 2). x In later stages – bamboo spine (Figure 3). x Fusion of the sacroiliac joints.

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A

Figure 1. The lateral cervical spine radiograph (A) shows delicate anterior and posterior syndesmophytes bridging the vertebral bodies. Note the fusion of several apophyseal joints. The lateral coned-down lumbar spine radiograph (B) shows similar delicate vertically oriented syndesmophytes (arrows).

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Figure 2. Anteroposterior radiograph of the lumbar spine shows ossifications of supraspinous and interspinous ligaments, producing a “dagger sign” (arrows). Also, note the symmetrical bilateral fusion of the sacroiliac joints (arrowheads).

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Figure 3. Anteroposterior (A) and lateral (B) radiographs of the lumbar spine show the typical appearance of a “bamboo spine,” representing the advanced stage of ankylosing spondylitis.

Pathology: Gross. x Calcifications and ossifications of spinal ligaments and annulus fibrosus. x Anterior syndesmophytes are fusing the vertebral bodies (Figure 4). x Fused facet joints. Histopathology. x Diffuse proliferative synovitis of the diarthrodial joints. x The synovium shows villous hypertrophy and synoviocyte hyperplasia. Occasionally multinucleated synoviocytes are present. x The subintima contains a lymphoplasmacytic inflammatory cell infiltrate. x The superficial subintima and the synoviocyte layer contain scattered neutrophils.

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x Destructive lymphocyte-mediated inflammatory enthesopathy of the anterior and posterior aspects of the vertebral bodies at the site of the insertion of the fibers of the anterior and posterior longitudinal ligaments. x Eroded disk-bone interface is replaced gradually by vascular fibrous tissue containing necrotic bone fragments and scanty islands of fibrous tissue. x The destructive phase is followed by healing with the formation of new bone that extends along the line of damaged anterior and posterior longitudinal ligaments (formation of syndesmophytes).

A

B

Figure 4. A photograph of the sagittal section of the lumbar spine (A) shows anterior syndesmophytes (arrowheads) fusing the intervertebral disk spaces (arrowheads). Photomicrograph (B) shows marginal syndesmophytes (arrowheads) at the site of the annulus fibrosus. (Reprinted from Bullough P. Orthopedic pathology, 5th ed., Maryland Heights, MO, 2009, Mosby, with permission from Elsevier. It also appears as Fig. 14.70, p. 764 in Greenspan A, Beltran J. Orthopaedic imaging – A practical approach, 7th ed., Philadelphia 2021, Wolters Kluwer, reprinted with permission of the Authors and Publisher).

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Figure 5. The lymphocytic destructive inflammatory enthesopathy of ankylosing spondylitis is seen at high power magnification (left). At low power magnification (right), note erosion of bone (B) and disk tissue (D). (Reprinted with permission of the Authors and Publisher from Klein MJ, Bonar SF, Freemont T, et al. Atlas of nontumor pathology. Non-neoplastic diseases of bones and joints. Washington, DC, 2011. American Registry of Pathology in collaboration with the Armed Forces Institute of Pathology. Figure 10-13, p. 800).

Complications and prognosis: x Pathologic fractures of the fused spine. x Physical therapy prevents spinal deformities and loss of motion in the joints. x Non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and treatment with tumor necrosis factor (TNF) inhibitors alleviate the symptoms. x Surgery is limited to the stabilization of fractures. Differential diagnosis: x Copenhagen syndrome. x DISH syndrome. x Spinal spondylosis.

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Diffuse idiopathic skeletal hyperostosis (DISH) syndrome Definition: x

Noninflammatory spondyloarthropathy is characterized by flowing ossification along the anterior aspect of the vertebral bodies, extending across the disk spaces, and affecting at least four adjacent vertebral bodies.

Epidemiology: x x x

The disorder usually affects those over the age of fifty. Occurs more commonly in European and North American populations. Male to female ratio is 2:1.

Clinical presentation: x x

Stiffness of the spine. Dysphagia – if the cervical spine is affected.

Imaging: x x x x

The radiographic appearance of candle wax dripping down the anterior aspect of the spine (Figure 1). Disk spaces are usually preserved. Facet joints are typically preserved. Sacroiliac joints are preserved.

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B

A

Figure 1. Lateral radiographs of (A) cervical, (B) thoracic, and (C) lumbar spine show the characteristic flowing hyperostosis extending across the vertebral disc spaces.

C

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Histopathology: x x

Anterior osseous excrescences grow from the rims of the adjacent vertebra (Figure 2). Biopsy shows a mixture of woven and mature lamellar bone.

Figure 2. Osseous excrescences (arrows) grow from the rims of two adjacent vertebral bodies. (Reprinted with permission of the Authors and Publisher from Klein MJ, Bonar SF, Fremont T, et al. Atlas of nontumor pathology. Non-neoplastic diseases of bones and joints. Washington, DC 2011, American Registry of Pathology, figure 10-16, p. 802).

