Background

As a group, tumors of the bone and joint are extremely rare.  It is important to seek care at a medical institution which has both diagnostic and treatment experience. Osteosarcoma, one of the most common malignant tumors of the bone is one of the great success stories with chemotherapy.  The treatment is multidisciplinary between surgery, chemotherapy, and radiation therapy.

Aneurysmal Bone Cyst
Chondroblastoma
Chondromyxoid Fibroma
Chondrosarcoma
Chondrosarcoma, Extraskeletal
Enchondroma
Ewing's Sarcoma
Fibrous Dysplasia
Giant Cell Tumor of Bone
Giant Cell Tumor of Tendon Sheath
Osteochondroma
Osteosarcoma
Pigmented Villonodular Synovitis
Primitive Neuroectodermal Tumor (PNET)
Sacrococcygeal Teratoma

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

PATHOGENESIS	CHARACTERIZATION
CARTILAGINOUS TUMORS
Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. Tallini G, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CD, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Sciot R, Van den Berghe H, Vanni R, Willen H. Department of Pathology, Yale University School of Medicine, New Haven, USA	J Pathol 2002 Feb;196(2):194-203 Abstract quote The evaluation of chondroid lesions requires full integration of clinical, radiographic, and pathological data; tumour typing is often a challenge for the diagnostic pathologist. Although a variety of chromosomal abnormalities have been documented in chondroid lesions, the potential usefulness of cytogenetic analysis remains unclear. This study has critically reviewed and analysed 117 karyotyped samples from 100 patients with cartilaginous and chordoid tumours. Cases were selected based on successful chromosomal analysis and adequacy of clinical, radiographic, and pathological information. To ensure objective evaluation, the cytogenetic results were correlated in a double-blind setting with consensus diagnoses independently determined on each case, after complete review of the histological, radiographic, and clinical findings. Karyotypic aberrations were identified in 41/92 cartilaginous tumours (5/11 osteochondromas, 2/3 chondromyxoid fibromas, 0/4 chondroblastomas, 11/29 chondromas, 0/3 chondroid tumours of undetermined malignant potential, 22/40 chondrosarcomas and 1/2 miscellaneous cartilaginous lesions) and 5/8 chordomas. Complex karyotypic changes were a feature of malignant tumours (chondrosarcoma and chordoma) and of chondrosarcoma among cartilaginous tumours, where they correlated with high tumour grade. Among primary well-differentiated cartilaginous lesions of bone, the finding of an abnormal karyotype was consistently associated with a grade 1 chondrosarcoma diagnosis. Among karyotypically abnormal cartilaginous tumours, loss of distal 8q was associated with osteochondroma, +5 with synovial chondroma/chondromatosis and parosteal or soft tissue chondroma, alterations of chromosome arm 6q with chondromyxoid fibroma, +7 with bone chondrosarcoma, and 17p1 alterations with grade 3 chondrosarcoma. Alterations involving 12q13 characterized synovial chondroma/chondromatosis in the chondroma group and myxoid chondrosarcoma of bone in the chondrosarcoma group. In conclusion, cytogenetic abnormalities in chondroid lesions are common and are not randomly distributed. They are associated with malignancy/tumour grade as well as with specific diagnoses in many cases, and can therefore be of potential value for tumour typing.
EPIDERMAL GROWTH FACTOR RECEPTOR
Aberration of epidermal growth factor receptor expression in bone and soft-tissue tumors: protein overexpression, gene amplification and activation of downstream molecules. Dobashi Y, Takei N, Suzuki S, Yoneyama H, Hanawa M, Ooi A. 1Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.	Mod Pathol. 2004 Dec;17(12):1497-505. Abstract quote   In order to evaluate the involvement of epidermal growth factor receptor, and to analyze the correlation between gene aberration and protein expression in mesenchymal tumors, we examined protein expression by immunohistochemistry in 125 cases of bone and soft-tissue tumors. Furthermore, amplification of epidermal growth factor receptor gene was determined by fluorescence in situ hybridization. Positive immunostaining was found in 23 cases (18.4%). Among these 23 cases, one of malignant fibrous histiocytoma showed the highest degree (3+) of protein overexpression and gene amplification as clusters of hybridization signals, indicating homogeneously staining regions. The second case of malignant fibrous histiocytoma also showed a higher degree (2+) of overexpression and coamplification of the epidermal growth factor receptor gene with the centromeric regions, indicating polysomy of chromosome 7. The levels of expression observed in immunohistochemistry were confirmed by immunoblotting and found to be comparable. Moreover, although expression of phosphorylated epidermal growth factor receptor was detected in those two cases of malignant fibrous histiocytoma, constitutive activation of extracellular signal-related protein kinase 1/2 was not observed, suggesting that activation of epidermal growth factor receptor does not necessarily and constantly lead to signal transduction to the downstream molecules. In the remaining 123 cases, including 21 cases exhibiting weak (1+) immunoreactivity, no gene amplification nor polysomy was found. Collectively, expression of epidermal growth factor receptor was observed not infrequently in mesenchymal tumors, but 'overexpression' is rare and can be attributed to an increase in gene copy number, resulting from amplification or polysomy. Although cases that scored positive for protein expression and/or gene amplification could be qualified candidates for antiepidermal growth factor receptor therapies, further examination of the status of downstream molecules in the signal cascade, such as phosphorylated epidermal growth factor receptor and extracellular signal-related protein kinase 1/2, may be required as the process of therapeutic strategy.

