An activating Gs alpha mutation is present in fibrous dysplasia of bone in the McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a sporadic disease characterized by polyostotic fibrous dysplasia, café-au-lait spots, and multiple endocrinopathies. The etiology of fibrous dysplasia is unknown. Activating mutations of codon 201 in the gene encoding the alpha-subunit of Gs, the G-protein that stimulates adenylyl cyclase, have been found in all affected MAS tissues that have been studied. Initial attempts to amplify DNA from decalcified paraffin-embedded bone specimens from MAS patients were unsuccessful. Therefore, we analyzed DNA from frozen surgical bone specimens from five MAS patients using polymerase chain reaction and allele-specific oligonucleotide hybridization. Most of the cells in four specimens of dysplastic bone contained a heterozygous mutation encoding substitution of Arg201 of Gs alpha with His, but the mutation was barely detectable in peripheral blood specimens from the patients. Only a small amount of mutant allele was detected in a specimen of normal cortical bone from the fifth patient, although this patient had a high proportion of mutation in other, affected tissues. The mosaic distribution of mutant alleles is consistent with an embryological somatic cell mutation of the Gs alpha gene in MAS. The presence of an activating mutation of Gs alpha in osteoblastic progenitor cells may cause them to exhibit increased proliferation and abnormal differentiation, thereby producing the lesions of fibrous dysplasia.

Cortical osteofibrous dysplasia of long bone and its relationship to adamantinoma. A clinicopathologic study of 30 cases.

Thirty cases of cortical osteofibrous dysplasia (COFD) were studied in an attempt at defining the relationship of COFD to adamantinoma. The patients ranged in age from newborn to 39 years (mean 13.4 years). The male:female ratio was 1:1. Presenting symptoms were most often pain or a mass. The tibia was involved in all 30 patients; in addition, the ipsilateral fibula was involved in five patients (17%). The histologic appearance of the lesions was dominated by the combination of woven bone trabeculae with prominent osteoblastic rimming and a loose, slightly myxoid stroma (less heavily collagenized in most instances than usually encountered in intramedullary fibrous dysplasia). Results of immunohistochemical study showed isolated cytokeratin-positive cells in the stroma of 28 of the lesions (93%). However, hyperchromatic epithelial islands characteristic of adamantinoma were not found in any of the 30 cases. A control population of 50 fibro-osseous lesions (intramedullary fibrous dysplasia, sclerosing fibroxanthoma, and cranial ossifying fibroma) was studied immunohistochemically; in none of these control cases were cytokeratin-positive cells found. Follow-up data were obtained in 17 cases (57%); the period ranged from 1 to 16 years (mean 6.05 years). Certain overlapping clinical features (including the location of the vast majority of the lesions in the tibia and, less often, the fibula) and the morphologic similarities of many areas of COFD and adamantinoma (particularly the shared presence of cytokeratin-positive cells) suggest a more than coincidental association between COFD and a adamantinoma. However, to date none of the 30 cases of COFD evaluated in this study has developed an adamantinoma.

Small cell osteosarcoma of bone: an immunohistochemical study with differential diagnostic considerations.

Seventy-nine cases of small round cell tumors involving bone were studied in an attempt to learn whether the immunohistochemical features of the lesions might allow distinction of small cell osteosarcoma from other potential differential diagnostic considerations, including Ewing's sarcoma, atypical Ewing's sarcoma, primitive neuroectodermal tumor, mesenchymal chondrosarcoma, lymphoma, and the Askin tumor. The tissues studied were all formalin-fixed, decalcified, paraffin sections from patients between the ages of 16 and 48 years. With one exception (a small cell osteosarcoma), none of the lesions was cytokeratin positive. Moreover, none of the lesions was epithelial membrane antigen, desmin, factor VIII-related antigen, synaptophysin, or Leu-M1 positive. Accordingly, strong positivity for these antibodies in a majority of tumor cells should prompt inclusion of tumor types other than those listed above in the differential diagnosis. Vimentin positivity was seen in a majority of the tumors studied irrespective of histologic type. Scattered tumor cells (< 25%) showed positivity with antibodies to muscle-specific actin and smooth muscle actin in several of the different tumor types studied. No lesions other than lymphoma were leukocyte-common antigen (LCA) positive; all but two lymphomas were LCA positive, while all but one lymphoma were L26 positive. One (lymphoblastic) lymphoma was LCA and L26 negative. S-100, neuron-specific enolase, and Leu-7 did not prove to be specific for "neural-associated" tumors, but rather appeared in some small cell osteosarcomas, Ewing's sarcomas, atypical Ewing's sarcomas, primitive neuroectodermal tumors, mesenchymal chondrosarcomas, lymphomas, and Askin tumors. Antibody to cell surface antigen HBA71 was positive in three Ewing's sarcomas (two typical and one atypical) and negative in small cell osteosarcoma (three cases), mesenchymal chondrosarcoma (two cases), and lymphoma (one case). While some guidance may be derived from analysis of immunohistochemical staining patterns in a given lesion, the results reported in the present study do not suggest that routine immunohistochemistry alone will permit distinction of these small cell tumors of bone from one another. The value of immunohistochemical studies appears to lie particularly in the use of antibodies to LCA and S-100 protein to distinguish lymphoma and mesenchymal chondrosarcoma, and perhaps antibody to HBA71 to distinguish neural family lesions (such as Ewing's sarcoma), from other small cell tumors, such as small cell osteosarcoma.