Differential diagnosis: x x x x

Ankylosing spondylitis. Spondylosis deformans. Melorheostosis. In the cervical spine – ossification of the posterior longitudinal ligament (OPLL).

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Sarcoidosis Definition: x Multisystemic inflammatory disease of unknown origin characterized histopathologically by the formation of noncaseating granulomas in affected organs. Epidemiology: x Worldwide distribution, with the most significant incidence in Sweden. x Most common in young adults. x Female predominance. Clinical presentation: x Diagnosis of sarcoidosis is mainly based on excluding other granulomatous inflammatory processes since there are no specific criteria for the disease. x Fatigue, weight loss, and night sweats are common. x Dyspnea, dry cough, and wheezing occur when the respiratory tract is affected. x Perihilar and paratracheal adenopathy. x Pleural effusion, pneumothorax, and respiratory failure may occur. x Cardiac involvement is associated with arrhythmias and heart failure. x Kidney involvement which accounts for about 5% of cases, is associated with nephrocalcinosis and interstitial nephritis. x Liver and spleen involvement presents with hepatosplenomegaly, portal hypertension, and cholestasis. x Lymph node involvement presents with peripheral lymphadenopathy; lymph nodes are swollen but not painful (20 %). x The bones and joints are involved in 10-35% of osteoporosis, arthralgia, and arthritis cases. x Soft tissue swelling and cutaneous lesions of the hands and feet are associated with osseous changes. x Maculae, papules, and plaques are common manifestations of skin involvement. x Eye involvement is seen in more than 40% of patients and manifests by photophobia, pain, and hyperemia.

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x Laboratory findings include decreased serum albumins, hypercalcemia.

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anemia, leukopenia, eosinophilia, elevated serum globulins, and

Imaging: x Cystic, punch-out lesions, lacy reticulations, and honeycomb pattern of destruction predominantly in short tubular bones of the hands and feet (Figure 1). x Rarely osteosclerosis of the terminal tufts.

Figure 1. Dorsovolar radiograph shows destructive lesions of the right hand's distal phalanx of the right hand's ring finger and proximal and distal phalanges of the index and middle fingers of the left hand. Note the destructive lesion in the left lunate (curved arrow) and the left distal radius (arrow).

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Histopathology: x Noncaseating epithelioid granulomas within the synovium (usually in subintima) with tightly packed epithelioid histiocytic cells, Langhans giant cells, and lymphocytic infiltrates (mostly T cells) (Figures 2 and 3). x Within granulomas, one can see diffuse interstitial fibrosis, hyalinization, and fibrinoid necrosis. x Characteristic presence of intracytoplasmic inclusions of two types: laminated concretions composed of calcium and proteins (so-called Schaumann bodies) and stellate inclusions with a central core of degenerating organelles encompassed but multiple rays of collagen filaments (so-called asteroid bodies).

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Figure 2. Low power view shows noncaseating granulomas with interstitial fibrosis.

Figure 3. The higher power view shows noncaseating epithelioid granulomas with tightly packed epithelioid histiocytic cells, Langhans giant cells, and lymphocytic infiltrates.

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Immunopathogenesis and genetics: x A magnified cell-mediated immune response can cause granulomatous inflammation to one or more unspecified antigen(s). x Possible etiologic agents include occupational and environmental exposures (beryllium, zirconium, aluminum), infectious agents (mycobacteria), Kveim-Siltzbach reagent, and serum amyloid A. x There is an increase in pulmonary T cell CD4:CD8 ratio and T cellderived cytokines IL-2 and IFN-gamma. x Genetic predisposition to sarcoidosis was linked with major histocompatibility complex (MHC) antigens. x Predisposition to acute sarcoid arthritis is carried by the HLA DQ2-DR3 haplotype transmitted as a dominant genetic trait. x The active granulomatous inflammation is associated with a dominant expression of T-helper (Th) 1-cytokines (interferon gamma [IFNgamma]), IL-12 and IL-18, and tumor necrosis factor (TNF). x Butyrophilin-like 2 (BTNL2) and annexin A11 (ANXA11) genes may be associated with increased sensitivity for sarcoidosis. Differential diagnosis: x x

Multicentric reticulohistiocytosis. Psoriatic arthritis.