 

LABORATORY/ RADIOLOGIC	CHARACTERIZATION
RADIOLOGY
Radiographic correlation in orthopedic pathology. Klein MJ. Section of Surgical Pathology, The University of Alabama at Birmingham, Division of Anatomic Pathology, Birmingham, Alabama 35249-7331, USA.	Adv Anat Pathol. 2005 Jul;12(4):155-79. Abstract quote   Radiographic correlation is an essential adjunct for the accurate diagnosis of orthopedic lesions, yet it is a skill neglected by pathologists. The purpose of this review is to demonstrate why performing this correlation is an essential part of the diagnostic process and not merely an interesting adjunct to the surgical pathology of orthopedic lesions. The relationships between x-rays and tissues are explored with an emphasis on bone and soft tissue composition and structure. In addition, the rudiments of complementary imaging studies and how to incorporate their data into diagnoses are examined.

 

CLINICAL VARIANTS/ GROSS DISEASE	CHARACTERIZATION
ADAMANTINOMA
Dedifferentiated adamantinoma with revertant mesenchymal phenotype. Hazelbag HM, Laforga JB, Roels HJ, Hogendoorn PC. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.	Am J Surg Pathol. 2003 Dec;27(12):1530-7. Abstract quote   In adamantinoma of long bones, an osteofibrous dysplasia-like form with scattered epithelial elements and a classic form with abundant epithelium are distinguished. Osteofibrous dysplasia-like adamantinomas occur in children and adolescents and behave relatively benign, whereas classic adamantinomas predominate in adults and have a more aggressive clinical course. Because some osteofibrous dysplasia-like tumors have progressed to classic adamantinomas, it is hypothesized that the former is a potential precursor of the latter, showing mesenchymal-to-epithelial transformation. We report a new morphologic variant of adamantinoma in three patients with sarcomatoid transformation of the epithelial component: one in a primary tumor and two in local recurrences. One patient died of metastatic disease. Histologically, the tumors showed loss of the original characteristic epithelial differentiation with transition to fields of highly pleomorphic cells without epithelial features, high mitotic count, and deposition of osteoid and chondroid matrix. These dedifferentiated areas showed pankeratin positivity as well, although there were some changes in keratin subclass profile compared with other classic adamantinomas. This peculiar variant of long bone adamantinoma shows that in addition to mesenchymal-to-epithelial transformation in the early stage of development, progression to an aggressive subtype may be associated with epithelial-to-mesenchymal transition ("sarcomatoid dedifferentiation"), in which the epithelial immunophenotype is conserved. Thereby it may serve as an example of the plasticity of the mesenchymal phenotype. When confronted with a biopsy of a cortical tumor of the tibia showing sarcomatoid morphology and keratin positivity, adamantinoma should be included in the differential diagnosis, as its distinction has important implications for treatment and prognosis.
ANEURYSMAL BONE CYST
Expression of Insulin-Like Growth Factor-I (IGF-I) in Aneurysmal Bone Cyst Andreas Leithner, M.D., Susanna Lang, M.D., Reinhard Windhager, M.D., Katharina Leithner, M.D., Heidrun Karlic, Ph.D., Rainer Kotz, M.D. and Oskar Arthur Haas, M.D. Children’s Cancer Research Institute (CCRI), St. Anna Children’s Hospital (AL, OAH), Vienna; Clinical Institute of Clinical Pathology (SL) and Department of Orthopedic Surgery (RK), Vienna University Hospital, Vienna; Department of Orthopedic Surgery, Karl Franzens University (RW), Graz; Department of Vascular Biology and Thrombosis Research, Vienna University (KL), Vienna; and L. Boltzmann Institute for Leukemia Research and Hematology, Hanusch Hospital (HK), Vienna, Austria	Mod Pathol 2001;14:1100-1104 Abstract quote The effects of insulin-like growth factor-I on bone tissue and its role in bone development have been extensively investigated, but there is little information on its role in the pathogenesis of aneurysmal bone cyst. Therefore, using the techniques of immunohistochemistry and in situ hybridization, the authors studied the expression of insulin-like growth factor-I in 19 specimens of aneurysmal bone cyst. Insulin-like growth factor-I or specific mRNA sequences encoding for insulin-like growth factor-I were detectable in all specimens tested and were mainly localized in multinucleate giant cells. In contrast, only insignificant levels of insulin-like growth factor-I expression were detectable in normal human bone tissue. Taken together with the previously reported role of insulin-like growth factor-I in the pathogenesis of giant cell tumor, the findings of this study suggest that insulin-like growth factor-I may play a role in the pathogenesis of aneurysmal bone cyst.
DESMOPLASTIC FIBROMA