Synovial hemangioma: a report of 20 cases with differential diagnostic considerations.

True synovial-based hemangiomas are uncommon lesions and, as such, may enter the differential diagnosis of other lesions encountered more frequently in clinical practice, including pigmented villonodular synovitis and traumatic hemarthrosis. The consultation files of the Armed Forces Institute of Pathology were searched for benign vascular lesions diagnosed as synovial or bursal hemangiomas vascular lesions diagnosed as synovial or bursal hemangiomas submitted between the years 1960 and 1985; 20 cases of synovial hemangioma were identified. The patients ranged in age from 9 to 49 years at the time of presentation (average age, 25 years). Sixty-five percent of the patients were male; 35% were female. Presenting symptoms included pain and swelling (31%), pain alone (31%), and a painless mass (31%). Affected regions included the knee (60%), the elbow (30%), and the finger (10%). In 65% of cases the lesion was confined to the intra-articular synovium; in 30% of cases the hemangioma was located in a bursa adjacent to a joint. One case was located largely within the joint cavity but had an area of extension into the suprapatellar recess. The dominant histologic patterns included cavernous hemangioma (50%), lobular capillary hemangioma (25%), arteriovenous hemangioma (20%), and venous hemangioma (5%). One lesion (which had been incompletely excised) was removed in its entirety 3 months after the initial subtotal resection; otherwise, none of the patients studied developed recurrent disease. The clinical diagnosis of hemangioma was made in 22% of cases, while an initial pathologic diagnosis of hemangioma was reached in 67% of cases. Pathologic differential diagnostic considerations include nonspecific synovitis/bursitis, pigmented villonodular synovitis, nodular synovitis, and organizing hemorrhage. A relationship between synovial hemangioma and pigmented villonodular synovitis was not suggested by this analysis of our material.

Radiology as gross pathology in evaluating chondroid lesions.

The study of large ("whole mount") histologic sections underscores the complexity of bone lesions and explains the great potential for misdiagnosis when a limited biopsy sample is assumed to be totally representative. Diagnostic pitfalls can generally be avoided by insisting on the opportunity for clinical-radiologic-pathologic correlation ("triangulation") before a final diagnosis is made. Essential to the method of triangulation is equal attention to the three lines of evidence. The ability to render reliable, clinically relevant, and individually pertinent consultations (as opposed to purely histologic opinions) derives from pursuing questions until all lines of evidence point ("triangulate") to the same answer. This is especially true in the realm of cartilage tumors where the limitations of histopathology are widely acknowledged. In this review, the use of radiographic data will be explored in general terms and in the special context of chondroid lesions.

Radiologic and pathologic analysis of solitary bone lesions. Part I: internal margins.

The interface between tumor and bone that is displayed radiographically is a zone of cellular activity. Its radiographic appearance represents the summation of bone lysis and production. This activity and the radiographic details of the resultant margin are an index of the biologic activity of a lesion. The anatomic site and extent of the lesion can be assessed by radiographs and special imaging techniques. Careful analysis of these patterns, when integrated with clinical data, enhances diagnosis, patient management, and therapy.

Radiologic and pathologic analysis of solitary bone lesions. Part II: periosteal reactions.

The activated periosteum has a deceptive anatomic constancy amidst change. The change involves the production of matrix and, in the process, proliferation and expenditure of cells. When the demand for a reaction is excessive, nearby extraperiosteal soft tissue serves as a ready source for additional modulating cells, just as it does for fracture callus. The configuration of a periosteal reaction is an index of the nature and intensity of the inciting process.

Radiologic and pathologic analysis of solitary bone lesions. Part III: matrix patterns.