CHAPTER 4 TRAUMATIC BONE ABNORMALITIES

Bone fractures Definition: x Loss of bone integrity due to trauma, overuse, or disease that weakens the bone structure. Epidemiology: x Most common traumatic fractures caused by falls, sports injuries, and car accidents. x Overuse stress fractures are seen in athletes. x Pathologic fractures occur due to medical conditions such as osteoporosis, infection, metastatic and primary bone neoplasms, or metabolic bone disease. Clinical presentation: x Pain is the most common feature. x Fractures are classified based on location, orientation, and presentation. x Bone fracture location described as proximal, distal, anterior, posterior, medial, and lateral. x Fracture orientation: transverse (across the bone), oblique (at an angle), spiral (extend down the length of the bone), comminuted (multiple fragments). x In children’s specific terms include greenstick (in young children with an immature skeletal system, bones tend to bow and not to break completely) and a torus (incomplete fracture in young children).

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Imaging: x

The radiographic evaluation of fractures includes: anatomic site and extent. the type of fracture – complete (adults, children) or incomplete (children); simple or compound (open); acute, subacute, or chronic; intra- or extraarticular; simple or comminuted; displaced or nondisplaced. - the alignment of the fragments regarding displacement, angulation, rotation, or foreshortening (Figure 1). - the fracture line (transverse, oblique, spiral, longitudinal). - the presence of specific features (impaction, depression, compression, distraction). - particular types (stress, insufficiency, pathologic) (Figure 2). x In children, the evaluation of fractures takes into consideration the involvement of the growth plate (physis): - Salter-Harris I – fracture through the growth plate, - Salter-Harris II –fracture through the growth plate and metaphysis, - Salter-Harris III – fracture through the growth plate and epiphysis (Figure 3), - Salter-Harris IV – fracture through the growth plate, metaphysis, and epiphysis, - Salter-Harris V – compression fracture through the growth plate, - Salter Harris VI (Rang) – trauma to the perichondrium (tethering of the growth plate), - Salter-Harris VII (Ogden) – fracture of epiphysis (chondral or osteochondral fracture), - Salter-Harris VIII (Ogden) – fracture of the metaphysis, - Salter-Harris IX (Ogden) -- evulsion injury to the periosteum. x Fracture healing and complications: - external (periosteal) or internal (endosteal) callus formation. - delayed union – fracture not healed within 16-24 weeks. - nonunion (pseudoarthrosis) – fracture not healed within nine months. - disuse osteoporosis. - reflex sympathetic dystrophy syndrome. - Volkman ischemic necrosis. - posttraumatic myositis ossificans. - osteonecrosis (ischemic necrosis, avascular necrosis). - growth disturbance (in immature skeleton). - posttraumatic arthritis. -

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B

Figure 1. Anteroposterior (A) and lateral (B) radiographs of the elbow demonstrate the extension of the fracture lines and the position of the various fragments. The capitellum is separated, laterally displaced, and subluxed (arrow); the lateral supracondylar ridge is avulsed and anterolaterally displaced (open arrow), and the medial epicondyle is externally rotated and medially displaced (curved arrow).

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Figure 2. Anteroposterior radiograph of the distal femur shows a lesion in the medullary portion of bone complicated by a pathologic fracture (arrow).

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Figure 3. 3D reconstructed color-coded CT image of the ankle with surfacerendering algorithm shows a fracture through the growth plate of the distal tibia (arrow) extending through the epiphysis (arrowhead), classified as Salter-Harris type III.

Pathology: Gross. x Loss of bone integrity with hemorrhage and involvement of adjacent tissue. Histopathology. x Fracture healing stages: - Hematoma formation: hematoma form around the fracture site with pro-inflammatory cytokine secretion (e.g., tumor necrosis factor-alfa TVF-alfa), which stimulate attraction of macrophages, monocytes and lymphocytes (days 1 to 5).

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-

-

-

Fibrocartilaginous callus formation: released vascular endothelial growth factor (VEGF) triggers angiogenesis and formation of fibrinrich granulation (Figure 4). The next step is the recruitment of fibroblasts, chondroblasts, and osteoblasts by BMP bone morphogenic proteins, which results in the production of the collagen-rich fibrocartilaginous network (fibrocartilaginous callus) (days 5 to 11) (Figure 5). Bony callus formation: RANK-L expression stimulates chondroblasts, osteoclasts, and osteoblasts with results in resorption of cartilaginous callus and formation of woven bone, which forms hard calcified callus of immature bone (days 11-28). Bone remodeling: migration of osteoclasts and osteoblasts causes repeat hard callus remodeling, which may last for months and in the form of normal regenerated bone (day 18, lasting for months).

Figure 4. Fibrin-rich granulation in fracture healing triggered by vascular endothelial growth factor (VEGF).

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Figure 5. Fibrocartilaginous and bony callus formation in the area of the previous fracture.

Prognosis: x Depends on the extent of the fracture, location, and patient age. x Treatment includes closed reduction and immobilization or open reduction and internal fixation. Differential diagnosis: x Chronic osteomyelitis. x Osteosarcoma. x Chondrosarcoma.