Desmoplastic fibroma of the rib. Barbashina V, Karabakhtsian R, Aisner S, Bolanowski P, Patterson F, Hameed M. Departments of Pathology and Laboratory Medicine (Drs Barbashina, Karabakhtsian, Aisner, and Hameed), Surgery (Dr Bolanowski), and Orthopedics (Dr Patterson), University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ.	Arch Pathol Lab Med 2002 Jun;126(6):721-2 Abstract quote Desmoplastic fibroma is a very rare primary tumor of bone, closely related to aggressive fibromatosis of soft tissue. Although considered a benign lesion, it is locally destructive, can extend into the soft tissues, and has a high rate of local recurrences after incomplete surgical excision. Recognition of this entity is important to ensure proper surgical treatment. According to the published data, the tumor is most common in the long tubular bones (56%), the mandible (26%), and the pelvis (14%). Rib involvement by desmoplastic fibroma is extremely rare, and to our knowledge, only 3 cases have been reported in the literature to date. We present the case of a desmoplastic fibroma in the rib of a 19-year-old man, adding a fourth case to the previously reported cases involving this unusual location. The clinical history and the radiological and pathologic findings are presented.
FIBROUS DYSPLASIA
Fibrous dysplasia with degenerative atypia: a benign lesion potentially mistaken for sarcoma. Bertoni F, Fernando Arias L, Alberghini M, Bacchini P. Department of Surgical Pathology, Istituti Ortopedici Rizzoli, Bologna, Italy.	Arch Pathol Lab Med. 2004 Jul;128(7):794-6. Abstract quote Fibrous dysplasia is a benign disorder of bone in which proliferating fibrous tissue replaces the bony spongiosa. Cytologic atypia is generally not considered a feature of this proliferating tissue. We present a case of fibrous dysplasia with marked atypical nuclear changes consistent with degenerative or regressive changes. A 42-year-old man presented with an osteolytic lesion of the right iliac bone. Histologic study demonstrated a fibro-osseous lesion with woven bone trabeculae and bland-looking fibrous tissue. Several areas showed atypical cells with enlarged pleomorphic nuclei and bizarre features. There was no change in the nuclear-cytoplasmic ratio nor were mitotic figures identified. The differential diagnosis is discussed. When radiographic and other histologic findings suggest fibrous dysplasia, the atypical nuclear changes should not, by themselves, alter the diagnosis.
OSTEOBLASTOMA
Epithelioid Multinodular Osteoblastoma: A Clinicopathologic Analysis of 26 Cases. Zon Filippi R, Swee RG, Krishnan Unni K. *Division of Anatomic Pathology †Department of Radiology, Mayo Clinic, Rochester, MN.	Am J Surg Pathol. 2007 Aug;31(8):1265-1268. Abstract quote We describe the clinical, radiologic, and pathologic features of 26 osteoblastomas with a multinodular growth pattern (defined as multiple nidi in a single tumor) and primarily epithelioid-appearing cells. Clinical information and histologic slides for all 26 patients and radiologic studies for 9 were examined. Follow-up information was obtained from medical charts at our institution and from correspondence with pathologists who submitted cases in consultation. Of the 23 patients with osteoblastoma whose sex had been recorded, 18 were male and 5 were female (median age, 17.8 y). The most common site was the jawbones, although long bones were also involved. Radiologic studies suggested a benign lesion in 5 patients, a malignant lesion in 2, and indeterminate features in 2. Histologically, the tumors appeared to be multiple nodules of epithelioid cells, most with a lacy, blue-bone matrix. Frequently, there were sheets of cells with no matrix. Follow-up information was obtained for 14 of the 23 patients. One patient died in an automobile accident; all others were alive as long as 29 years after treatment. Epithelioid osteoblastomas mimic osteosarcoma because of similar cellularity and cytologic features. Although follow-up is limited, we are cautiously optimistic that these are benign lesions.
SUBUNGUAL EXOSTOSIS
Subungual exostosis of the third toe Waqas Ilyas, MD Larisa Geskin, MD Aaron K. Joseph, MD Mark P. Seraly, MD Pittsburgh, Pennsylvania, and Pasadena, Texas	J Am Acad Dermatol 2001;45:S200-1. Abstract quote Subungual exostosis is a variant of osteochondroma that appears as a pinkish nodule under the free end of the nail plate. It becomes symptomatic when large enough to disrupt the overlying nail on the digit or through mechanical irritation of the exostosis from physical activity. Appropriate workup of such a lesion is important, because many cases of subungual exostosis are initially misdiagnosed by a variety of specialists, including dermatologists. With the use of history and roentgenography, subungual exostosis can be effectively diagnosed or excluded. Appropriate treatment of subungual exostosis can be selected— surgical excision of the lesion with significant cure rates achieved. Although most cases of subungual exostosis are localized to the great toe, we describe a 32-year-old woman who developed a subungual exostosis on her right third toe. Appropriate diagnostic workup and surgical treatment of the right third-toe exostosis has resulted in complete relief of symptoms with no signs of recurrence 7 months after surgery.

