Donald E. Sweet

Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive “grungy” calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

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 adamantinoma. However, to date none of the 30 cases of COFD evaluated in this study has developed an adamantinoma.

Tenosynovial (extraarticular) chondromatosis: An analysis of 37 cases of an underrecognized clinicopathologic entity with a strong predilection for the hands and feet and a high local recurrence rate

Tenosynovial chondromatosis is a multinodular cartilaginous proliferation that arises from the tenosynovial membranes. This report describes the clinical, radiologic, and histopathologic findings in 37 cases of this uncommon entity. There were 17 males and 20 females, ranging in age from 20 to 86 years (mean and median age, 46 years). The process involved tenosynovium of the fingers (n = 19), feet (n = 8), wrists (n = 4), ankles (n = 2), hand, not otherwise specified, or palm (n = 2), knee (n = 1), and forearm (n = 1). Signs of disease or symptoms were present for 5 weeks to 18 years (median duration, approximately 2 years) before surgical excision. The two most common complaints were a painless mass and a mass that was mildly tender with pressure. None of the tumors had clinical, radiologic, or histopathologic evidence of articular or bone involvement. Histologically, all tumors consisted of a multinodular cartilaginous proliferation involving tenosynovium and/or subsynovial connective tissue. Mild or moderate atypia, as encountered in chondroma of soft parts and synovial chondromatosis, was a frequent finding. Follow-up information was available for 16 patients (43%). Only two patients with follow-up information remained disease free after their initial surgical procedure. Seven patients had one recurrence and seven patients had two or more recurrences. Tenosynovial chondromatosis appears to be an extraarticular counterpart of synovial (intraarticular) chondromatosis. Our review indicates this process is often confused with chondroma of soft parts, in part, because both entities have a predilection for the hands and feet. Diagnosis of this underrecognized entity is of clinical importance because of the high local recurrence rate.

Synovial-type giant cell tumors of the vertebral column: a clinicopathologic study of 15 cases, with a review of the literature and discussion of the differential diagnosis.

Synovial and tenosynovial giant cell tumors only rarely arise in close proximity to the axial skeleton; to date, fewer than 30 examples have been reported in the English-language medical literature. In this report we describe the clinical, radiologic, histopathologic, and immunohistochemical findings in 15 cases retrieved from our files. The study group comprised 7 males and 8 females, ranging in age from 17 to 44 years (mean age, 32 years). The tumors involved the cervical (n = 11), thoracic (n = 1), lumbar (n = 2), and sacrococcygeal (n = 1) regions and ranged in size from 1.0 to 6.0 cm in greatest dimension (median size, 3 cm). Symptoms were present for 2 months to at least 2 years, with the most common complaint being pain localized to the spinal region (n = 12). Ten patients also had radicular symptoms. Radiologic studies, available for 11 cases, usually demonstrated a mass involving the posterior aspect of adjoining vertebrae. Bony abnormalities (including scalloping, erosion, and destruction), facet joint and soft tissue involvement, and extradural extension were typically present. Histologically, all tumors contained a proliferation of epithelioid (histiocytoid) cells, admixed with varying numbers of osteoclast-like giant cells, siderophages, xanthoma cells, lymphocytes, and some spindled fibroblast-like cells. Only 1 tumor had the classic villiform architecture of pigmented villonodular synovitis. The remaining 14 tumors had a nodular appearance with varying amounts of collagen. Seven of these had definite histological evidence of infiltrative growth, and 6 had some features that warranted concern for possible infiltration. Only 1 tumor had findings fully compatible with a localized synovial-type giant cell tumor/nodular (teno)synovitis. All tumors had mitotic activity, with mitotic counts ranging from 1 to 21 mitotic figures per 50 high-power fields (HPFs) (mean mitotic count, 5 mitotic figures/50 HPFs). Immunohistochemistry was performed on 5 tumors, and immunoreactivity was present for CD68, CD163, and vimentin. Limited immunoreactivity for muscle actin (HUC1-1) was also noted. Follow-up information was available for 9 of the 15 patients (60%). Five patients had no evidence of recurrent or persistent disease 4 months to 9 years after undergoing either a local excision with gross total tumor removal (with or without irradiation) or a wide en bloc resection. Four patients had persistent disease after undergoing either an incomplete resection or biopsy with spinal fusion procedure. All 4 of these patients had additional surgical intervention (accompanied by irradiation in 2 instances), but only one was known to be disease-free at last follow-up (10 years after gross total tumor removal). No patient has experienced a metastasis or died of disease. The best predictor of outcome was gross total tumor removal at the surgical outset.