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Osteonecrosis (ischemic necrosis, avascular necrosis) Definition: x Noninfectious bone necrosis due to vascular insufficiency (ischemic necrosis) or infarct (avascular necrosis). Epidemiology: x Mostly seen in middle-aged or older patients. x May be unifocal, bilateral, or multifocal. x Main causes - Trauma (fracture of femoral neck, dislocation of femoral head, burns, radiation exposure) - Alcohol consumption, cigarette smoking - Vasculitis - Hemoglobinopathies and other blood disorders (sickle cell disease, hemophilia, polycythemia) - Local infiltrative lesions (Gaucher disease, Fabry disease, sarcoidosis, lymphoproliferative disorders) - Congenital disorders (Ehlers-Danlos syndrome, Legg-Calve-Perthes disease, hereditary dysostosis) - Metabolic conditions (corticosteroid medications, Cushing disease, hyperlipidemia) - Rheumatologic conditions (rheumatoid arthritis, necrotizing arteritis, systemic lupus erythematosus) - Infectious and inflammatory conditions (osteomyelitis, pancreatitis, chronic liver disease, HIV) - Idiopathic Clinical presentation: x x x x

May present as reduced and painful joint motion. Mostly affects hip (femoral head) and knee (femoral condyles). In the hand, it affects the scaphoid and lunate bones (Kienbock disease). Pathologic fracture may occur.

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Imaging: x Preliminary stages show no or minor changes. x Subchondral crescent sign is a characteristic feature (Figure.1). x Later stages may show flattening of the articular surface, subchondral collapse, joint space narrowing, and degenerative changes (Figure 2). x MRI is an effective imaging modality to diagnose osteonecrosis (Figure 3).

Figure 1. The radiograph of the hip shows the crescent sign (arrow).

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Figure 2. A radiograph of the pelvis shows an advanced stage of osteonecrosis of both femoral heads with subchondral collapse.

A

B

Figure 3. Coronal T1-weighted MR image of the hip (A) shows a serpentine band of low signal intensity (arrows) representing the reactive interface surrounding the central area of bone necrosis. Coronal short-time inversion recovery (STIR) pulse sequence MRI (B) shows a serpentine low signal intensity line adjacent to a high signal intensity line (arrows), a so-called double-line sign of osteonecrosis.

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Pathology: Gross. x Yellow subchondral necrotic bone with marginal fibrosis. x Subchondral infarct demarcated from the viable bone by a zone of hyperemia and fracture of subchondral bone (Figure 4).

A

B

Figure 4. A Photomicrograph of the coronal section of the femoral head specimen (A) shows the subchondral infarct (yellow) demarcated from the viable bone by a zone of hyperemia (red). Note the crescent sign representing a fracture of the subchondral bone. A radiograph of the same specimen (B) shows the crescent sign. (Reprinted with permission of the Authors and Publisher from Greenspan A, Beltran J. Orthopaedic Imaging – A practical approach, 7th ed., Philadelphia 2021, Wolters Kluwer, figure 4.88 A, B, p. 117).

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Histopathology. x Necrosis of subchondral bone, fat, and hematopoietic tissue with sharp peripheral collagenized rim separating necrotic bone from viable tissue (Figure 5).

Figure 5. Necrosis of subchondral bone, fat, and hematopoietic tissue with sharp peripheral collagenized rim separating necrotic bone from viable tissue.

Prognosis: x May result in cartilage detachment and secondary degenerative change (secondary osteoarthritis). x Osteonecrosis of the femoral head usually requires resection of the femoral head followed by either hemiarthroplasty or total hip arthroplasty. x In the early stages core decompression procedure may provide positive results. Differential diagnosis: x Osteoarthritis. x Subchondral insufficiency fracture. .

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Myositis ossificans (MO) Definition: x Benign fibro-osseous pseudotumor of soft tissue exhibiting a characteristic zonal phenomenon consisting of immature osseous tissue in the center and more mature bone at the periphery. Epidemiology: x Wide age ranges from 1 to 95 years, with a mean age of 32. x Male to female ratio 3:2. Clinical presentation: x Rapidly growing painful soft tissue mass. The pain tends to become more localized and may increase in intensity for 4 to 6 weeks. x History of trauma common. x May develop anywhere in the body; however, common locations include the elbow area, shoulder, buttocks., and thighs (involve large skeletal muscles). x Lesions involving digits of hands are known as fibro-osseous pseudotumor of digits. Imaging: x On radiography, the early lesions show features of soft tissue mass. x Later stages of the lesion show well-circumscribed ossific mass with characteristic zonal phenomenon consisting of well-mature bone on the periphery and less mature, more radiolucent center. The lesion is commonly separated from the adjacent cortex by a narrow cleft (Figure 1). x Zonal phenomenon is well demonstrated on CT images (Figure 2). x Characteristically, with time, the lesion becomes smaller with an increased maturation pattern.

