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Save time identifying and diagnosing pathology specimens with High Yield Bone and Soft Tissue Pathology, edited by Drs. Andrew Horvai and Thomas Link. Part of the High-Yield Pathology Series, this title is designed to help you review the key pathologic features of bone and soft-tissue malformations, recognize the classic look of each disease, and quickly confirm your diagnosis. Its templated format, excellent color photographs, concise bulleted text, and authoritative content will help you accurately identify more than 160 discrete disease entities.

  • Find information quickly and easily with a templated, easy-to-reference format.
  • Confirm your diagnoses with excellent color photographs that demonstrate the classic appearance of each disease.
  • Find the answers you need fast with concise, bulleted text.
  • Depend on authoritative information from leading experts in the field.


Osteogénesis imperfecta
Embryonal rhabdomyosarcoma
Nuchal fibroma
Palisaded encapsulated neuroma
Inflammatory myofibroblastic tumor
Fibroma of tendon sheath
Mesenchymal chondrosarcoma
Chondromyxoid fibroma
Cutaneous myxoma
Spindle cell lipoma
Chondroid lipoma
Solitary neurofibroma
Plexiform fibrohistiocytic tumor
Collagenous fibroma
Intravascular papillary endothelial hyperplasia
Angiolymphoid hyperplasia with eosinophilia
Metastatic carcinoma
Epithelioid hemangioendothelioma
Fibrous hamartoma of infancy
Fibromatosis colli
Aponeurotic fibroma
Kaposi's sarcoma
Osteoid osteoma
Alveolar rhabdomyosarcoma
Juvenile xanthogranuloma
Traumatic neuroma
Aneurysmal bone cyst
Synovial chondromatosis
Acute myeloid leukemia
Subungual exostosis
Ossifying fibroma
Pyogenic granuloma
Osteitis fibrosa cystica
Giant cell
Large cell
Desmoplastic fibroma
Inclusion body
Malignant peripheral nerve sheath tumor
Langerhans cell histiocytosis
Fibrous dysplasia of bone
Benign fibrous histiocytoma
Dermatofibrosarcoma protuberans
Hereditary multiple exostoses
Paget's disease of bone
Ewing's sarcoma
Squamous cell carcinoma
Multiple myeloma
Soft tissue
Soft tissue sarcoma
Necrotizing fasciitis
Rheumatoid arthritis
Magnetic resonance imaging


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High-Yield Pathology
Bone and Soft Tissue Pathology
Andrew E. Horvai, MD, PhD
Associate Clinical Professor, Department of Pathology,
University of California, San Francisco, San Francisco,
Thomas Link, MD
Professor in Residence, Department of Radiology, University
of California, San Francisco, San Francisco, California
S a u n d e r sFront Matter
High-Yield Pathology Bone and Soft Tissue Pathology
Andrew E. Horvai, MD, PhD
Associate Clinical Professor, Department of Pathology, University of
California, San Francisco, San Francisco, California
Radiology Editor
Thomas Link, MD
Professor in Residence, Department of Radiology, University of California,
San Francisco, San Francisco, California>
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
Copyright © 2012 by Saunders, an imprint of Elsevier Inc.
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copyright by the Publisher (other than as may be noted herein).
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With respect to any drug or pharmaceutical products identi ed, readers are
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To the fullest extent of the law, neither the Publisher nor the authors,contributors, or editors assume any liability for any injury and/or damage to
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Library of Congress Cataloging-in-Publication Data
Bone and soft tissue pathology / [editor], Andrew E. Horvai; radiology editor,
Thomas Link. — 1st ed.
p. ; cm. — (High-yield pathology)
Includes index.
ISBN 978-1-4377-2520-9 (hardcover : alk. paper)
I. Horvai, Andrew E. II. Link, Thomas M. III. Series: High-yield pathology.
[DNLM: 1. Bone Diseases—pathology. 2. Soft Tissue Neoplasms—pathology.
WE 225]
616.71071—dc23 2011040031
Executive Content Strategist: William R. Schmitt
Senior Content Development Specialist: Kathryn DeFrancesco
Publishing Services Manager: Anne Altepeter
Associate Project Manager: Jessica L. Becher
Design Direction: Steve Stave
Printed in the United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1Dedication
To Terrie, Brooke, my dear mother, Gizella, and my late father George
Andrew E. Horvai, MD, PhD
To my wife, Heike, and my parents, Sieglinde and Bruno Link
Thomas Link, MDContributors
Michael Barnes, MD, Neuropathology Fellow,
Department of Pathology, University of California, San
Francisco, San Francisco, California
Michael Bonham, MD, PhD, Clinical Instructor,
Anatomic Pathology, Department of Pathology,
University of California, San Francisco, San Francisco,
Nancy Ciau, MD, Clinical Instructor, Department of
Pathology, University of California, San Francisco, San
Francisco, California
Vijay George, MD, Clinical Pathology Resident,
Department of Pathology, University of California, San
Francisco, San Francisco, California
Ryan Gill, MD, PhD, Assistant Clinical Professor,
Department of Pathology, University of California, San
Francisco, San Francisco, California
Anne Hiniker, MD, PhD, Neuropathology Fellow,
Department of Pathology, University of California, San
Francisco, San Francisco, California
Andrew E. Horvai, MD, PhD, Associate Clinical
Professor, Department of Pathology, University of
California, San Francisco, San Francisco, California
Abel Jarell, MD, Dermatopathology Fellow, Department
of Pathology, University of California, San Francisco,
San Francisco, California
Cindy Jimenez, MD, Surgical Pathology Fellow,
Department of Pathology, University of California, San
Francisco, San Francisco, CaliforniaEllen Krasik, MD, Clinical Pathology Resident,
Department of Pathology, University of California, San
Francisco, San Francisco, California
Thomas Link, MD, Professor in Residence, Department
of Radiology, University of California, San Francisco,
San Francisco, California
Judy Pang, MD, Assistant Professor, Department of
Pathology, University of Michigan, Ann Arbor, Michigan
Raga Ramachandran, MD, PhD, Assistant Professor of
Clinical Pathology, Department of Pathology, University
of California, San Francisco, San Francisco, California
Anatoly Urisman, MD, PhD, Anatomic Pathology
Resident, Department of Pathology, University of
California, San Francisco, San Francisco, California
Maria Vergara, MD, Surgical Pathology Fellow,
Department of Pathology, University of California, Los
Angeles, Los Angeles, California

Specimens from the musculoskeletal system are infrequently encountered by the
practicing pathologist. Many of the most common diagnoses, such as traumatic
fractures, usually do not require tissue diagnosis. Furthermore, the rarity of bone
and soft tissue neoplasms and the dis guring surgery endorsed by a malignant
diagnosis present unique challenges for the pathologist. The di culty is
compounded by the myriad diagnostic entities and the absence of universal
classi cation systems. For the pathologist-in-training, learning the material has
been equally demanding. The purpose of this textbook is to present the pathology
of bone and soft tissue in a practical, focused, and easily accessible format. The
text emphasizes the diagnostic hallmarks of each entity, to allow straightforward,
rapid comparison of diagnoses within a single di erential. More than 1000
illustrations are provided to supplement the critical details of the text. To achieve
this format, discussion of minutiae and controversies is reduced.
In most organ systems, non-neoplastic diseases constitute a signi cant
proportion of diagnoses. Although this is also true of the skeletal system, the
pathology of somatic soft tissue is dominated by neoplasms. The resulting disparity
between the bone and soft tissue sections of this book, thus, reveals the reality of
routine pathology practice rather than omission.
Finally, although this book is intended for pathologists, diseases of bone cannot
be diagnosed accurately without evaluation of corresponding radiographic studies.
The fundamental radiographic ndings for each diagnosis are described and
illustrated with high-quality images so that the pathologist can e ectively
contribute to the multidisciplinary care of the patient.
This volume would not have been possible without the hard work and
dedication of the contributors. Thanks especially to Dr. Andrew Folpe and Dr.
Carrie Inwards for their assistance and guidance.