The mineralized matrix patterns demonstrated in clinical radiographs of primary bone neoplasms and related disorders help to predict matrices, and have diagnostic significance. These radiographic patterns may yield important clues as to the true nature of a lesion, especially when only limited biopsy material is available from extraosseous or nonrepresentative areas. Therefore, in the evaluation of bone tumors and tumor-like conditions, it is of extreme importance to correlate the histologic findings with the radiographic examination and to know precisely the location at which the biopsy material was obtained. Patterns of mineralization may be the only remnants of a pre-existing lesion that has undergone sarcomatous transformation, such as in bone infarcts, enchondromas, or osteochondromas. The pre-eminent item of importance for patient care is the diagnosis of a malignant process. However, failure to appreciate antecedent benign conditions will not contribute toward a better understanding of tumor biology or a determination of those benign lesions that warrant removal or close clinical follow-up. Integration of matrix data with knowledge of the anatomic location of a lesion, the character of its margins, and the periosteal reaction patterns it produces permits prognostication and often, specific diagnosis.

Parosteal lipomas: a new perspective.

Parosteal lipomas, benign adipose tissue tumors situated directly on bone cortex, are unusual neoplasms that appear to emerge from multidirectional mesenchymal "modulation" within the periosteum. These tumors have been described as "periosteal lipomas", "chondrolipomas of soft tissue" and "lipomas of nerves" but they are most commonly believed to originate from the periosteum. Although over 100 of such tumors have been described in the literature, they have not been the subject of a comprehensive review, nor their potential for chondroid modulation and enchondral ossification emphasized. A review of 14 parosteal lipomas from the Bone Tumor Registry, Armed Forces Institute of Pathology, indicates these tumors are frequently associated with chondroid and/or osseous modulation, which permits subclassification into 4 distinct variants. Each of the 4 subtypes (I: No Ossification; II: Pedunculated Exostosis; III: Sessile Exostosis; IV: Patchy Chondro-Osseous Modulation) is illustrated to demonstrate the morphologic basis for radiologic/pathologic correlation and subclassification. A brief overview of the literature and pathogenesis of this unusual lesion is presented and discussed.

Skeletal-extraskeletal angiomatosis. A clinicopathological study of fourteen patients and nosologic considerations.

We reviewed the consultation files of the ARmed Forces Institute of Pathology for 1951 through 1989 and identified fourteen patients who had had skeletal-extraskeletal angiomatosis. Skeletal-extraskeletal angiomatosis was defined as a benign vascular proliferation involving the medullary cavity of bone and at least one other type of tissue. The age of the patients at the time of initial biopsy ranged from nine months to sixty-nine years (average, twenty-two years; median, ten years). Ten of the patients were male and four were female. The presenting signs and symptoms were highly variable; they included pain (four patients), a mass noted at birth (three patients), a painless mass that developed after birth (two patients), both pain and a mass (one patient), a localized deformity of the thoracic spine (one patient), and anemia associated with chronic bleeding of the gastrointestinal tract (one patient); in this last patient, skeletal lesions subsequently were found and biopsied. Skeletal-extraskeletal angiomatosis was an incidental finding in the remaining two patients. Multiple bones were involved in thirteen of the fourteen patients. Histologically, three patterns of lesion could be identified: cavernous lymphangioma (six patients), cavernous hemangioma (six patients), and arteriovenous hemangioma (two patients). Five of the patients died (three of sepsis associated with persistent lesions of angiomatosis and two of unrelated causes); eight of the patients survived but had residual disease, and one survived and had no evidence of residual disease.

Fat-cell changes as a mechanism of avascular necrosis of the femoral head in cortisone-treated rabbits.

Large doses of cortisone were given to growing and adult rabbits over a five-month period to produce avascular necrosis of the femoral head. The cortisone caused an increase in the serum cholesterol, fatty metamorphosis of the liver, and fat emboli visible in sections of the femur and humerus. These emboli partially obliterated the microcirculation of the subchondral vessels of both femoral and humeral heads. The average diameter of the marrow fat cells also increased more than ten micrometers. This increase in cell volume might be significant because in the closed chamber of the femoral head it could increase tissue pressure, diminish perfusion, and be the mechanism for avascular necrosis induced by cortisone.

Angiography in the diagnosis of osteoid-osteoma of the hand.

Angiographic findings characteristic of osteoid-osteoma are described in two cases of osteoid-osteoma of the bones of the wrist. While the etiology of the disease is not understood, a developmental relationship between the osteoid-osteoma nidus and increased vascularity is suggested.

Rectus femoris muscle tear appearing as a pseudotumor.