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A

B Figure 1. Anteroposterior hip (A) radiograph shows a mineralized lesion within the soft tissues adjacent to the lateral cortex of the proxinmproximal exhibiting features of the zonal phenomenon. On the frog-lateral projection (B), note the cleft (arrows) separating the ossific mass from the posterolateral cortex, a characteristic feature of juxtacortical myositis ossificans.

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Figure 2. Axial CT of the shoulder shows an ossific mass within the soft tissues adjacent to the humeral cortex. High attenuation of the periphery of the lesion and low attenuation of its center (zoning phenomenon) are characteristic features of juxtacortical myositis ossificans. Observe also a narrow cleft separating the ossific mass from the adjacent cortex.

Pathology: Gross. x More mature lesions show external ossification and central soft tissue component.

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Histopathology. x Less mature tissue in the center of the lesion and more mature at the periphery. x Early lesions show the proliferation of myofibroblast cells with loose vesicular growth patterns, myxoid stroma, chronic inflammation, and extravasated red blood cells (Figure 3). x Stellate or fusiform myofibroblast cells have round to ovoid nuclei with one or two nucleoli and pale eosinophilic cytoplasm (Figure 4). x Rare mitotic activity in myofibroblast cells. x Necrosis is absent. x In time, zonation with peripheral ossification and central spindle cell proliferation becomes prominent. x Ossified zone shows bone with osteoblastic rimming, hyaline, or fibrocartilage which may resemble callus formation. x More mature lesions show an external ossified zone composed of lamellar bone without osteoblastic rimming, and marrow fat may be prominent (Figure 5).

Figure 3. The proliferation of myofibroblast cells with loose vesicular growth patterns, myxoid stroma, and chronic inflammation.

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Figure 4. Stellate or fusiform myofibroblast cells have round to ovoid nuclei with one or two nucleoli and pale eosinophilic cytoplasm.

Figure 5. External ossified zone composed of lamellar bone without osteoblastic rimming and marrow.

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Immunohistochemistry: x Myofibroblast may express smooth muscle actin (MSA) and desmin. x USP6 rearrangements have been described. Prognosis: x Local excision is curative with rare recurrences. Differential diagnosis: x x x x x

Nodular fasciitis. Fracture callus. Soft tissue osteosarcoma. Parosteal osteosarcoma. Periosteal osteosarcoma.

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Posttraumatic intraarticular osteochondral body(bodies) – Osteochondritis dissecans (OD); Osteochondral fracture Definition: x Osteocartilaginous fragment (s) floating in the joint space or embedded in synovial tissue. Epidemiology: x Most affected are middle-aged and older patients (osteochondral fracture). x Most affected are children and adolescents (osteochondritis dissecans). x Most common site is the knee joint. x Males are more commonly affected. Clinical presentation: x Decreased joint range of motion, pain, stiffness, and swelling. x Frequently joint effusion. x In some cases, it may present as a single soft tissue mass. Imaging: x OD most frequently affects the non-weight-bearing portion of the medial femoral condyle (the lateral aspect of the condyle and the intercondylar notch). x The imaging appearance depends upon stages of OD: osteochondral body in-situ, osteocartilaginous flap, detached osteochondral body, or dislodged osteochondral body into the joint (Figure 1). x May present as calcified or ossified nodules in the joint space. x MRI is the most accurate imaging modality to provide information about the status of articular cartilage covering the osteocartilaginous body (Figure 2). x Imaging findings of osteochondral fracture are similar to OD, but there is a history of the traumatic event (Figure 3).

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C Figure 1. Postero-anterior tunnel (A) and lateral (B) radiographs of the knee show a defect in the subchondral bone at the inferocentral aspect of the lateral femoral condyle (arrows) and an osteochondral body that has been discharged into the joint (curved arrow). Arthrography (C) shows contrast filling the subchondral defect (open arrow), indicating damage to the articular cartilage.

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Figure 2. Coronal proton density-weighted MR image (A) shows an osseous fragment well separated from the medial femoral condyle by the low-signal intensity line (arrow). Sagittal MRI (B) demonstrates intact articular cartilage overlying the in-situ osteochondral body.

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C Figure 3. Anteroposterior (A), lateral (B), and tunnel (C) views of the knee reveal joint fluid (white arrow), infrapatellar soft tissue swelling (open arrow), a defect in the lateral femoral condyle (black arrow), and a large osteochondral body (curved arrow), representing an osteochondral fracture.

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Pathology: Gross. x Nodule with a smooth, glistening surface. Histopathology. x Hyaline and fibrocartilage surrounding the ossified lesion center (Figure 4). x Presence of tidemark at the osteochondral junction (Figure 5).