Andrew E. Horvai, MD, PhD
Thomas Link, MDTable of Contents
Front Matter
I: Bone and Joint
A: Metabolic Conditions
Chapter 1: Paget Disease
Chapter 2: Osteoporosis
Chapter 3: Osteomalacia
Chapter 4: Rickets
Chapter 5: Osteogenesis Imperfecta
Chapter 6: Hyperparathyroidism
Chapter 7: Serous Fat Atrophy
Chapter 8: Xanthomatosis
Chapter 9: Osteopetrosis
Chapter 10: Ochronosis
Chapter 11: Melorheostosis
Chapter 12: Gaucher Disease
B: Infectious and Inflammatory Conditions
Chapter 13: Osteoarthritis
Chapter 14: Rheumatoid Arthritis
Chapter 15: Septic Arthritis
Chapter 16: Gout
Chapter 17: Other Crystal-Induced Synovitis and Calcium DepositionChapter 18: Acute Osteomyelitis
Chapter 19: Chronic Osteomyelitis
Chapter 20: Osteonecrosis
Chapter 21: Bone Fracture and Fracture Callus
C: Cystic Lesions
Chapter 22: Aneurysmal Bone Cyst
Chapter 23: Unicameral Bone Cyst
Chapter 24: Intraosseous Ganglion
D: Giant Cell–Rich Lesions
Chapter 25: Giant Cell Tumor
Chapter 26: Giant Cell–Reparative Granuloma
Chapter 27: Brown Tumor
Chapter 28: Tenosynovial Giant Cell Tumor, Localized Type
Chapter 29: Tenosynovial Giant Cell Tumor, Diffuse Type
E: Mixed Periosteal Lesions
Chapter 30: Bizarre Parosteal Osteochondromatous Proliferation
Chapter 31: Subungual Exostosis
Chapter 32: Florid Reactive Periostitis
F: Cartilage-Forming Lesions
Chapter 33: Solitary Osteochondroma
Chapter 34: Multiple Hereditary Exostoses
Chapter 35: Enchondroma
Chapter 36: Multiple Chondroma Syndromes (Ollier Disease, Maffucci
Chapter 37: Periosteal Chondroma
Chapter 38: Synovial Chondromatosis
Chapter 39: Chondro-Osseous Loose Body
Chapter 40: Chondromyxoid Fibroma
Chapter 41: Chondroblastoma
Chapter 42: Conventional Intramedullary Chondrosarcoma
Chapter 43: Chondrosarcoma of the Small Bones of the Hands and FeetChapter 44: Periosteal Chondrosarcoma
Chapter 45: Secondary Chondrosarcoma
Chapter 46: Clear Cell Chondrosarcoma
Chapter 47: Dedifferentiated Chondrosarcoma
Chapter 48: Mesenchymal Chondrosarcoma
G: Bone-Forming Lesions
Chapter 49: Bone Island
Chapter 50: Osteoid Osteoma
Chapter 51: Osteoblastoma
Chapter 52: Conventional Osteosarcoma
Chapter 53: Small Cell Osteosarcoma
Chapter 54: Telangiectatic Osteosarcoma
Chapter 55: High-Grade Surface Osteosarcoma
Chapter 56: Post-Treatment Osteosarcoma
Chapter 57: Parosteal Osteosarcoma
Chapter 58: Periosteal Osteosarcoma
Chapter 59: Low-Grade Central Osteosarcoma
Chapter 60: Chondroblastoma-Like Osteosarcoma
H: Notochordal Tumors
Chapter 61: Benign Notochordal Cell Tumor
Chapter 62: Chordoma
I: Fibrous Lesions
Chapter 63: Fibrous Dysplasia
Chapter 64: Osteofibrous Dysplasia
Chapter 65: Desmoplastic Fibroma
Chapter 66: Nonossifying Fibroma
Chapter 67: Ossifying Fibroma
J: Vascular Lesions
Chapter 68: Hemangioma
Chapter 69: Synovial HemangiomaChapter 70: Epithelioid Hemangioma
Chapter 71: Epithelioid Hemangioendothelioma
Chapter 72: Angiosarcoma of Bone
Chapter 73: Massive Osteolysis
Chapter 74: K. Ewing Sarcoma
L: Hematopoietic Lesions
Chapter 75: Primary Osseous Lymphoma
Chapter 76: Acute Myeloid Leukemia
Chapter 77: Plasmacytoma
Chapter 78: Langerhans Cell Histiocytosis
Chapter 79: Mastocytosis
Chapter 80: M. Undifferentiated Pleomorphic Sarcoma of Bone
Chapter 81: N. Adamantinoma
O: Lipomatous Tumors
Chapter 82: Intraosseous Lipoma
Chapter 83: Synovial Lipomatosis
P: Carcinoma
Chapter 84: Metastatic Carcinoma
Chapter 85: Squamous Cell Carcinoma Arising in a Draining Sinus of
Chronic Osteomyelitis
II: Soft Tissue
A: Inflammatory and Pseudosarcomatous Myofibroblastic Proliferations
Chapter 86: Nodular Fasciitis
Chapter 87: Proliferative Myositis and Proliferative Fasciitis
Chapter 88: Ischemic Fasciitis
Chapter 89: Postoperative Spindle Cell Nodule
Chapter 90: Necrotizing Fasciitis
B: Fibrosing Lesions and Fibromatoses
Chapter 91: Elastofibroma
Chapter 92: Desmosplastic Fibroblastoma
Chapter 93: Hypertrophic ScarChapter 94: Keloid
Chapter 95: Fibrous Hamartoma Of Infancy
Chapter 96: Gardner Fibroma
Chapter 97: Nuchal Fibroma
Chapter 98: Fibromatosis Colli
Chapter 99: Calcifying Aponeurotic Fibroma
Chapter 100: Fibroma Of Tendon Sheath
Chapter 101: Superficial Fibromatosis
Chapter 102: Deep Fibromatosis
Chapter 103: Inclusion-Body Fibroma
Chapter 104: IgG4-Related Sclerosing Disease
C: Myofibroblastic Tumors
Chapter 105: Myofibroblastoma (Mammary Type)
Chapter 106: Inflammatory Myofibroblastic Tumor
Chapter 107: Myofibroma and Myofibromatosis
Chapter 108: Intranodal Myofibroblastoma
Chapter 109: Myofibroblastic Sarcoma
D: Perivascular Tumors
Chapter 110: Glomus Tumor
Chapter 111: Glomuvenous Malformation
Chapter 112: Myopericytoma
E: Fibroblastic and Fibrohistiocytic Tumors
Chapter 113: Reticulohistiocytoma
Chapter 114: Juvenile Xanthogranuloma
Chapter 115: Benign Fibrous Histiocytoma
Chapter 116: Angiomatoid Fibrous Histiocytoma
Chapter 117: Plexiform Fibrohistiocytic Tumor
Chapter 118: Superficial Acral Fibromyxoma
Chapter 119: Superficial Angiomyxoma
Chapter 120: Dermatofibrosarcoma ProtuberansChapter 121: Giant Cell Fibroblastoma
Chapter 122: Fibrosarcoma Arising in Dermatofibrosarcoma Protuberans
Chapter 123: Adult Fibrosarcoma
Chapter 124: Infantile Fibrosarcoma
Chapter 125: Sclerosing Epithelioid Fibrosarcoma
Chapter 126: Low-Grade Fibromyxoid Sarcoma
Chapter 127: Atypical Fibroxanthoma
Chapter 128: Intramuscular Myxoma
Chapter 129: Myxofibrosarcoma
F: Adipose Tumors
Chapter 130: Lipoblastoma
Chapter 131: Lipoma and Lipomatosis
Chapter 132: Angiolipoma
Chapter 133: Neural Fibrolipoma
Chapter 134: Hibernoma
Chapter 135: Chondroid Lipoma
Chapter 136: Spindle Cell and Pleomorphic Lipoma
Chapter 137: Well-Differentiated Liposarcoma and Atypical Lipomatous
Chapter 138: Dedifferentiated Liposarcoma
Chapter 139: Myxoid and Round Cell Liposarcoma
Chapter 140: Pleomorphic Liposarcoma
G: Smooth Muscle Tumors
Chapter 141: Angioleiomyoma
Chapter 142: Pilar Leiomyoma
Chapter 143: Leiomyoma of Deep Soft Tissue
Chapter 144: Leiomyosarcoma of Soft Tissue
Chapter 145: Vascular Leiomyosarcoma
Chapter 146: Epstein-Barr Virus–Associated Smooth Muscle Tumor
H: Genital Stromal Tumors
Chapter 147: FibroepithelIal PolypChapter 148: Angiomyofibroblastoma
Chapter 149: Cellular Angiofibroma
Chapter 150: Aggressive Angiomyxoma
I: Skeletal Muscle Tumors
Chapter 151: Adult Rhabdomyoma
Chapter 152: Fetal Rhabdomyoma
Chapter 153: Genital Rhabdomyoma
Chapter 154: Alveolar Rhabdomyosarcoma
Chapter 155: Embryonal Rhabdomyosarcoma
Chapter 156: Pleomorphic Rhabdomyosarcoma
J: Nerve and Nerve Sheath Tumors
Chapter 157: Traumatic Neuroma
Chapter 158: Schwannoma
Chapter 159: Ancient Schwannoma
Chapter 160: Ganglioneuroma
Chapter 161: Neurothekeoma
Chapter 162: Cellular Schwannoma
Chapter 163: Neurofibroma
Chapter 164: Plexiform Neurofibroma
Chapter 165: Palisaded Encapsulated Neuroma
Chapter 166: Perineurioma
Chapter 167: Malignant Peripheral Nerve Sheath Tumor
Chapter 168: Malignant Triton Tumor
Chapter 169: Granular Cell Tumor
Chapter 170: Malignant Granular Cell Tumor
Chapter 171: Neuroglial Heterotopia
Chapter 172: Neuroblastoma
Chapter 173: Esthesioneuroblastoma
Chapter 174: Paraganglioma
Chapter 175: Melanotic Neuroectodermal Tumor of InfancyK: Vascular Tumors
Chapter 176: Papillary Endothelial Hyperplasia
Chapter 177: Pyogenic Granuloma
Chapter 178: Arteriovenous Malformation
Chapter 179: Capillary Hemangioma
Chapter 180: Cavernous Hemangioma
Chapter 181: Lymphangioma
Chapter 182: Epithelioid Hemangioma
Chapter 183: Kimura Disease
Chapter 184: Spindle Cell Hemangioma
Chapter 185: Sinusoidal Hemangioma
Chapter 186: Epithelioid Hemangioendothelioma
Chapter 187: Hobnail Hemangioendothelioma
Chapter 188: Angiosarcoma
Chapter 189: Intimal Sarcoma
Chapter 190: Kaposi Sarcoma
Chapter 191: Kaposiform Hemangioendothelioma
L: Bone and Cartilage Tumors of Soft Tissue
Chapter 192: Soft Tissue Chondroma
Chapter 193: Extraskeletal Myxoid Chondrosarcoma
Chapter 194: Nuchal Fibrocartilaginous Pseudotumor
Chapter 195: Myositis Ossificans
Chapter 196: Ossifying Fibromyxoid Tumor
Chapter 197: Soft Tissue Osteosarcoma
Chapter 198: M. Perivascular Epithelioid Cell Neoplasms
N: Tumors of Uncertain Lineage
Chapter 199: Pleomorphic Hyalinizing Angiectatic Tumor of Soft Parts
Chapter 200: Soft Tissue Myoepithelioma
Chapter 201: Alveolar Soft Part Sarcoma
Chapter 202: Clear Cell SarcomaChapter 203: Synovial Sarcoma
Chapter 204: Extrarenal Rhabdoid Tumor
Chapter 205: Epithelioid Sarcoma (Proximal and Distal)
Chapter 206: Desmoplastic Small Round Cell Tumor
Chapter 207: Primitive Neuroectodermal Tumor (Ewing Sarcoma)
Chapter 208: Giant Cell Tumor of Soft Tissue
Chapter 209: Undifferentiated Pleomorphic Sarcoma
Chapter 210: Phosphaturic Mesenchymal Tumor
Chapter 211: Myxoinflammatory Fibroblastic Sarcoma
Chapter 212: Ectopic Hamartomatous Thymoma
Chapter 213: Solitary Fibrous Tumor and Hemangiopericytoma
Bone and JointA
Metabolic ConditionsPaget Disease
Definition and synonyms
• A chronic skeletal bone disorder due to overactivation of osteoblasts and
osteoclasts with resultant abnormal remodeling of bone (osteitis deformans)
Clinical features
Epidemiology and presentation
• Bone pain, warmth, tenderness, and arthritis
• Localized skeletal deformity and spinal stenosis
• Stress fractures with minimal trauma
• Headaches, deafness, and increased hat size with skull involvement
• Markedly elevated serum alkaline phosphatase with normal calcium and
Prognosis and treatment
• Usually asymptomatic; may be focal, multifocal, and progressive
• Severe forms show marked deformity, intractable pain, neurologic symptoms,
and cardiac failure
• One to 3% of cases complicated by sarcoma (osteosarcoma, undifferentiated
• Asymptomatic patients require no treatment except in extensive skull
• Symptomatic treatment with analgesics
• Bisphosphonates and calcitonin medical therapy
• Osteolytic change in the early phase
• Initial lesions may be destructive and radiolucent, especially in the skull
(osteoporosis circumscripta)• Later bone deformity, thick cortical bone, coarsening of bone trabeculae, and loss
of demarcation between cortical and trabecular bone
• Window frame appearance of vertebral bodies: increased density of the vertebral
body periphery and accentuation of the trabeculae in the body
• Hot on bone scans unless it is in the inactive phase
• Stress fractures with multiple fissures in long bones at later stages
• Focal bone proliferation with malignant transformation
• Bone is hyperemic with distortion of the normal contour and structure
• Osteolytic phase shows primarily osteoclastic activity with increased
multinucleated osteoclasts mimicking hyperparathyroidism
• Active or mixed phase shows increased osteoclastic and osteoblastic activity with
remodeling, fibrosis, and osteoid formation
• Thick and thin bone trabeculae are often present
• Sclerotic phase shows prominent irregular, wavy cement lines that reflect
abnormal remodeling and may be the only feature in inactive disease
• Reticulin stain highlights disorganization of lamellar bone
Main differential diagnosis
• Hyperphosphatasia
• Polyostotic fibrous dysplasia
• Chronic osteomyelitis4
Fig 1 Lateral radiograph of the skull in a patient with Paget disease showing
thickening of the cortex with increased sclerosis mixed with lytic areas, also
referred to as a cotton-wool appearance.