 

HISTOPATHOLOGY

CHARACTERIZATION

Treatment Effects in Pediatric Soft Tissue and Bone Tumors Practical Considerations for the Pathologist Cheryl M. Coffin, MD, Amy Lowichik, MD, PhD, and Holly Zhou, MD

Am J Clin Pathol 2005;123:75-90 Abstract quote Dramatic improvements in survival for children with cancer have led to increased numbers of posttreatment pathologic specimens, particularly in bone and soft tissue sarcomas. Current therapeutic protocols in North America require specific pathologic classification and stratify patients based on clinical, biologic, and pathologic features. For osteosarcoma, the pathologic response to therapy predicts prognosis and modifies the treatment regimen. Ongoing studies aim to assess the response to therapy and outcome in other types of soft tissue and bone tumors. The pathologic evaluation of pretreatment and posttreatment specimens is critical for therapeutic decisions and prognostic assessment. A standardized approach to posttherapy pathologic specimens, with attention to appropriate use of ancillary tests, and assessment of clinical and biologic significance of therapy-induced pathologic changes has significance for patient management and treatment protocols.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
EPITHELIOID AND EPITHELIAL TUMORS OF THE BONE
Epithelioid and epithelial neoplasms of bone. Deyrup AT, Montag AG. Department of Pathology, Emory University, Atlanta, GA, USA.	Arch Pathol Lab Med. 2007 Feb;131(2):205-16. Abstract quote CONTEXT: Epithelioid and epithelial neoplasms seen in bone are rare and include epithelioid variants of vascular lesions, osteoblastoma, osteosarcoma, chordoma, and chondroblastoma as well as adamantinoma and metastatic carcinoma. OBJECTIVE: To provide an overview of tumors with epithelioid histology and address the clinical context and diagnostic issues. DATA SOURCES: Pertinent literature is reviewed with emphasis on recent and controversial issues. CONCLUSIONS: The differential diagnosis in epithelioid/epithelial lesions of bone is limited. The primary consideration in many cases is distinguishing primary from metastatic lesions.
METASTATIC TUMORS TO THE BONE
Surgery of skeletal metastases. Katzer A, Meenen NM, Grabbe F, Rueger JM. ENDO-Klinik Hamburg, Holstenstrasse 2, 22767 Hamburg, Germany	Arch Orthop Trauma Surg 2002 Jun;122(5):251-8 Abstract quote During a period of 5 years, 74 female and 27 male patients with an average age of 63.3 years underwent a total of 117 operations for the management of impending ( n=41) or already existing ( n=76) pathologic fractures due to osseous metastases. The average stay in hospital was 17.8 days, and the average postoperative survival 15.8 months. The patients whose limbs were stabilized as a preventive measure were discharged 1.5 days earlier and survived surgery 5.9 months longer than the patients with pathologic fractures. The large percentage of female patients is due to the predominant role of mammary cancer (50%) and the comparatively long survival of patients after a primary diagnosis of this type of carcinoma. The other diagnoses involved were (in order of frequency): bronchial carcinoma (11%), hypernephroma (8%) and non-Hodgkin's