Figure 4. Hyaline and fibrocartilage surround the ossified center of the osteochondral loose body.

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Figure 5. Presence of tidemark at the osteochondral junction of osteochondral loose body.

Differential diagnosis: x Synovial osteochondromatosis. x Osteoarthritis complicated by intraarticular osteochondral bodies.

CHAPTER 5 TUMORS AND TUMOR-LIKE LESIONS

(A) BONE FORMING (OSTEOGENIC) TUMORS Osteoma Definition: x Benign tumor composed primarily of lamellar/cortical-type bone arising on the surface of bone cortex. Epidemiology: x Mostly incidental findings. x Commonly diagnosed between the fourth and fifth decade of life. x No gender predilection. Clinical presentation: x Slow growing and asymptomatic. x Most lesions affect calvaria, facial and jaw bones, paranasal sinuses, and occasionally long and short tubular bones. x If located in paranasal sinuses, it may cause mucocele, sinusitis, nasal discharge, and headache. x Multiple osteomas are identified in autosomal dominant Gardner syndrome (colonic polyposis, skin fibromatosis, desmoid tumors, and epidermal and sebaceous skin cysts). Imaging: x Present as a homogeneously dense ivory-like sclerotic mass attached to the bone surface without cortical invasion (Figure 1).

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Figure 1. A radiograph of the femur shows osteoma as a dense, well-defined ivorylike lesion attached to the underlying cortex without invasion. (Reprinted with permission of the Authors and Publisher from Greenspan A, Borys D. Radiology, and pathology correlation of bone tumors. A quick reference and review. Wolters Kluwer, Philadelphia 2016, fig. 2.1 A, p. 33).

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Pathology: Gross. x Well-circumscribed mass broadly attached to the underlying cortex. Histopathology. x Composed of mature lamellar/cortical-type bone and divided into compact (Figures 2 to 4) and cancellous subtypes. x In the cancellous type, the bone may be well-vascularized and moderately cellular, with fibrous stroma filling the marrow spaces. x Osteoblasts and osteocytes are unnoticeable.

Figure 2. Osteoma is composed of dense, compact bone.

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Figure 3. Compact bone with fibrous stroma filling marrow spaces.

Figure 4. Dense, compact bone with Haversian channels.

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Prognosis: x Those occurring on the surface of long or short tubular bones have an excellent prognosis. No recurrence after surgical excision. x Symptomatic lesions (particularly those occurring in the paranasal sinuses) can also be surgically excised. Differential diagnosis: x x x x x x x x

Normal cortex. Osteoid osteoma. Juxtacortical myositis ossificans. Monostotic form of melorheostosis (forme fruste). Sessile osteochondroma. Periosteal osteoblastoma. Ossified parosteal lipoma. Parosteal osteosarcoma.

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Osteoid osteoma Definition: x Benign bone-forming lesion with characteristic small nidus ( 2.0 cm). Epidemiology: x Less than 1% of primary bone tumors and 3% of all benign bone tumors. x Majority of cases (75%) were seen in patients 10 to 30 years old. x Male to-female ratio 2.5:1. Clinical presentation: x Frequently painful; however, NSAID does not always provide relief, unlike in osteoid osteoma. x Osteoblastoma of the spine may cause back pain, scoliosis, and nerve root compression. x Jaw lesions may produce tooth pain. x Most cases are seen in the spine, followed by pelvic bones, femur, and proximal tibia. x Osteoblastoma of the jaw, also known as cementoblastoma, may be attached to the tooth’s root. x Toxic osteoblastoma, a rare variant, has been recognized, exhibiting systemic manifestations including diffuse periostitis, fever, and weight loss. Imaging: x Osteoblastoma has four distinctive radiographic presentations: - A giant osteoid osteoma. Radiolucent, well-circumscribed oval or round lesion, usually more than 2 cm in diameter, exhibits less sclerosis and more prominent periosteal reaction than o.o. (Figure 1). - A expansive blow-out lesion like an aneurysmal bone cyst with small radiopacities in the center. This pattern is particularly common in lesions involving the spine. - An aggressive lesion simulates a malignant tumor. - Periosteal lesion that lacks peripheral bone sclerosis but exhibits a thin shell of newly formed periosteal bone.

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x In the spine usually involves posterior elements and may be associated with a secondary aneurysmal bone cyst.

Figure 1. A radiograph of the humerus shows a lytic well-circumscribed oval lesion (> 2cm) with little surrounding reactive sclerosis (sclerotic rimming) but a prominent periosteal reaction. (Reprinted with permission of the Authors and Publisher from Greenspan A, Borys D. Radiology, and pathology correlation of bone tumors. A quick reference and review. Wolters Kluwer, Philadelphia 2016, fig. 2.11 A, p. 41).