Fig 2 Lateral radiograph of the right tibia and bula (A) and anteroposterior
radiographs of the ankle (B) and knee (C). Note transverse fractures in the tibia
and bula, which are common because bone is inherently weak. There is marked
cortical thickening of the tibia extending from the articular surface of the knee to
the articular surface of the ankle. Deformity of the right tibia with anterior and
lateral bowing is also shown.4
Fig 3 Polarized light histopathology of normal bone (A) and bone from a patient
with Paget disease (B). In Paget disease, the laminar sheetlike orientation is
disrupted, leading to less refractile, interrupted collagen.
Fig 4 Scanning magni cation in a patient with Paget disease showing thick and
thin irregular trabecular bone, extensive brosis, and increased vascularity of bone
marrow and irregular cement lines.4
Fig 5 Higher magni cation in a patient with Paget disease showing thick and
prominent trabecular bone with large multinucleated osteoclasts.
Fig 6 In the sclerotic phase of Paget disease bone is formed with thickened,
irregular trabeculae with osteoid seams creating a mosaic pattern of cement lines.
This reflects prior incidences of bone resorption and formation.Osteoporosis
Definition and synonyms
• Decrease in bone density of normally mineralized bone; the World Health
Organization defines it as a bone mineral density that is 2.5 standard deviations
(SD) below the mean peak value in young adults (porous bone)
Clinical features
• Most common metabolic bone disease
• Most common in patients older than 50 years
• Postmenopausal women are affected because of estrogen deficiency
• Secondary causes include endocrine disorders, gastrointestinal disturbances,
drugs, and immobilization
• Risk factors include smoking, caffeine, and alcohol consumption
• 1.5 million fractures per year leading to 37,500 deaths per year in the United
• Back pain, loss of height, thoracic kyphosis, fractures with minimal trauma
• Vertebral crush fractures and spontaneous fractures in severe form
• Cancellous compartment of vertebral bone, pelvis, and wrist most commonly
• Normal serum parathyroid hormone, calcium, phosphorus, and alkaline
Prognosis and treatment
• Increased mortality rate due to complications of fractures; better prognosis with
early maintained treatment
• Vitamin D and calcium supplementation• Bisphosphonates increase bone thickness and lower the risk for fractures and are
used for prevention and treatment
• Selective estrogen receptor modulators (raloxifene) act on bone to slow resorption
by osteoclasts
• Substantial bone loss (approximately 30% to 40%) must occur before routine
radiographs are sensitive enough to detect
• Techniques to measure bone mineral density include dual energy X-ray
absorptiometry and quantitative CT
• A bone mineral density 2.5 SD below the mean of a young adult is considered
osteoporosis (T score of −2.5); between 1 and 2.5 SD below the mean is
• Conventional radiographs show cortical thinning, increased radiolucency,
vertebral compression, widening and swelling of intervertebral disks
• Three types of spinal fractures are identified in advanced disease: wedge
fractures, biconcave fractures, and crush fractures
• The most severe complication is proximal femur fracture, typically femoral neck
and intertrochanteric
• Loss of trabecular bone
• Kyphosis of the thoracic spine due to osteoporosis involving more than one
vertebral body (dowager sign)
• Cortical and trabecular bone is decreased with trabecular bone more severely
• Bone cortices are thin with widened haversian canals
• Osteoid seams are of normal width
• Trabeculae are thin, discontinuous, and separated
Main differential diagnosis@
Main differential diagnosis
• Osteogenesis imperfecta
• Malabsorption
• Cushing’s syndrome
• Osteomalacia
Fig 1 Anteroposterior plain radiograph of the pelvis in a female patient with an
osteoporotic intertrochanteric left proximal femur fracture with avulsion of the
lesser trochanter ( a r r o w). The large calcification in the pelvic soft tissues is a uterine
Fig 2 Osteoporotic bone initially a ects the trabeculae in the medulla, but this
more advanced example shows involvement of the cortex ( b o t t o m) that is markedly
thinned.Fig 3 Scanning magniAcation of normal bone with broad, anastomosing
trabeculae (A) and bone from a patient with osteoporosis (B) showing thin,
separated, and discontinuous trabeculae.
Fig 4 Sequelae of osteoporosis in the lumbar spine. Anteroposterior (A) andlateral (B) radiographs of the lumbar spine with an osteoporotic fracture of the L3
vertebra ( a r r o w) associated with a concave end plate and height loss of the
vertebral body.Osteomalacia
• General term for a defect in skeletal mineralization that results in the
accumulation of unmineralized bone (osteoid); rickets represents defective
endochondral ossification at the growth plate resulting in dwarfism (see
Osteogenisis Imperfecta, later)
Clinical features
• Commonly seen in deficiencies or disorders of calcium, vitamin D, or phosphorus
• Aluminum and iron metal poisoning
• Associated with certain bone and soft tissue tumors (oncogenic osteomalacia),
specifically phosphaturic mesenchymal tumor (see Section IIM, Phosphaturic
Mesenchymal Tumor)
• Generalized musculoskeletal weakness and bone pain
• Fractures with minimal trauma, particularly in vertebral bodies and femoral
• Low vitamin D with or without low calcium or low phosphorus levels with high
levels of alkaline phosphatase
Prognosis and treatment
• May be a contributing factor to hip fractures in elderly patients
• Treatment is aimed at correcting vitamin deficiencies or underlying medical
• Adequate sunlight exposure and supplemental oral calcium and vitamin D
• Symmetrical pseudofractures: unmineralized areas caused by rapid boneresorption and slow mineralization (Looser zones)
• Generalized osteopenia with coarse bone structure
• Multiple bilateral and symmetrical linear insufficiency fractures
• Technetium-99 bone scanning reveals multiple hot spots corresponding to
pseudofractures and insufficiency fractures
• Bone particularly from the vertebral column is soft, weak, and prone to fracture
• Bone must be processed without decalcification, and usually embedded in plastic
for sectioning
• Increased amount of unmineralized bone or osteoid, surface osteoid greater than
25% (normal is ~2%)
• Increase in osteoid seam thickness, presence of greater than five birefringent
lamellar lines in the osteoid seam
• Decreased mineralization or calcification rate
• Tongues of uncalcified cartilage extending into metaphysis
Ancillary studies
• Tetracycline taken before bone biopsy labels sites of new bone formation; a
diminished number of osteoid seams taking up tetracycline reflects an absence of
• Osteoid evaluation can be performed using von Kossa, Goldner, modified
trichrome, or Villanueva stain
Main differential diagnosis
• Osteopenia, osteoporosis7
Fig 1 Plain anteroposterior radiographs of bilateral feet in a patient with
oncogenic osteomalacia. The bones are severely osteopenic, and a diaphyseal
insufficiency fracture is visualized at the left third metatarsal (arrow).
Fig 2 Bone biopsy using von Kossa stain in an undecalci ed section with
osteomalacia. Osteoid is the eosinophilic unmineralized portion of bone at the
surface of trabeculae. The mineralized front is stained dark gray to black (A and B).
Note that a significant fraction of the bone (~50%) is unmineralized.
(Courtesy of Roberto Garcia, MD.)7
Fig 3 Undecalci ed normal bone stained with hematoxylin-eosin (A and B).
Compared with Figure 2, the mineralization front (purple) extends essentially up to
the surface of the trabeculae, with very little unmineralized osteoid (pink).Rickets
• A metabolic bone disorder due to vitamin D, calcium, or phosphate depletion
that impairs mineralization of bones in children before growth plate closure,
resulting in growth retardation and delayed skeletal development
Clinical features
• Occurs only in children whose growth plates have not closed, before age 17 years
in females and 19 years in males
• Boys and girls are equally affected
• Commonly due to vitamin D deficiency, also from abnormal metabolism of
phosphate or gastrointestinal tract disorders
• Hypophosphatasia is a rare X-linked disease characterized by extremely low
levels of alkaline phosphatase
• Rare autosomal recessive type I and II vitamin D–dependent rickets (VDDR) due
to impaired renal synthesis of 1,25(OH)-D or organ hyporesponsiveness to vitamin
• Clinical findings depend on age of onset and severity of defective mineralization
• Bone pain, tenderness, muscle weakness, fractures, and skeletal deformity are
• Toddlers present with bowing of the legs; older children present with knock-knees
• Type II VDDR presents in childhood with bone deformity and total-body alopecia
Prognosis and treatment
• No increase in morbidity with adequate treatment
• Prevention of vitamin D deficiency is achieved with adequate sunlight exposure
and vitamin D supplementation• Vitamin D deficiency is treated with ergocalciferol
• Patients with X-linked or idiopathic hypophosphatemia are treated with oral
phosphate supplements and calcitriol
• Human recombinant growth hormone reduces phosphaturia
• Type I VDDR is treated with high-dose vitamin D
• Plain radiographs show widening and cupping of the metaphyseal region,
widening of the growth plate, and fraying of the metaphysis
• Bowing of long bones
• Knock-knees (genu valgum)
• Beading of the ribs at the costochondral junctions (“rachitic rosary”)
• Symmetrical and linear pseudofractures (Looser zones)
• Early disease is radiographically difficult to diagnose with nonspecific findings
(e.g., osteopenia)
• Frontal bossing of skull, chest deformation, anterior protrusion of the sternum
(pigeon breast deformity), kyphosis, scoliosis, and narrowing of the pelvis
• Wide osteoid seams due to excess osteoid
• Failure of mineralization of the epiphyseal growth plate
• Disordered endochondral ossification with persistence of cartilage growth plate
penetrating into medullary cavity>
Fig 1 A, In this term infant with rickets, disorganized growth plate with cartilage
penetrating into the medulla is seen at scanning magni cation. B, By comparison,
a normal growth plate has a sharp line of ossi cation replacing the cartilage of the
growth plate.>
Fig 2 Higher magni cation demonstrates marked disorganization of the growth
plate with haphazard mixture of hypertrophic zone of chondrocytes and bone in
this infant with rickets.
Fig 3 Lateral radiograph of the tibia and bula in a patient with rickets
demonstrating bowing of the tibia and bula as well as a pseudofracture at the
tibia (Looser zone). Coarse trabecular bone structure in the proximal tibia, which is
typical of osteomalacia and rickets, is shown.Osteogenesis Imperfecta
Definition and synonyms
• A family of genetic bone disorders primarily due to defective synthesis and secretion of
collagen type I, characterized by fragile bones that break easily (brittle bone disease,
Lobstein disease).