Parosteal lipomas: A new perspective

Summary 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 radio‐logic/pathologic correlation and subclassification. A brief overview of the literature and pathogenesis of this unusual lesion is presented and discussed.

RPC of the Month from the AFIP

A symptomless swelling of an 8-year-old boys right mandible was considered to be a dentoalveolar abscess but was unsuccessfully treated with antibiotics. From the intrinsic morphologic data in Figure 1, list the most probable radiographic diagnoses and indicate which one should be primarily considered prior to biopsy and histologic diagnosis. Radiographic Findings and Discussion Frontal and lateral projections of the mandible (Fig. 1) reveal a poorly marginated area of destruction extending from the alveolar ridge to the inferior border of the mandible. This ill-defined, “moth-eaten” destructive process engulfs the periapical portion of the second bicuspid and part of the first molar. There is no reparative sclerosis or other evidence of mineralization around the lesion, but the medullary cavity is slightly expanded laterally and inferiorly where periosteal new bone formation of a thick homogeneous (“swedged”) variety is present. Except for those lesions engendered by the peculiarity of odontogenesis, th...

Multiple skeletal fibroxanthomas: radiologic-pathologic correlation of 72 cases

Out of a series of 900 biopsy-proven cases of skeletal “fibroxanthoma” (nonossifying fibroma, fibrous cortical defect), we studied 72 patients with more than one lesion. Age, sex, coexistent conditions such as neurofibromatosis, and histologic and radiographic appearance of the lesions were evaluated. Multiple skeletal fibroxanthomas are probably more common than previously suspected. (At least 8% of the 900 patients in our archives had multiple lesions). Only a small percentage (5%) of patients with multiple skeletal fibroxanthomas had coexistent neurofibromatosis. These lesions are histologically indistinguishable from their solitary counterparts and most commonly present in the lower extremities. Four radiographic patterns were noted: (1) clustered lesions-usually about the knee. (2) nonclustered lesions-in opposite ends of long bones. (3) coalescent lesions-several lesions coalescing over time. This observation has not been previously reported. (4) emergent lesions-lesions appearing in previously unaffected bone. Familiarity with these features may obviate biopsy.

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.

MIC2 detection in tumors of bone and adjacent soft tissues.

The diagnosis of Ewings sarcoma has been based classically in large part on the exclusion of other similar small round-cell tumors by light microscopic and histochemical criteria. This study was undertaken to explore the use of a recently developed immunohistochemical stain directed against the glycoprotein p30/ 32MIC2 antigen (the gene product of MIC2), as a diagnostic tool and as a probe for the examination of potential interrelationships among the putative members of the family of peripheral primitive neuroectodermal tumors. Fifty-six small round-cell tumors of bone were selected for study from the files of the Armed Forces Institute of Pathology and Rhode Island Hospital; all tissues had been formalin fixed and paraffin embedded. Nine of 10 Ewings sarcomas were MIC2 positive, as were 2 of 3 atypical Ewings sarcomas (small round-cell tumors that diverged from the classic pattern of Ewings sarcoma by exhibiting a greater degree of cytologic atypia and pleomorphism), and 7 of 8 Askin tumors of the thoracopulmonary region. Ten of 11 mesenchymal chondrosarcomas, 1 primitive neuroectodermal tumor of bone, 10 small cell osteosarcomas, 10 malignant lymphomas, and 3 sarcomas of bone (not additionally sub-classified) were negative. The finding of MIC2 positivity in the majority of Ewings sarcomas and Askin tumors provides additional support for earlier proposals (based on a shared cytogenetic abnormality, among other criteria) that these lesions be considered members of the same family, the peripheral primitive neuroectodermal tumors. The present study, drawing on archival and current case material (including decalcified and undecalcified specimens), indicates that neither the specimen age nor the application of any of a variety of decalcification solutions appears to adversely influence MIC2 staining of paraffin-embedded tissues. This suggests that this antibody has use in retrospective and prospective studies. The rare occurrence of false negative (in the case of Ewings sarcoma) and positive results in tumors other than peripheral primitive neuroectodermal tumors (as in 1 of the mesenchymal chondrosarcomas) suggests that MIC2 staining should not be relied on as the sole criterion for identification or exclusion of Ewings sarcomas and related tumors.

Case report 634

Fig. 1. A An AP radiograph of the right femur demonstrates a dominant sclerotic lesion in its proximal half. B A 99mTcMDP bone scintigram shows increased radionuclide activity in the metasphyses of multiple long bones, ribs, vertebrae, mandible, and pelvis, in addition to the right femoral diaphysis. C Corresponding radiographs of the knees demonstrate metaphyseal osteosclerosis in the metaphyses of the distal ends of the femora and proximal ends of the tibiae and fibulae