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Pathology: Gross. x Red or red-brown (vascular), soft and friable, often gritty or sandpaper in consistency, variable size ranging from 2 to 3 cm. x May show bone expansion with cortical thinning or perilesional sclerosis. Histopathology. x Composed of interconnecting, woven bone spicules or trabeculae lined by a single layer of osteoblasts (Figure 2). x Scattered osteoclast-type multinucleated giant cells may be present (Figure 3). x No nuclear pleomorphism or atypia. x Loose, rich vascular stroma with dilated type capillary vessels and sometimes red blood cell extravasation (Figure 4). x Focal blood-filled spaces mimicking aneurysmal bone cysts may be present (Figure 5). x No destructive bone permeation.

Figure 2. Osteoblastoma is composed of interconnecting, woven bone spicules or trabeculae lined by a single layer of osteoblasts.

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Figure 3. The proliferation of osteoblasts with woven bone production (osteoblastic rimming) and scattered osteoclast-like giant cells.

Figure 4. Osteoblastic proliferation with no nuclear atypia, loose vascular stroma, and scattered osteoblast-like giant cells.

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Figure 5. Blood-filled spaces resemble aneurysmal bone cyst.

Immunohistochemistry and genetics: x FOS gene rearrangement, or rarely FOSB gene rearrangement, is found in most osteoblastoma. Prognosis: x Prognosis is good. x Treatment with curettage and en-block resection. x Recurrences unusual if well excised. Differential diagnosis: x x x x x

Osteoid osteoma. Giant cell tumor. Aneurysmal bone cyst. Bone abscess. Osteoblastic osteosarcoma.

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Osteosarcomas Conventional osteosarcoma (osteoblastic, chondroblastic, fibroblastic) Definition: x Primary malignant high-grade bone tumor producing immature osteoid. Epidemiology: x Most common primary non-hematopoietic bone tumor comprising approximately 20% of all primary bone malignancies. x Incidence of 4-5 per million population. x Mostly affects patients younger than 25 years. x Male to-female ratio 1.3:1. Clinical presentation: x Presents as deep-seated, progressively enlarging (weeks to months), painful mass which may restrict motion of the affected joint. x Pathologic fractures were discovered in 5 – 10 % of cases. x Mostly involves long bones of extremities, with the most common sites being the distal femur, proximal tibia, and proximal humerus. x Mostly centered in the metaphysis (90%) followed by diaphysis (9%), and rarely in the epiphysis. x Osteosarcoma of the jaws primarily occurs in the third to fourth decades of life. Imaging: x Present as a large, ill-defined, destructive, mixed lytic and blastic mass accompanied by cortical destruction and tumor extension into soft tissue (Figure 1). x Periosteal elevation (Codman's triangle) seen due to tumor growth. x Cortical destruction and mechanical displacement of the periosteum may produce reactive ossification, which may be perpendicular to the "sunburst” or parallel to the tumor (Figure 2). x CT and MRI may be helpful in delineating the tumor extent to soft tissue.

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Figure 1. Radiograph of the proximal tibia shows a large, ill-defined, destructive, mixed lytic and sclerotic lesion within the medullary portion of bone accompanied by cortical destruction and tumor extension into soft tissue (Reprinted with permission of the Authors and Publisher from Greenspan A, Borys D. Radiology, and pathology correlation of bone tumors. A quick reference and review. Philadelphia 2016, Wolters Kluwer, fig. 2.21 A, p. 52.)

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Figure 2. A radiograph of the distal femur shows sclerotic changes within the bone and cortical destruction with periosteal reaction in the form of a “sunburst” appearance. (Reprinted with permission of the Authors and Publisher from Greenspan A, Borys D. Radiology, and pathology correlation of bone tumors. A quick reference and review. Philadelphia 2016, Wolters Kluwer, fig. 2.19 B, p. 51).

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Figure 3. Coronal T1-weighted MR image of the distal femur (A) shows a large intermediate-to-low signal intensity tumor in the bone marrow associated with a large soft tissue mass. After intravenous administration of gadolinium, there is diffuse enhancement of both tumor and soft tissue mass (B). (Reprinted with permission of the Authors and Publisher from Greenspan A, Borys D. Radiology and pathology correlation of bone tumors, Philadelphia 2016, Wolters Kluwer, fig. 2.27, p. 55).

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Pathology: Gross. x Large (over 5 cm), metaphyseal centered, fleshy, hard mass with variable extension to adjacent parts of bone, diaphysis, epiphysis, and soft tissue (Figure 4). x Heavily mineralized tumors show tan-white/yellow and densely solid cut surfaces. x Non-mineralized cartilaginous component shows grey to the rubbery cut surface. x Necrosis, hemorrhage, and cystic changes may be identified.