Clinical features
• Rare heritable connective tissue disorder with most cases caused by a dominant
mutation of type 1 collagen ( C O L 1 A 1 or C O L 1 A 2) genes
• Approximately 35% of patients with OI have no family history
• Type V through type VIII do not involve deficits in type I collagen genes
• Fibrogenesis imperfecta ossium is an extremely rare acquired disorder in which normal
bone is replaced by a collagen-deficient tissue that is excessively fragile
• Flattened skull, scoliosis, and kyphotic collapsing deformities
• Discoloration of sclera
• Conductive and sensorineural hearing loss
• Small, misshapen, translucent gray-yellow teeth, with enamel that fractures easily
(dentinogenesis imperfecta)
• Presentation varies depending on the type of OI inherited
• Type I: mild bone fragility, rib deformities, blue sclerae
• Type II: perinatal lethal
• Type III: progressive severe deformities, fractures, short stature
• Types IV to VII: moderate growth retardation, deformities
• Type VIII: severe growth deficiency, normal scleraeFig 1 Anteroposterior (A) and lateral (B) radiographs of a fetus at 32 weeks’ gestation
with osteogenesis imperfecta type II. Bones show di5use demineralization and limited
calvarial mineralization. Limbs are severely malformed with very short, broad femurs and
marked bowing of the tibiae and fibulae.
Prognosis and treatment
• No cure currently; treatment directed toward preventing and controlling symptoms and
maximizing independence
• Bisphosphonates improve bone strength
• Percutaneous surgical pinning of fractures and surgical insertion of metal rods through
long bones
• Type II usually perinatal lethal
• Marked osteoporosis with severe thinning of cortical bone, multiple fractures, and
nonunion of healed fractures
• Severe bony deformities
• Diaphysis is thin and wavy; metaphysis is expanded
• Calcified cartilaginous nodules at the growth plates look like popcorn on conventional
Gross• Biopsy rarely done on lesions
• Fetal cases may be seen at autopsy
• Widened and irregular growth plates
• Cartilaginous nodules at growth plates
• Severe forms have increased osteocytes, absence of an organized trabecular pattern,
and large areas of woven bone
• Bone trabeculae are thin, delicate, and widely separated
• Less severe forms have increased osteocytes with thin lamellar bone
Main differential diagnosis
• Child abuse
• Vitamin D deficiency
Fig 2 The bone is hypercellular with increased osteocytes in osteogenesis imperfecta.Fig 3 Osteogenesis imperfecta type II in a fetus at 16 weeks’ gestation. A, Fracture
callus ( l e f t) and abnormal growth plate with very scant ossi; cation of cartilage matrix
( r i g h t) are shown. B, Higher magnification of calcifying cartilage at growth plate.Fig 4 Osteogenesis imperfecta type II in a fetus at 32 weeks’ gestation. Increased
osteocytes in a disorganized trabecular pattern (A) and hypercellular cortical bone (B) are
Fig 5 Fracture callus from a patient with osteogenesis imperfecta type V. At low (A) and
intermediate (B) magni; cation, the callus has exuberant cartilage with very scant new
bone formation, despite osteoblast activity.Hyperparathyroidism
• Hyperparathyroidism, primary or secondary, leads to the overproduction or
excessive secretion of parathyroid hormone, which plays a role in calcium
metabolism and contributes to the regulation of osteoblast and osteoclast activity
Clinical features
• Peak incidence in 50s
• Female predilection
• Associated with other endocrine disorders, including multiple endocrine
neoplasia types I and IIA
• Secondary hyperparathyroidism is commonly associated with renal failure or
• Marked hypercalcemia and hypophosphatemia
• Bone pain and pathologic fractures
• Brown tumors are the result of the accumulation of fibrovascular tissue and giant
cell reactions (see Section ID, Giant Cell–Rich Lesions)
• Later in the course, may present with multiple large cystic lesions (osteitis fibrosa
• Nephrolithiasis, polyuria, and polydipsia
• Constipation, nausea, peptic ulcers, pancreatitis, and gallstones
• Weakness, fatigue, lethargy, depression, and seizures
Prognosis and treatment
• Parathyroidectomy of adenomas generally results in a permanent cure
• Patients with multiple endocrine neoplasia undergoing subtotalparathyroidectomy will have a long remission, but hyperparathyroidism usually
• Bone deformity, fractures, and severe cyst formation will heal if a parathyroid
tumor is successfully removed
• Treatment of primary or secondary hyperparathyroidism will cause brown
tumors to regress
• Severe chronic disease shows osteopenia, subperiosteal bone resorption typically
at the second and third phalanges on the radial side as well as the tufts of the
distal phalanges
• Occasionally, osteosclerosis may be observed
• Brown tumors are well-circumscribed lytic lesions that frequently are in multiple
locations and may resemble cysts on plain radiographs
• Brown tumors are highly vascular lesions, red to brown in color as a result of
hemorrhage and hemosiderin deposition
• Increased osteoclasts, intratrabecular osteoclastic tunneling, and resorption holes
• Secondary hyperparathyroidism is associated with abundant fibrosis and bone
• Acellular holes may be present after treatment in areas of previous osteoclast
• Brown tumors consist of aggregates of osteoclasts, numerous reactive giant cell
aggregates around hemorrhage, and hemosiderin (see Part D, Giant Cell–Rich
Main differential diagnosis
• Myelofibrosis
• Acute-phase Paget disease• Giant cell tumor of bone
• Giant cell reparative granuloma (histologically indistinguishable from brown
Fig 1 Anteroposterior radiograph of the second and third digit of the right hand
showing subperiosteal bone resorption at the radial aspect of the middle and
proximal second and third phalanges as well as the tufts consistent with
hyperparathyroidism.Fig 2 Coronal computed tomographic reconstruction of the lumbar spine
demonstrating multiple lytic lesions throughout the vertebral bodies consistent with
multiple small brown tumors.
Fig 3 Histologically, bone in a patient with hyperparathyroidism shows marrow
space replaced by 5brous tissue with multiple osteoclasts located on the surface of
resorbing bone.Fig 4 At higher magni5cation, the trabeculae of bone show central replacement
by 5brous stroma and numerous osteoclasts (a process known as t u n n e l i n g
r e s o r p t i o n).
Fig 5 Marked, continuous resorption results in thin delicate trabeculae surrounded
by a loose fibrous matrix.Fig 6 A and B, Brown tumor is characterized by a proliferation of scattered
osteoclasts and 5broblasts in a vascular 5brous background with hemorrhage and
hemosiderin deposition and entrapped lamellar bone (see also Part D, Giant Cell–
Rich Lesions).Serous Fat Atrophy
• Changes of bone marrow characterized by atrophy of fat cells and hematopoietic
cells and accumulation of extracellular gelatinous substance (serous degeneration,
gelatinous bone marrow transformation, mucoid atrophy of fat)
Clinical features
• A rare disorder of unknown pathogenesis associated with extreme
• Condition is seen in adults and elderly people; rare in children
• Male predominance
• In young individuals, it is most commonly associated with anorexia nervosa,
AIDS, or acute febrile illnesses
• In middle-aged adults, it is associated with alcoholism and lymphoma
• In older individuals, it is associated with congestive heart failure
• Weight loss, anemia, or pancytopenia
Prognosis and treatment
• The condition is reversible with resolution of the nutritional deficit
• Findings are nonspecific
• MRI is characterized by a low signal intensity on T1-weighted images and a high
signal intensity on T2-weighted images, reflecting the presence of serous marrow
and myxoid degeneration
• Bone marrow changes include fat cell atrophy, focal loss of hematopoietic cells,
and deposition of extracellular gelatinous material (gelatinous transformation)
• The gelatinous material is mucopolysaccharides rich in hyaluronic acid that
stains with Alcian blue at pH 2.5
• Eosinophilic serous fluid accumulation in the interstitium with a fine granular
appearance on routine hematoxylin and eosin staining and pale pink on periodic
acid–Schiff and Giemsa stain
Main differential diagnosis
• Amyloidosis
• Aplastic anemia
• Liposarcoma
Fig 1 Scanning magni cation of hypocellular bone marrow with marrow fat
surrounded by amorphous eosinophilic material (A) and fat cell atrophy (B). The4
eosinophilic “gelatinous” material is thought to represent an increase in the normal
acid mucopolysaccharide ground substance of the bone marrow.
Fig 2 High magni cation of bone marrow with atrophic medullary fat and
extensive eosinophilic material with a ne brillary appearance. Atrophic fat cells
may contain multiple vacuoles but should not be mistaken for liposarcoma, which is
an exceedingly rare primary bone tumor.Xanthomatosis
• Proliferation of foamy histiocytes, which may be solitary (xanthoma) or
multifocal (xanthomatosis); Erdheim-Chester disease is a rare histiocytic disorder
of unknown etiology that involves bone and lung preferentially (lipid
Clinical features
• Rare disease in mid to late adulthood
• No gender or race preference
• Some cases associated with hyperlipidemia
• Pathologic fractures have been reported
• Clinically can mimic osteomyelitis
• Tissue destruction and bone distortion lead to orthopedic complications
Prognosis and treatment
• Prognosis depends on extent of extraosseous disease; extensive disease can
potentially be fatal
• Xanthomatosis of the Achilles tendon treated with local excision has a 50%
recurrence rate
• Poor cortical medullary distinction with zones of radiolucency and radiodensity
• Most often, sclerotic bone lesions
• Pathologic fractures at the site of osseous, lytic lesions
• Yellow replacement of normal tissue
• Progressive infiltration of bone marrow
• Diffuse infiltration of large, foamy histiocytes with conspicuous nuclei, lymphoid
aggregates, fibrosis, and giant cell proliferations
• Clefts of cholesterol deposition in tissue
Ancillary studies
• Histiocytes are CD68 positive
• Histiocytes are S-100 and CD1a negative
Main differential diagnosis
• Gaucher disease
• Langerhans cell histiocytosis
• Chronic osteomyelitis
• Fibrous dysplasia (foam cells and cholesterol clefts)
Fig 1 Localized xanthomatosis involving the distal radius presents as apredominantly lytic, well-circumscribed lesion. This patient had
hypercholesterolemia, tendinous xanthomas, and xanthelasmas.
Fig 2 Bilateral and nearly symmetrical increased sclerosis of the distal tibias are
shown in this patient with Erdheim-Chester disease.
Fig 3 Scanning magni8cation of xanthomatosis. Bone has thick trabeculae and is
distorted and partially destroyed by a histiocytic infiltrate.Fig 4 Extracellular cholesterol produces slitlike clefts associated with a foreign
body reaction. This is a nonspeci8c 8nding, however, and may be seen as a
degenerative feature in a number of bone lesions.
Fig 5 A and B, At higher magni8cation, the lesion consists of sheets of round,
polygonal, and spindle cells with foamy cytoplasm of variable sizes.Osteopetrosis
Definition and synonyms
• A group of rare genetic disorders of skeletal development due to a defect in bone
remodeling caused by osteoclast dysfunction (marble bone disease,
AlbersSchönberg disease)
Clinical features
• Autosomal dominant or adult forms, type I and type II
• Autosomal recessive forms related to carbonic anhydrase-2 deficiency
• All bones are affected, but those most severely affected include the long bones of
the extremities, vertebrae, pelvic bones, and base of the skull
• Infantile form is characterized by profound anemia, leukopenia,
thrombocytopenia, extramedullary hematopoiesis, fractures, failure to thrive, and
increased infections
• Adult form is characterized by bone pain and increased fractures with the
absence of severe hematopoietic abnormalities
• Cranial nerve abnormalities include optic atrophy, deafness, and facial paralysis
• Failure to acidify urine
Prognosis and treatment
• Infantile form is fatal in utero or infancy
• Adult form has a near-normal life expectancy
• Bone marrow transplantation
• Bones are diffusely dense, and the cortex is thick
• Skull base shows increased density and thickeningFig 1 Whole-mount transverse section of the humerus in a patient with
osteopetrosis showing increased density of the cortex and absence of the medullary
canal with no evidence of hematopoietic marrow.