lymphoma (8%). The metastases were mainly located at the proximal end or shaft of the femur (59.8%) and in the humerus (18.8%) so that in the majority of cases it was possible to implant weight-bearing prostheses or at least achieve enough stability to allow non-weight-bearing physiotherapy and thus early remobilization. The rate of systemic complications (excluding fatalities) was 14.5%. Local complications in the operated area occurred in 24.8% of cases. As a result, revision surgery was necessary in 10 cases (8.5%), and the fatality rate in hospital (6 weeks) was 7.9%. In view of the advanced stage of the disease in most of the patients, some of them with polypathia, we see these results as a basis for the generous indication for preventive stabilization of osseous metastases. Except in some cases, the primary intention of this therapy is not to cure the disease or prolong life but to improve the quality of life remaining for these patients while keeping their stay in hospital as short as possible and the rate of complications at an acceptable level.
REACTIVE CONDITIONS MIMICKING BONE TUMORS	Avulsion Injuries of Bone (Cortical Irregularity Syndrome, Subperiosteal Desmoid) Brown Tumor of Hyperparathyroidism Hemophilic Pseudotumors Osteomalacia with Fracture Pubic Osteolysis Reactive Mixed Mesenchymal Pseudotumors of Periosteal Origin (Including Florid Reactive Periostitis, Bizarre Parosteal Osteochondromatous Proliferation of Nora, and Subungual Exostosis
Post-traumatic fibro-osseous lesion of the ribs and scapula (sclerosing xanthofibroma) Mario Blanco, MD Beria Cabello-Inchausti, MD Marco Cura, MD Lianne Fernandes, MS	Ann Diagn Pathol 2001;5:343-349 Abstract quote Fibrous lesions of bone may be difficult to classify. Their etiology is controversial, most being considered to be developmental lesions rather than true neoplasms. We describe a patient with post-traumatic fibro-osseous lesion of the ribs, also known as sclerosing xanthofibroma; a lesion believed to be a reactive response to intramedullary hemorrhage following chest wall trauma. Clinically, the lesions in our patient were thought to be metastatic disease because of their multifocal appearance. An extensive clinical and laboratory metastatic evaluation with surgical resection of one of the lesions using intraoperative gamma probe was undertaken. In addition to the multiple rib involvement, our case also showed a lesion in the scapula. The pathologic and radiologic features of this entity are reviewed along with the summary of the differential diagnosis.

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Decalcification-Process where heavily calcified tissue has the calcium leached from it, softening the tissue and allowing for routine tissue processing. 

Permeation-A growth pattern where cancerous cells infiltrate through benign normal tissue.  It is a characteristic pattern of malignancy.

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Got Path?
Recent teaching cases and lectures presented in conferences

• Pathologists Who Make A Difference
• Search for a Physician Specialist

Last Updated August 7, 2007

Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.

Copyright © The Doctor's Doctor