Figure 4. The gross specimen shows a large, metaphyseal-centered, fleshy, hard mass with extension to the adjacent diaphysis, epiphysis, and into soft tissues.

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Histopathology. x Based on the predominant component, conventional osteosarcoma is divided into three subtypes: osteoblastic (50%), chondroblastic (25%), and fibroblastic (25%). x The tumor grows in an expansile, permeative pattern, replacing bone marrow space and eroding bone trabeculae and cortex. x Tumor cells show prominent pleomorphism and may be epithelioid, plasmacytoid, fusiform, ovoid, small round cells, clear cells, mono- or multinucleated giant cells, or spindle cells with characteristic production of osteoid (nonmineralized bone) (Figure 5). x Cells growing in sheets may predominate with scant matrix and variable cellularity. x Increased mitotic activity with atypical mitotic figures. x Conventional osteosarcoma may produce varying amounts of cartilage and fibrous tissue.

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Osteoblastic osteosarcoma: x Neoplastic epithelioid to spindle tumor cells are producing immature neoplastic bone as thin, lace-like trabeculae (Figure 5). x The extremes of matrix production are thin arborizing osteoid to dense, compact osteoid and bone (sclerotic) (Figure 6). x Osteoid production (immature bone) is a characteristic and predominant component in osteoblastic osteosarcoma compared to other subtypes (Figure 7).

Figure 5. The proliferation of epithelioid to spindle tumor cells producing immature osteoid together with prominent pleomorphism is characteristic of osteoblastic osteosarcoma.

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Figure 6. Characteristic thin arborizing dense osteoid produced by pleomorphic tumor cells.

Figure 7. Osteoid production, which comprises the predominant matrix in osteoblastic osteosarcoma.

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Chondroblastic osteosarcoma: x Chondroid matrix is predominant (Figure 8) x High-grade hyaline cartilage is admixed with non-chondroid, mostly osteoblastic osteosarcoma components (Figure 9) x There is no sharp margin between the two components.

Figure 8. In chondroblastic osteosarcoma chondroid matrix is predominant.

Figure 9. High-grade hyaline cartilage admixed with non-chondroid, mostly osteoblastic components without sharp margination between two parts.

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Fibroblastic osteosarcoma: x A high-grade spindle-cell malignancy with a minimal osseous matrix with or without cartilage (Figures 10 and 11). x In general, the overall histological appearance is like fibrosarcoma or pleomorphic undifferentiated sarcoma (malignant fibrous histiocytoma). In these cases, it is essential to correlate with patient age and radiologic findings.

Figure 10. Fibroblastic osteosarcoma is composed of spindle cell proliferation with a minimal osseous matrix.

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Figure 11. The proliferation of spindle cells with prominent pleomorphism and scant osteoid production.

Immunohistochemistry and genetics: x Positive for SATB2 immunohistochemistry stain. x High-grade osteosarcoma is characterized by genetic instability and multiple mutations. x Structural abnormalities were found in chromosomes 1p11-p13, 1q11q12, 1q21-q22, 11p14-p15, 14p11-p13, and 19q13. x Losses of portions of chromosomes 3q,6q, 9,10,13, 17p, and 18q, and gain of portions of chromosomes 1p, 1q, 6p, 8q, and 17p are the most common abnormalities. x Gains of chromosome arms 6p (RUNX2, VEGFA, E2F3) and 8q (MYC) were detected in about 50% of cases. x FGFR1 amplifications were demonstrated in 18.5% of cases. x Homozygous loss of CDKN2A (p16) occurs in about 10% of cases and is associated with an adverse outcome. x RB1 was deleted in about 50% of osteosarcomas. x Osteosarcoma can have increased incidence in many syndromes such as Li–Fraumeni syndrome (TP53 gene mutations or loss of heterozygosity/deletions, tumor predisposition syndrome),

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x Hereditary retinoblastoma (deleted RB1 gene), Bloom syndrome (BLM [RECQL3]), Werner syndrome (WRN), and Rothmund–Thomson syndrome (mutations in RECQL4 gene, chromosome 8q24.3). Prognosis: x Untreated, conventional osteosarcoma is fatal. x Aggressive local growth and rapid hematogenous systemic dissemination are bad prognostic features. x Pulmonary metastases are the most frequent site of clinically significant systemic disease. x In children, the treatment of conventional osteosarcoma is targeted to the location, size, and stage of the tumor. x Limb salvage resection is the convention for appendicular tumors, and surgical excision in combination with radiation is employed for tumors that are not entirely respectable with negative margins. x Adjuvant chemotherapy is usually employed in the preoperative setting and continued after surgical resection. x Survival is related to response to neoadjuvant therapy. In those patients whose tumors have >90% tumor necrosis, long-term survival is 80-90%. x In patients with < 90% response to therapy, survival is poor, usually