• Bone-in-bone appearance, particularly at the lumbar spine and pelvis
• Long bones are bulbous and misshapen with flaring of the distal femoral
metaphysis (Erlenmeyer flask deformity), but this finding is not specific and may
also be seen with bone marrow replacing processes such as Gaucher disease and
• Increased fracture occurrence, in particular in type II
• Adult type I is characterized by marked sclerosis of the cranial vault
• Adult type II is characterized by skull sclerosis at the base and by bone-in-bone
appearance at the spine and the pelvis
• Lack of cortical-medullary demarcation
• Infantile form lacks development of bone marrow cavity
• Increased density and thickness of the cortex, in extreme examples with complete
absence of medulla
• Increase in the number and size of bony trabeculae0
• Central core of cartilage with dense and irregular bony trabeculae
• Persistence of spicules of calcified cartilage in medullary and cortical bone in
• No consistent reported change in osteoclast number
Main differential diagnosis
• Osteoblastic metastases
• Myelosclerosis
• Paget disease
• Melorheostosis
Fig 2 Anteroposterior radiograph of bilateral knees showing di use sclerosis of
the bones with mild lucency in the epiphyseal and metaphyseal portions of the
femur, tibia, and fibula.Fig 3 A, Marked reduction in both the marrow space and haversian system. B,
Note the absence of osteoclasts and cortical-appearing bone.
Fig 4 Osteopetrotic bone from an adult with calcifying cartilaginous tissue not
remodeling into mature bone.0
Fig 5 Anteroposterior radiograph of the pelvis (A) and frog-leg lateral view of the
right hip (B) in a patient with osteopetrosis showing di use sclerosis of the
proximal femur and the pelvis with femoral bowing. The bone-in-bone appearance
of the pelvic bones is well visualized. Deformity of the right femoral head suggests
remote fracture.Ochronosis
Definition and synonyms
• Deposition of dark pigment in cartilage and connective tissue due to a metabolic
disorder of homogentisic acid oxidase (alkaptonuria) or from exposure to various toxic
substances (ochronotic arthropathy)
Clinical features
• Alkaptonuria is a rare autosomal recessive disease with equal sex distribution
• Large peripheral joints are most commonly affected, including knees, shoulders, and
• Early degenerative arthritis and tendon insufficiency
• Narrowing of the joint spaces and disk calcifications
• Spine is affected through degenerative changes of the intervertebral disks
• Dark urine and skin pigmentation, particularly the axilla
• Gray to brown patch of pigmentation in the sclera, between the margin of the cornea
and the outer or inner canthus
• Accumulation of pigment in cardiac tissue leads to heart valve dysfunction
Prognosis and treatment
• No cure is available for alkaptonuria
• Diets low in tyrosine and phenylalanine and high in vitamin C may reduce the toxic
byproduct homogentisic acid
• Ochronotic arthropathy is treated with physiotherapy, analgesia, rest, and prosthetic
joint replacement when necessary
• Accelerated degenerative changes, particularly at the spine and hip
• Joint and disk space narrowing with minimal osteophytosis• Calcification of disk spaces
• Fusion of disk spaces
• Cartilage, tendons, and ligaments have a black pigmentation
• Cartilage is brittle and easily fragmented
• Deposits of brown pigmentation in cartilage and elastic tissue
• Skin sections have yellowish brown pigment deposits seen in the dermis, macrophages,
endothelial cells, apocrine glands, and the epidermal basement membranes
Main differential diagnosis
• Argyria pseudo-ochronosis
• Minocycline-induced hyperpigmentation
Fig 1 Lateral radiograph of the lumbar spine showing severe multilevel disk space
narrowing and calci, cation as well as minimal osteophytosis. In addition, anterior fusion
of the T12-L2 disk spaces with osteopenia is present.Fig 2 Dark pigmented fragments of cartilage engulfed by synovium at low power.
Because cartilage is easily fragmented in patients with ochronosis, the particles of
destroyed cartilage embed in the synovium. These small shards of cartilage may lead to
synovitis or hypertrophic synovium.
Fig 3 Grossly, the articular cartilage of the tibial plateau and femoral condyles are
darkly pigmented in this specimen from a total knee replacement in a patient with
(Courtesy Kenneth Leipper, MD.)Fig 4 A and B, Articular cartilage has a darkly pigmented appearance histologically that
tends to be greatest around chondrocytes.Melorheostosis
Definition and synonyms
• Sporadic abnormality involving hyperostosis of cortical bone, predominantly affecting
the cortex of affected limb long bones with a characteristic radiographic finding
resembling flowing candle wax (flowing hyperostosis). O s t e o p o i k i l o s i s is an autosomal
dominant disorder with multiple, asymptomatic bone islands (see Section IG, Bone
Island) in the medullary cavity
Clinical features
• Wide age range, may present in children or adults
• No gender predilection
• Most cases affect a single limb or single bone
• Long bones of limbs most commonly involved
• Axial skeleton spared
• Children usually asymptomatic; rarely limb deformity
• Adults present with pain, deformity or decreased range of motion
• Distribution may be related to a spinal root (sclerotome)
Prognosis and treatment
• Pain usually self-limited, so management in adults consists of observation
• Surgery to correct deformities in children or severe adult cases
• Rare reported cases of sarcoma arising in affected bone
• Characteristic hyperostosis of the cortical surface in a characteristic flowing or candle
wax appearance
• Nearby soft tissue mineralization may be present
• Increased and irregular endosteal and periosteal cortical surfaces
• Small biopsies are usually nonspecific
• If sufficient tissue present: irregular contour of cortical surface
• Increased woven or lamellar bone expanding cortex
• Cellularity of abnormal areas higher than surrounding normal cortex
• Fibrosis and calcification in surrounding soft tissue may be present
Main differential diagnosis
• Parosteal osteosarcoma
• Florid reactive periostitis
Fig 1 Anteroposterior radiograph of the proximal femur demonstrating candle wax–like
ossifications along the femur diaphysis.2
Fig 2 Irregular cortical periosteal surface ( l e f t) characterizes melorheostosis.
Fig 3 Increased amounts of woven and lamellar bone expand the cortex with uneven
endosteal surface (A, t o p) and irregular haversian canals (B). However, these ndings are
relatively nonspeci c, and the diagnosis of melorheostosis requires radiographic
Fig 4 The periosteal surface is markedly irregular with brous tissue and new bone
formation covering the surface, as seen at low (A) and high (B) magnification.Gaucher Disease
• A lysosomal storage disease caused by a hereditary deficiency of the enzyme
glucocerebrosidase leading to the accumulation of glucocerebroside primarily in
cells of the reticuloendothelial system
Clinical features
• The most common lysosomal storage disease
• 1 in 100 individuals in the U.S. population is a carrier for type I Gaucher disease,
with a prevalence of 1 in 40,000
• Most common among people of Ashkenazi Jewish descent
• Affects men and woman equally
• Three common clinical subtypes; presentation is related to the subtype inherited
• Type I: weakness, bone disease, anemia
• Type II: rapidly progressive central nervous system damage,
hepatosplenomegaly, bone disease
• Type III: chronic neuropathy, bone disease, hepatosplenomegaly
• Bone involvement includes osteoporosis, bone pain, aseptic necrosis of the femur
• Yellow-brown skin pigmentation
Prognosis and treatment
• Prognosis and treatment are related to the subtype
• Type I: slight decrease in life expectancy
• Type II: rapid progression, fatal by age 2 years
• Type III: chronically progressive, death often by age 30 years
• Treatment with intravenous enzyme replacement therapy improves outcome,
especially in type I
• Bone symptoms and deformities can regress after enzyme replacement therapyRadiology
• Plain radiographic abnormalities include diffuse osteopenia, osteonecrosis,
periosteal reactions, bone erosions, and infarcts
• Pathologic fractures commonly affect the distal femur, proximal tibia, and
thoracic and lumbar regions of the spine
• Erlenmeyer flask deformity (widening of the distal femoral metaphysis) due to
defective remodeling and bone marrow expansion
• Erlenmeyer flask deformity and epiphyseal osteonecrosis on the same radiograph
is suggestive of Gaucher disease
• MRI can be useful in demonstrating bone marrow infiltration and to calculate
bone marrow burden; it also allows differentiation of bone marrow infiltration
versus bone marrow infarct
• Accumulation of glucocerebroside (glycosphingolipid) in macrophages (Gaucher
cells) replacing bone marrow space
• Gaucher cells are large, vacuolated cells with abundant crumpled cytoplasm and
small nucleus pushed to one side
• Gaucher cells are primarily identified in the spleen, liver, lymph nodes, and bone
• Gaucher cells stain positive for periodic acid–Schiff and iron
Main differential diagnosis
• Storage diseases and macrophage proliferation disorders
• Von Gierke disease
• Niemann-Pick diseaseFig 1 Anteroposterior radiograph of the left knee showing osteopenia and
Erlenmeyer flask deformity.
Fig 2 T1-weighted coronal (A) and fat-saturated T2-weighted coronal (B)9
magnetic resonance images of bilateral knees. Bilateral di use bone marrow
in ltration is shown with Erlenmeyer : ask deformity. The substantial bone marrow
edema pattern at the left distal femur in the fat-saturated T2-weighted image (B)
suggests additional bone marrow infarction. Typically, Gaucher cell in ltration is
low in signal in T1- and T2-weighted images.