Quadriceps muscle strains are common sporting injuries, but occasionally a tear of the rectus femoris muscle can appear as a soft tissue mass of the anterior thigh with or without a significant history of trauma. Between 1992 and 1996, seven patients were referred to the Orthopaedic Oncology Unit at Walter Reed Army Medical Center with an unexplained soft tissue mass of the thigh. Three were active duty soldiers, three were military dependents, and one was a retired serviceman. All patients were men, and the mean age was 32 years (range, 15 to 73). A palpable, mildly tender mass was confirmed on clinical examination. Laboratory studies and plain radiographs were normal. Magnetic resonance imaging showed an obvious, but often ill-defined, lesion at the musculotendinous junction of the rectus femoris muscle. Four patients subsequently underwent a tissue biopsy to rule out a soft tissue sarcoma. Histologic studies showed fibrosis, degeneration of muscle fibers, and chronic inflammatory cells with no evidence of malignancy. A chronic rectus femoris muscle tear can mimic a soft tissue tumor or sarcoma and needs to be excluded in the differential diagnosis. These tears may occur acutely or may represent an overuse injury caused by repeated microtrauma. Careful history taking, physical examination, and selective radiographic studies, specifically magnetic resonance imaging, can confirm the diagnosis of muscle tear and full functional recovery can be anticipated.

Well-differentiated extraskeletal osteosarcoma. A soft-tissue homologue of parosteal osteosarcoma.

We describe a unique case of a low-grade extraskeletal osteosarcoma revealing both histologic and radiologic features reminiscent of parosteal osteosarcoma. The tumor, which had been present for 10 years, occurred in the left axilla of a 74-year-old black woman. To date, all the published cases of extraskeletal osteosarcoma have been high-grade neoplasms; to our knowledge, this is the first reported case of a low-grade extraskeletal osteosarcoma.

Epithelioid hemangioendothelioma and related lesions.

Epithelioid hemangioendothelioma (EH) is the prototype of a group of vascular tumors characterized by an epithelioid or histiocytoid endothelial cell. This family also includes the epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) and epithelioid forms of angiosarcoma. This review discusses the principal clinical, pathologic, and biologic differences among these three lesions. In particular the various manifestations of EH of soft tissue, bone, lung (previously called intravascular bronchioloalveolar tumor), and liver are discussed. Long-term follow-up data of EH of soft tissue and lung are provided.

Femoral neck stress fractures and metabolic bone disease.

OBJECTIVE: To determine whether metabolic bone disease plays a role in the cause of femoral neck stress fractures. STUDY DESIGN: Twenty-three patients with femoral neck stress fractures were enrolled prospectively in the study. Examination included computed tomography bone densitometry, trace mineral analysis, and histomorphometric analysis of the iliac crest in thirteen patients who underwent surgical treatment of their stress fractures. A control group of fifteen patients undergoing iliac crest bone grafting for scaphoid nonunions underwent similar examinations. SETTING: Tertiary military medical center. RESULTS: Patients with femoral neck stress fractures had lower bone mineral density than did control patients (p = 0.010), but no trace mineral deficiencies or consistent histomorphometric differences were noted. CONCLUSIONS: Bone mineral density is decreased in patients with femoral neck stress fractures. Despite observations of decreased bone mineral density in the stress fracture group, osteoporosis, as determined by histomorphometry, is not a consistent finding.

Osteoblastoma of the foot and ankle.

A total of 329 patients with osteoblastoma were retrospectively reviewed from the archives of the Armed Forces Institute of Pathology, of which 41 (12.5%) presented with tumors in the foot and ankle. This was the third most common site of disease after the spine and femur. Overall, the mean age was 22.5 years, which was the same for the foot and ankle subset of patients; however, there was a significant male predominance in foot and ankle patients compared with the whole group. The majority of patients were skeletally mature (85.4%). Clinically, most patients presented with pain (97.2%), although one-third of the total related a history of antecedent trauma. The interval between the onset of symptoms and biopsy was 84 days (range, 0-572 days). Radiographically, the majority of lesions were in the hindfoot (N = 18; 44%) of which 16 of 18 tumors (89%) were in the talus. Of these, one-half were subperiosteal and dorsally based and were associated with osseous tumor matrix and a soft tissue mass. Two osteoblastomas, both in the metatarsals, transitioned into sarcomas; the rest were histologically benign. For diagnostic purposes, it was essential to obtain clinical, radiographic, and histologic correlation.

Asymptomatic HIV infection. A primary care disease.

Asymptomatic human immunodeficiency virus infection is a disease entering the primary care arena more and more frequently. Patients may be monitored in this setting until complications and clinical deterioration develop (typically after several years). As the disease progresses, referral to consultants who specialize in AIDS may be appropriate. However, many patients do not live near a major healthcare center and do not have the financial, physical, or emotional capability to travel to one as they become sicker. In these cases, primary care physicians, with the aid of a personally chosen network of specialized consultants, should offer care as the disease progresses to its terminal stage.

Oral and dermatologic manifestations of HIV infection.

Because an estimated 1 million persons in the United States are infected with HIV, all physicians, especially those in primary care, need to be able to recognize the protean manifestations of the disease and make a diagnosis as early as possible. In this article, Drs Jewell and Sweet review the mucocutaneous conditions that occur in patients with HIV infection and discuss diagnostic clues and treatment.