Fig 3 Scanning magni cation of bone involved by Gaucher disease shows
infiltration of the marrow space by a uniform population of eosinophilic cells.9
Fig 4 At higher magni cation, Gaucher cells have abundant cytoplasm and small
nuclei (A). The cells are lled with abundant crumpled cytoplasm and a single,
eccentrically placed nucleus (B and C). The lipids within Gaucher cells are
glucocerebroside, a lipid molecule with a single sugar residue that accumulates as a
result of the absence of the enzyme.B
Infectious and Inflammatory
Definition and synonyms
• Non-neoplastic joint disorder characterized by progressive erosion of articular
cartilage associated with aging, trauma, occupational injury, or genetic
predisposition manifested by cycles of degradation and repair of cartilage, bone, and
synovium (degenerative joint disease)
Clinical features
• Common condition, may be present in up to 80% of people older than 65 years
• Onset usually after age 40 years
• Commonly affected joints: cervical and lumbar spine, first carpometacarpal,
proximal interphalangeal, distal interphalangeal (Heberden nodes), hip, knee,
subtalar, first metatarsophalangeal
• Uncommonly affected joints: shoulder, wrist, elbow, metacarpophalangeal
• Most cases limited to one or same joint bilaterally, at least initially
• Symptoms: pain (worse in joints), stiffness, gelling
• Physical examination: crepitus, bony enlargement, decreased range of motion,
misalignment, tenderness to palpation
• Synovial fluid: usually clear, normal viscosity, white blood cell count (WBC) less
3than 2000 cells/mm
• Patterns of presentation
• Monoarticular in young adults
• Pauciarticular, large joint in middle age
• Polyarticular generalized; rarely rapidly progressive
• Classified as idiopathic (localized or generalized) or secondary (due to trauma,
congenital abnormality, or systemic disease)
• Charcot joint: severe secondary osteoarthritis due to diabetes or other neuropathic
condition, such as tabes dorsalis or pernicious anemia; knee or ankle mostcommonly affected
Prognosis and treatment
• Variable clinical course, generally slowly progressive
• Treatment: analgesics, anti-inflammatory agents, weight loss, alternative medicine
• Conventional radiographs
• Joint space narrowing
• Subchondral sclerosis
• Marginal osteophytes
• Subchondral cysts
• Extensive cartilage loss and meniscal damage (degenerative tears)
• Subchondral bone marrow edema pattern
• Synovitis
• Degeneration of cartilage at articular surface characterized by granularity or
grooving, fragmentation, thinning, and overgrowth of apposing joint surfaces
• Eburnation (exposure of underlying bone with smooth polished appearance
resembling ivory)
• Alteration of joint shape due to bone loss
• Sclerosis of bone underlying eroded articular cartilage
• Fibrous walled cysts filled with mucoid fluid immediately below articular surface
• Osteophytes (bony outgrowths) at joint periphery
• Chondro-osseous loose bodies (see Section IF, Chondro-Osseous Loose Body)
• Thinning, surface cracking, deep clefting, and loss of articular cartilage
• Necrotic chondrocytes
• Irregular, thickened, granular, or reduplicated tidemark (interface betweenarticular cartilage and bone; see Fig. 4B)
• Foci of cartilage regeneration
• Intrinsic: hypercellular nests of dividing chondrocytes within cartilage matrix
• Extrinsic: new fibrocartilage extending over the surface from periphery of the
• Depletion of proteoglycan in cartilage matrix
• Sclerosis of underlying and exposed bone
• Subchondral cysts, often containing acellular or hypocellular myxoid matrix
• Focal synovial hypertrophy and hyperplasia
• Usually no significant inflammatory component, although synovial lymphocytic
inflammation, rarely with lymphoid follicles, may be seen
Ancillary Tests
• No specific tests available
• Proteoglycan stains (e.g., Alcian blue or safranin O) highlight depletion of
Main differential diagnosis
• Rheumatoid arthritis
• Crystal-induced arthritis
• Septic arthritis
Fig 1 Lateral radiograph of the cervical spine (A) and sagittal CT reconstruction (B)
showing multilevel disk space narrowing (A, a r r o w), osteophytes (A, a r r o w h e a d), andsubchondral cystic changes (B, a r r o w s).
Fig 2 Anteroposterior radiograph of the pelvis demonstrating severe left hip
osteoarthritis with superolateral joint space narrowing, osteophytes, subchondral
sclerosis, and a subchondral cyst in the femur. Mild to moderate right hip
osteoarthritis with osteophytes at the femoral head and os acetabuli is visible.
Fig 3 Photograph of proximal femur with cartilage fragmentation and cracking.Fig 4 Microscopic changes of osteoarthritis. A, Cartilage necrosis with scattered
ghost chondrocytes ( a r r o w s) and loss of proteoglycan matrix density. B, Reduplication
and irregularity of tidemark ( a r r o w s). C, Cartilage cracking and clefting. D, Exposure
and sclerosis of bone at a site of eburnation. E, Subchondral cysts.Rheumatoid Arthritis
Definition and synonyms
• Chronic systemic nonsuppurative inflammatory disorder primarily affecting synovial
lining of joints, bursae, and tendon sheaths, not uncommonly associated with systemic
nonarticular manifestations in the skin, blood vessels, muscles, heart, lungs, kidneys, and
Clinical features
• Common disease, annual U.S. incidence about 30/100,000, prevalence 0.1% to 5%
(~1% of whites)
• Women affected two to three times more than men, about 5% of women older than 65
years affected
• Peak onset between 30 and 55 years of age
• Risk factors: female gender, nulliparity, smoking, HLA-DR β gene variant (“shared
epitope”), gene polymorphisms in TNF-α, STAT4, PTPN, TCR
• Affected joints: typically symmetrical peripheral polyarthritis; classically
metacarpophalangeal, metatarsophalangeal, and proximal interphalangeal joints of
hands and feet; also wrist, elbow, knee; less commonly axial joints or monoarthritis
• Symptoms: morning stiffness; swelling of joints with redness, pain, deformities, limited
range of motion, subcutaneous nodules, fatigue, muscle weakness
• Extra-articular manifestations: anemia, subcutaneous rheumatoid nodules, myositis,
vasculitis, neutrophilic dermatitis, pericarditis or myocarditis, interstitial lung disease
• Laboratory findings: 50% to 70% have rheumatoid factor (immunoglobulin M [IgM]
autoantibodies to Fc portion of IgG), which has low specificity; autoantibodies to cyclic
citrullinated peptides (CCPs) both sensitive and more than 90% specific
• Synovial fluid: leukocytosis with neutrophil predominance (particularly in acute stage)
but WBC lower than in septic arthritis (<_752c_000 _cells2f_c2b5_l29_2c_="" protein=""
approaching="" plasma="" _concentration2c_="" low="" _glucose2c_="" c3=""
Prognosis and treatment• Variable clinical course—most patients have periodic flares, some have unabating
activity, remissions are possible; structural damage is cumulative and irreversible over
years; if untreated may progress to destruction of articular cartilage and joint ankylosis
• Treatment: nonsteroidal anti-inflammatory drugs (NSAIDs), immunosuppressive drugs,
surgery (joint replacement, synovectomy)
• Joint effusions and soft tissue swelling
• Juxta-articular osteopenia
• Bone and cartilage erosions, typically at marginal joint regions
• Narrowing of joint space
• Joint deformities: radial wrist deviation, ulnar deviation of digits, swan-neck finger
• Affects typically metacarpophalangeal joints and carpal region at the hand and
metatarsophalangeal joints at the foot
• Joint destruction and joint deformities
• Little or no reparative tissue, proliferative cartilage, bone sclerosis, or osteophytes
(unlike osteoarthritis)
• Joints have edematous, thick, hyperplastic synovium covered by delicate and bulbous
• Hypertrophic and hyperplastic synovium
• Chronic inflammation, uncommonly with lymphoid follicles and germinal centers
cuffed by a dense population of plasma cells
• Hyperplasia of synovial cells may result in multinucleation (Grimley-Sokoloff giant
• Focal fibrinoid exudate and neutrophils at the synovial surface
• Organizing fibrin may float into joint space as rice bodies
• Reactive synovium extends from periphery to cover entire articular surface forming apannus with destructions of underlying cartilage characterized by enlarged and often
empty chondrocyte lacunae (Weichselbaum lacunae)
• Wall thickening and onion-skin appearance of synovial arteries
• Chronic inflammation also often involves subchondral bone
• Synovitis typically less pronounced in advanced disease with little remaining cartilage
or following joint replacement but typically recurs following synovectomy
• Rheumatoid nodules in about 25% of cases
• Usually in subcutaneous tissue along extensor surfaces of forearm, elbow, and shin
• Less commonly in visceral organs (heart, lungs, intestinal tract) or in joint synovium
• Characterized by central fibrinoid necrosis rimmed by palisaded histiocytes and
giant cells and a cuff of lymphocytes and plasma cells
• Joint aspirate may have inflammatory exudate with neutrophils, which may suggest
septic arthritis
Ancillary tests
• Serology (rheumatoid factor, CCPs) used as one of the diagnostic criteria
Main differential diagnosis
• Osteoarthritis
• Crystal-induced arthritis
• Septic arthritis, particularly if monoarticular disease
• Rheumatoid nodule: infection, epithelioid sarcomaFig 1 Radiographic Nndings of Rheumatoid arthritis. Lateral (A), oblique (B), and
anteroposterior (C) radiographs of the left wrist show typical erosions at the carpal
bones, in particular the scaphoid, capitate, and lunate (cystic erosions). Erosions are also
seen at the styloid process of the ulna. Adjacent soft tissue swelling is present. Findings at
the Nrst carpometacarpal joint are related to coincidental osteoarthritis and not
Rheumatoid arthritis.Fig 2 Subcutaneous rheumatoid nodule. A, At low magniNcation, the nodule is composed
of zones of Nbrinoid necrosis surrounded by a rim of inPammatory cells embedded in
dense collagenous stroma. B, The necrosis is rimmed by palisading histiocytes and a rim
of plasma cells and lymphocytes.Fig 3 Microscopic Nndings of rheumatoid arthritis. A, At low magniNcation, inPamed,
hypertrophic, and hyperplastic synovium is present. B, The inPammation commonly
forms lymphoid follicles with germinal centers. C, The synovial membrane is covered by a
Nbrinous exudate (at left) . D, High magniNcation of the inPamed synovium shows
numerous plasma cells, admixed lymphocytes, and macrophages, without signiNcant
neutrophilic component. E, Russell bodies (arrows) may be present.Septic Arthritis
Definition and synonyms
• Joint inflammatory condition due to intra-articular infection by a microbial pathogen
resulting from hematogenous seeding, extension from neighboring bone or soft tissue
site, or direct implantation from trauma or surgery (infectious arthritis)
Clinical features
• Bacterial (suppurative) arthritis (most common)
• More common in children than adults, male-to-female ratio of 1.5:1
• Large weight-bearing joints most commonly affected (usually by hematogenous
• Small joints of hands and feet (usually due to penetrating trauma)
• Usually monoarticular (85%), polyarticular often associated with
• Risk factors: preexisting joint disease (particularly rheumatoid arthritis), chronic
skin ulcers, intravenous drug use, alcoholism, chronic steroid use, or
immunosuppressed state (e.g., AIDS, diabetes)
• Prosthetic joint: may be responsible for loosening of prosthesis
• Most common pathogens: Staphylococcus aureus (40% to 50%), Streptococcus
pyogenes, Streptococcus pneumoniae, gram-negative bacilli (10%, often associated
with intravenous drug use)
• Gonococcal arthritis (Neisseria gonorrhoeae): most common arthritis due to sexually
transmitted bacterial infection
• Lyme arthritis (Borrelia burgdorferi)
• Acute Lyme arthritis seen in 50% to 60% of cases
• Associated with erythema migrans (90% of Lyme cases)
• Mycobacterial arthritis (Mycobacterium tuberculosis)
• Usually follows infection of the spine and affects hip or knee most commonly
• Fungal arthritis
• Rare, usually in immunocompromised hosts
• Candida species most common
• Symptoms: fever; swollen, warm, erythematous and painful joint
• Synovial fluid: gray-green, WBC 20,000 to 200,000 cells/ μL, more than 75%
neutrophilsPrognosis and treatment
• Adjacent tendon sheath or bursa may be involved; secondary osteomyelitis in about 8%
• May result in severe destruction of musculoskeletal structures, permanent disability
(30%), and, very rarely, death
• Diagnosis relies on compatible history, physical examination, and synovial fluid Gram
stain, microbiology culture, and cell count
• Treatment: prompt appropriate antibiotic therapy, joint tap with drainage,
debridement in some cases
• Loosening of prosthetic joint: intraoperative frozen section and Gram stain to assess for
acute inflammation and organisms; if evidence of infection is present, prosthetic
replacement delayed until after antibiotic therapy
• Plain films and CT
• May be normal in early-stage disease
• Joint effusion
• Joint space narrowing
• Bony erosion and later destruction
• Periosteal bone formation
• Synovial thickening and enhancement
• Joint effusion, surrounding edema
• Bone marrow edema pattern and bony erosions
• Swollen periarticular soft tissue
• Thickened or nodular synovial tissue with or without exudate
• Cloudy, milky, or thick green joint aspirate
• Scarring and erosion of articular cartilage
• Suppurative inflammation (pyogenic bacteria, gonococcal arthritis, Lyme arthritis,
Candida species)
• Synovial edema and dense neutrophilic infiltrate
• If not treated promptly, necrosis and destruction of articular cartilage• Eventually, lymphocytes, plasma cells, and histiocytes predominate with
development of chronic papillary synovitis, fibrin deposits and thickening of arterial
walls (similar to that seen in other inflammatory arthritides)
• Organisms can be demonstrated with special histochemical stains (see later)
• Granulomatous inflammation (mycobacteria, most fungi)
• Acute and chronic synovitis with necrotizing or non-necrotizing granulomas and
giant cells
• Septic loosening of prosthesis
• Neutrophil count on intraoperative frozen section of synovium or prosthetic capsule:
• Five neutrophils per high-power field in more than 5 high-power fields (Feldman
• Ten neutrophils per 10 high-power fields (Athanasou criteria)
• Neutrophils in fibrinous exudate or blood are not counted
Ancillary tests
• Gold standard of diagnosis is positive microbiologic culture
• Tissue stains
• Molecular tests (polymerase chain reaction and reverse-transcriptase polymerase chain
reaction techniques) can detect a wide range of microorganisms
• Serology (Lyme arthritis, viral arthritides)
Main differential diagnosis
• Rheumatoid arthritis
• Gout
• Other crystal-induced arthritides
• OsteoarthritisFig 1 Septic arthritis, radiographic Cndings. A, Axial CT section of the pelvis shows
erosive changes at the right hip joint (in particular the femoral head). B, Fluid-sensitive
coronal magnetic resonance image of the pelvis demonstrates large joint eDusion at the
right hip (arrows) with erosive changes at the femoral head and bone marrow edema
pattern at the proximal femur. In addition, extensive soft tissue edema is present around
the right hip, as are abscesses of the iliopsoas and adductor (arrowheads).Fig 2 A, Early changes of septic arthritis from Staphylococcus aureus with dense
neutrophilic inCltrate, synovial edema, and Cbrin. B, Later changes of articular cartilage
destruction and necrosis. Bacterial colonies are rarely evident in routine histologic
Fig 3 In the intraoperative evaluation of septic loosening, the quantity of neutrophils in
synovium, implant capsule (A), or granulation tissue should be scored. Neutrophils
associated with fibrin (B) do not correlate with septic loosening.Gout
Definition and synonyms
• Inflammatory joint condition resulting from deposition of monosodium urate in
and around affected joints due to hyperuricemia (monosodium urate crystal
deposition disease)
Clinical features
• Common condition, affects 3 to 5 million people in the United States, accounts
for 2% to 5% of chronic joint disease
• Age of onset usually between 40 and 50 years
• Risk factors
• Men older than 40 years with hypertension, obesity, alcohol-use
• Women older than 70 years with chronic kidney disease, on diuretics, with
• Transplant recipients on calcineurin inhibitors (cyclosporine) with or without
• Patients with leukemia or other malignancy
• High uric acid levels (>8 mg/dL) are required, but only about 10% of people
with elevated uric acid will have clinically evident gout
• Primary gout (~90% of cases): hyperuricemia due to a primary error in synthesis
or excretion of purine (~58% idiopathic); known defects include
hypoxanthineguanine phosphoribosyl transferase deficiency (including Lesch-Nyan syndrome),
other defects in purine biosynthesis, and renal excretion
• Secondary (~10% of cases): hyperuricemia due to increased cell breakdown
(leukemia or other malignancy), chronic renal disease, or use of diuretics (e.g.,
• Episodic acute attacks of inflammatory arthritis, usually monoarticular
• Predilection for the first metatarsophalangeal joint (most common initialpresentation), but also affects ankles, heels, knees, wrists, fingers, elbows
• Development of sodium urate deposits (tophi) around affected joints
• Uric acid nephrolithiasis, chronic nephropathy, or both
Prognosis and treatment
• Chronic relapsing condition with variable rate of progression and frequency of
acute flares
• Treatment: uric acid–lowering agents, discontinuation of diuretics, fluid
administration, and alkalinization of urine during chemotherapy
• Swelling of periarticular soft tissues, typically at the first metatarsophalangeal
• Subsequent erosion of periarticular bone leading to classic punched-out
appearance with overhanging edges
• Tophi are radiolucent but may also calcify
• Little reactive sclerosis
• Usually no regional osteopenia (in contrast to rheumatoid arthritis)
• Occasionally soft tissue deposits, which mimic soft tissue tumors
• Tophaceous deposits in the joints and periarticular soft tissue have chalky-white
• Destruction of articular cartilage and adjacent bone
• Synovial fluid cytology in acute gouty synovitis
• Inflammatory exudate (neutrophils and lymphocytes) can be mistaken for
septic arthritis
• Sodium urate crystals: needle shaped, with strong negative birefringence
(appear bright yellow under polarized light)• Sections of tophi show variably sized deposits of fluffy eosinophilic material
rimmed by macrophages, giant cells, and fibrous tissue
• Crystals are usually dissolved by conventional aqueous processing; for better
preservation, ethanol fixation with or without examination of fresh tissue is
Ancillary tests
• Demonstration of sodium urate crystals in synovial fluid
• Blood uric acid level may be elevated but is neither diagnostic nor specific
Main differential diagnosis
• Septic arthritis
• Other crystal-induced synovitis
• Rheumatoid arthritis
• Osteoarthritis
Fig 1 Radiographic changes of gout. This plain dorsoplantar radiograph of the
right foot shows extensive periarticular, bony erosions at the metatarsophalangeal
1, 2, 3, and 5 joints with surrounding soft tissue swelling. Joint space narrowing is
consistent with secondary degenerative changes. A small punched-out lytic lesion in
the distal lateral portion of the second middle phalanx (arrow) also represents an
intraosseous tophus.Fig 2 Tophaceous deposits; ethanol-Dxed tissue. A, Large crystalline deposits of
monosodium urate are preserved and easily visualized as yellow-brown aggregates.
B, The crystals are needle shaped and are negatively birefringent under polarized
light (bright yellow).Fig 3 Microscopic Dndings of gout; formalin-Dxed tissue. A, Low magniDcation
shows amorphous eosinophilic deposits rimmed by inEammatory cells and
embedded in dense collagenous stroma; urate crystals have been dissolved by
conventional formalin Dxation and processing. B, Intermediate magniDcation
shows epithelioid histiocytes, scattered lymphocytes, and giant cells at the
periphery of the tophaceous deposits. C, High magniDcation of smaller deposits
surrounded by foreign body–type giant cell reaction.Other Crystal-Induced Synovitis and Calcium
• Several unrelated conditions characterized by different forms of calcium deposits
involving articular and periarticular synovial tissue as well as nonsynovial soft
• Calcium pyrophosphate deposition disease (CPPD), including pseudogout and
• Calcium hydroxyapatite deposition
• Metastatic calcification
• Dystrophic calcification
• Tumoral calcinosis
Clinical features
• Primary (most cases): familial or sporadic
• Secondary: associated with hyperparathyroidism, hypothyroidism, gout, or
• C h o n d r o c a l c i n o s i s : term used in the past by radiologists to describe calcium
deposits in the knee menisci of elderly patients (most cases are due to CPPD)
• P s e u d o g o u t : term used to describe clinically CPPD cases presenting with an
acutely swollen joint mimicking gout (<_2525_ of="" cppd="">
• Most common presentation is similar to osteoarthritis; about 50% have
progressive arthritis, usually affecting multiple joints; onset is usually in the
fourth decade
• Most commonly affected joints are knees, ankles, wrists, elbows, hips, and
shoulders; involvement of metacarpals and metatarsals is rare
• Other forms include rapidly degenerating arthritis similar to Charcot joint, a
tumor-like mass (very rare), or involvement of the spine with stiffening (usually
• Treatment: joint aspiration, corticosteroid injection, NSAIDs
• Hydroxyapatite deposition
• Deposits are in nonsynovial soft tissues (calcific tendonitis)
• May be associated with trauma, renal failure, scleroderma,
hyperparathyroidism, sarcoidosis, metastatic malignancy, myeloma, or
hypermetabolic state• Metastatic calcification
• Occurs in patients with disturbed calcium homeostasis and hypermetabolic
states (e.g., hyperparathyroidism or Paget disease of bone), particularly if
prolonged bed rest
• Frequent sites of involvement include kidneys, lungs, cornea, conjunctiva,
stomach mucosa, media, and intima of blood vessels
• Dystrophic calcification
• Not related to disturbances in calcium homeostasis
• Common at sites of coagulative necrosis and fat necrosis
• May be secondary to trauma
• Tumoral calcinosis
• Most cases sporadic, some familial cases reported
• Usual onset in second decade of life
• Characterized by deposition of painless calcific masses around hips, elbows,
shoulders, and gluteal areas
• Lesions are usually bilateral, affect multiple sites and can be massive
• Rarely, intra-articular or intraosseous deposits are present
• Serum phosphate is usually elevated
• Treatment: excision, low phosphate diet, phosphate binders, diuretics
• Radiodense deposits (unlike radiolucent deposits in gout) are
characteristically in fibrocartilage in particular menisci (punctate or linear) but
may also be in hyaline cartilage (usually parallel subchondral bone end plate)
• Punctate deposits may also be seen in synovium
• Accelerated degenerative changes, including joint space narrowing and bony
• Hydroxyapatite deposition, metastatic calcification, dystrophic calcification,
tumoral calcinosis
• Radiodense soft tissue deposits (calcifications)
• Small chalky-white deposits in the affected tissues
• Hydroxyapatite deposition• Small calcified soft tissue deposits
• Metastatic calcification
• Small calcified deposits may not be apparent grossly
• Dystrophic calcification
• Small calcified deposits may not be apparent grossly
• If large enough, may form irregular calcified nodules or masses
• Tumoral calcinosis
• Irregular calcified soft tissue deposits, masses
• Crystalline or amorphous deposits composed of small rhomboidal crystals
with weak positive birefringence (appear dim blue)
• For optimal crystal preservation, ethanol fixation or examination of fresh
tissue (smears), or both, may be needed (particularly if gout is in the
• In nonvascularized tissue, inflammatory changes are typically not present
• Deposits in vascularized tissue may be surrounded by chronic inflammatory
and giant cell reaction, often mimicking findings of gout
• Hydroxyapatite deposition, metastatic calcification, dystrophic calcification,
tumoral calcinosis
• Calcified deposits of varying size surrounded by varying, usually mild degree
of chronic inflammation with macrophages and frequently giant cells
• No birefringent crystals
Ancillary tests
• Demonstration of sodium pyrophosphate crystals in synovial fluid (see earlier)
• Hydroxyapatite deposition, metastatic calcification
• Specific testing for associated conditions
• Tumoral calcinosis
• Serum phosphate is usually elevatedFig 1 A and B, Tumoral calcinosis appears as amorphous basophilic deposits
associated with a < brotic stroma and limited in= ammation. Polarizable crystals are
Main differential diagnosis
• Gout
• Osteoarthritis
• Rheumatoid arthritis
• Septic arthritisFig 2 A and B, The crystals of calcium pyrophosphate deposition disease are
dense and basophilic on hematoxylin and eosin staining, often with little to no
inflammation. C, Under polarized light, the crystals are small and rhomboid.Fig 3 Anteroposterior (A) and lateral (B) radiographs of the knees show bilateral
meniscal and periarticular calci< cations consistent with calcium pyrophosphate
deposition disease (CPPD). In addition, severe degenerative disease of the
patellofemoral joint is more advanced compared with the other joint
compartments, which is a typical finding for CPPD.Fig 4 A and B, Hydroxyapatite (HA) deposition disease, seen here within a tendon
(calci< c tendonitis), demonstrates dense, basophilic matrix similar to bone. The
distinction between HA deposition disease and tumoral calcinosis rests on the
clinical setting and the absence of other underlying metabolic disease (e.g.,
hypervitaminosis D, renal failure, milk-alkali syndrome) in tumoral calcinosis.Acute Osteomyelitis
Definition and synonyms
• Acute inflammation of the bone resulting from infection by a microbial pathogen
(acute bacterial osteomyelitis, acute suppurative osteomyelitis)
Clinical features
• Most cases are caused by bacteria, less commonly fungi
• Three modes of pathogen entry: hematogenous, contiguous spread, and direct
• Osteomyelitis from hematogenous spread (~20% of cases)
• Most common in children (1 to 16 years old), male-to-female ratio of 2:1
• Risk factors: indwelling catheters, chronic infections, debilitating conditions,
immunocompromised states, nonpenetrating trauma, intravenous drug use
• Most common sites:
• Children: long bones, usually limited to metaphysis
• Adults: spine more than pelvis more than long bones
• Usually solitary and primary and associated with a single pathogen
• Most frequent pathogens: S. aureus, S. pyogenes, enteric gram-negative rods;
Salmonella frequently complicates sickle cell disease
• Neonatal osteomyelitis (<1 year="">
• Risk factors: prematurity, immunocompromised states
• Up to 40% of cases are polyostotic
• Most common pathogens: group A and B streptococci
• Osteomyelitis from contiguous spread
• Bacteria gain entry through periosteum or articular cartilage
• Periodontal disease, decubitus ulcers, often polymicrobial
• Osteomyelitis from direct inoculation
• Post-traumatic (3% to 30% of open fractures become infected)
• Implant related
• Most common pathogens: Staphylococcus and Streptococcus species
• Pain• Fever
• Leukocytosis; elevated C-reactive protein and erythrocyte sedimentation rate
• Blood cultures are frequently negative; biopsy with culture needed to establish
Prognosis and treatment
• Inadequate or delayed treatment may lead to chronic infection
• Treatment: antibiotics, typically several weeks of intravenous administration,
with or without curettage of necrotic bone
• Soft tissue swelling and gas within lesion may be present in the early phase of
• Plain films may not show any changes until sufficient bone destruction is present
• Focus of infection appears as radiolucency with destructive or erosive changes in
radiographs; however, depending on how aggressive the infectious organism is,
this may take 10 to 14 days
• In addition to erosive changes, bony proliferations are demonstrated, typically as
periosteal bone formation
• Later, reactive bone deposition (involucrum) is seen at the lesion periphery and
beneath the raised periosteum
• MRI is the most sensitive technique to diagnose osteomyelitis in the early phase
• Most specimens are from curettage and may have subtle findings
• May contain green-tan pus, can be putrid
• Resection specimens are usually from long-standing chronic disease (see separate
section on chronic osteomyelitis)
• Initially neutrophilic inflammation with edema, fibrin, and hemorrhage• Within days, bone necrosis with empty lacunae (sequestrum)
• Colonies of bacteria or fungal elements
• Periosteal new bone deposition (involucrum)
• May evolve to chronic osteomyelitis: reactive fibrovascular tissue with
lymphocytes, plasma cells, and macrophages
Ancillary tests
• Microbiologic culture of the curetted tissue is the gold standard in diagnosis
• Bacterial histochemical stains on formalin-fixed sections
• Systemic markers of inflammation (C-reactive protein, erythrocyte sedimentation
rate) are nonspecific
Main differential diagnosis
• Acute subchondral inflammation in severe arthritis
• Acute stages of fracture
• Langerhans cell histiocytosis (eosinophilic granuloma)
• Radiographically: osteosarcoma, Ewing sarcoma, lymphomaFig 1 Osteomyelitis involving the base of the = rst metacarpal. Lateral radiograph
of the wrist shows erosive lesion (arrowheads) with periosteal bone formation
(arrow) at the base of the metacarpal. The carpometacarpal joint is also involved,
and marked swelling of the surrounding soft tissue is present.
Fig 2 Necrotic bone (sequestrum) is characterized by the presence of empty
lacunae. The surfaces of the bony trabeculae are undergoing destruction, imparting
a “chewed” or scalloped configuration.
Fig 3 At low magni= cation, acute osteomyelitis consists of necrotic bone
(sequestrum) and a fibrinopurulent exudate.Fig 4 An infiltrate of neutrophils replaces the marrow space.
Fig 5 Involucrum, new periosteal bone formation associated with osteomyelitis,
develops several days to weeks after infection in a pattern similar to fracture
callus.Chronic Osteomyelitis
• Established (>6 weeks), nonsuppurative bone inflammation arising as a
complication of untreated or treatment-refractory acute osteomyelitis or as a result
of infection by an indolent pathogen (includes granulomatous osteomyelitis)
Clinical features
• Fifteen to 30% of acute osteomyelitis (see separate section) go on to chronic
• Other causes: nonpyogenic bacteria, fungi, and very rarely parasites or viruses
• Mycobacterial osteomyelitis
• Tuberculous osteomyelitis (Mycobacterium tuberculosis)
• One to 3 percent of cases of pulmonary and 10% of extrapulmonary
• Usually a solitary bone lesion, frequently multifocal in patients with AIDS
• Most frequent sites: spine (Pott disease) usually involves anterior column,
T6-L3; hips; knees
• Nontuberculous mycobacterial osteomyelitis (atypical mycobacteria)
• Five to 10 percent of infections have bone involvement
• Risk factors: immunocompromised state, trauma, surgery
• Lepromatous osteomyelitis
• Most common sites: facial bones, hands and feet
• Treponemal osteomyelitis
• Skeletal syphilis (Treponema pallidum)
• Congenital
• Usually bilateral symmetrical bone involvement with variable severity
• Most common in diaphysis of long bones and costochondral junction
• Acquired
• Usually not before early tertiary stage (2 to 5 years after initial infection)
• Most common sites: facial and skull bones, clavicle, tibia
• Fungal osteomyelitis
• Candida species (most common)
• Bone involvement in 1% to 2% of bloodstream Candida species infections• Risk factors: immunosuppression; chronic illness, particularly diabetes;
invasive catheters; and parenteral drug use
• Most common sites: lumbar spine and long bones, usually single focus
• Other fungi: Aspergillus, Cryptococcus, Coccidioides, Paracoccidioides,
Histoplasma, Blastomyces species (rare, usually in patients with a primary lung
infection); Sporothrix (usually due to penetrating trauma)
• Chronic, recurrent multifocal osteomyelitis
• Multifocal inflammatory disorder involving skeletal system of children and
• Female preponderance (5:1 female-to-male ratio)
• Protracted relapsing course
• Cultures typically negative for organisms
• Definition evolving, may represent an autoimmune syndrome rather than true
• Low-grade fever
• Weight loss
• Pain over affected area
• Swelling, local warmth, erythema
Prognosis and treatment
• May result in severe disability, pathologic fracture, or extensive soft tissue
• Treatment: usually a combination of intravenous antibiotics and surgical
• Compared with acute osteomyelitis, osteopenia and soft tissue swelling are less
frequently observed and relatively atypical
• Lytic destructive bone lesions with surrounding sclerosis; sclerosis is characteristic
and can be abundant
• Periosteal reaction is typically solid but can be atypical, including complex,
irregular, and layered appearance
• Involvement of surrounding soft tissue or sinus tract formation, or both• Bone tumors can have a similar appearance, and differential diagnosis can be
• Spine: cortical bone collapse, disk destruction, intervertebral body fusion
• Gibbus deformity: kyphosis caused by collapse of vertebral bodies in
tuberculous osteomyelitis (Pott disease)
• In curettings, infected bone is discolored white-yellow-gray
• In larger specimens, areas of bone destruction are poorly circumscribed and
appear as firm white-yellow-gray fibroinflammatory tissue
• Larger granulomas can sometimes be seen grossly as nodules, often with
• Extension through cortex into soft tissue may be present
• Variable histology depending on the causal agent and host immune factors
• Necrotizing or non-necrotizing granulomatous inflammation (mycobacteria,
fungi), or both
• Lymphoplasmacytic or histiocytic inflammation (Treponema species,
Mycobacterium leprae), or both
• May see a component of suppurative inflammation (fungi)
• Areas of bone necrosis with osteoclastic activity and bone resorption
• Marrow replacement with fibrosis
• Reactive bone formation and periosteal reaction at the lesion periphery
• Microorganisms are visualized by histochemical stains or routine hematoxylin
and eosin staining
• Diagnosis relies on presence of diagnostic fungal forms or positive culture, or
Ancillary tests
• Culture, Gram, and acid-fast stains from biopsy material
• Tissue stains• Acid fast stain (Mycobacteria species)
• Warthin-Starry or similar silver stains (Treponema species)
• Gomori methenamine silver (fungi)
• Immunohistochemical stains
• Molecular tests (polymerase chain reaction)
• Serology
Fig 1 Chronic osteomyelitis radiographic > ndings. A, Anteroposterior radiograph
of a femur showing a large lytic lesion with surrounding sclerosis and exuberant
periosteal reaction with a sunburst pattern mimicking osteosarcoma. B,
Anteroposterior radiograph of the knee joint demonstrating mixed
osteolyticosteosclerotic lesion in the proximal tibia (small arrows) and periosteal reaction atthe lateral aspect of the tibia (large arrow).
Main differential diagnosis
• Subchondral inflammation in severe arthritis
• Hematopoietic malignancies (myeloma, lymphoma)
• Sarcoidosis (1% to 13% of cases have bone involvement)
• Langerhans cell histiocytosis (eosinophilic granuloma)
• Plasmacytoma/myeloma
Fig 2 Granulomatous osteomyelitis due to Coccidioides immitisA, Low
magni> cation showing granulomatous inBammation. B, Diagnostic spherules of
Coccidioides are seen within giant cells at higher magnification.Fig 3 Chronic osteomyelitis microscopic > ndings. A, Intermediate magni> cation
showing osteonecrosis and marrow replacement by > brosis. B, Higher
magni> cation of the > brosis with sparse patchy lymphoplasmacytic inBammation.
C, A plasma cell in> ltrate is most common in chronic osteomyelitis and raises the
differential diagnosis of a plasma cell neoplasm.