Steven D. Billings

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.

Cutaneous angiosarcoma following breast-conserving surgery and radiation: An analysis of 27 cases

Iatrogenic angiosarcomas (AS), following treatment of breast carcinomas and attributed to chronic lymphedema, were first described by Stewart and Treves. With emphasis on breast-conserving therapy combined with adjuvant radiation, a recently recognized form of cutaneous postradiation angiosarcoma of the breast (CPRASB) has emerged. To more completely characterize CPRASB, 27 cases were analyzed. Histologic features studied included pattern of growth (vasoformative, sieve-like, or solid), nuclear grade, necrosis, and mitotic rate. Clinical and follow-up information was obtained. The patients received relatively standard radiation treatment. The median interval to diagnosis of CPRASB was 59 months; 5 occurred in less than 3 years. Lymphedema was largely absent, and when present was only mild in nature. CPRASB was frequently multifocal at presentation (13 of 27). All tumors had a vasoformative pattern of growth; the majority (16 of 27) had areas with a sieve-like pattern. The solid pattern was less frequent (7 of 27). The majority had high-grade nuclear features (16 grade 3, 8 grade 2, 3 grade1). The mean mitotic rate was 9/10 HPF. Necrosis was rare (2 of 27). All were treated with wide excision or mastectomy. Follow-up was available on 22 of 27 cases (median 44 months). Fourteen experienced local recurrence and 6 had multiple recurrences. Metastasis was documented in 9 of 22 patients and involved lungs (6), contralateral breast (3), skeleton (2), lymph nodes (1), and soft tissue (1). Eight patients died of disease, 2 died with disease, 4 were alive with disease, and 8 are alive without disease. The median interval to death was 33.5 months. All 4 patients with disease have documented metastasis. CPRASB differs from Stewart-Treves AS by its shorter latency period and lack of association with lymphedema.

Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics

Perineuriomas are rare benign soft tissue tumors having an immunophenotype paralleling the normal perineurial cell [S-100 protein negative and epithelial membrane antigen (EMA) positive]. Because EMA expression in perineuriomas may be focal and/or faint, there is continued interest in the development of new markers of perineurial differentiation. Perineurial cells differ from almost all other mesenchymal cell types by virtue of their formation of tight junctions. In the course of evaluating a group of novel tight junction-associated proteins, we noted high levels of expression of claudin-1 by normal perineurial cells and have systematically extended these observations to perineuriomas. Twelve EMA-positive/S-100-negative perineuriomas were retrieved from our consultation archives and compared with 39 tumors in the differential diagnosis of perineurioma (seven dermatofibrosarcoma protuberans, eight low-grade fibromyxoid sarcomas, three desmoplastic fibroblastomas, seven fibromatoses, nine neurofibromas, and five schwannomas). All cases were immunostained for claudin-1 using standard avidin-biotin technique. Cases were scored as 3+ (>50% positive cells), 2+ (25–50% positive cells), and 1+ (5–24% positive cells). In all cases positive internal controls in the form of epithelium, normal perineurium, or endothelial cells were present. Positive staining for claudin-1 was visualized in a distinctly particulate pattern along the cell membrane. Cytoplasmic staining was infrequent and was not scored as positive. Claudin-1 expression was present in 11 of 12 (92%) perineuriomas studied (seven at 3+, three at 2+, and one at 1+). In all but two cases, the degree of claudin expression was equal to or greater than the corresponding EMA immunostain. Claudin-1 expression was not noted in any cases of dermatofibrosarcoma protuberans, low-grade fibromyxoid sarcoma, desmoplastic fibroblastoma, or fibromatosis. Six of nine cases of neurofibroma contained a significant number of claudin-1-positive cells that were thought to be perineurial in origin, based on the staining of long, delicate cytoplasmic processes. One of four schwannomas contained a subpopulation of perivascular, dendritic, claudin-1-positive cells of presumed perineurial lineage. This is the first study to document expression of claudin-1 in perineurial cells and suggests a role for claudin-1 immunohistochemistry in the diagnosis of perineuriomas. Although claudin-1 should not replace EMA in the diagnosis of perineurioma, we think that it may play a valuable adjunctive role in difficult cases. In particular, claudin-1 is often a more robust marker than EMA in a given perineurioma. Claudin-1 is not expressed within the lesional cells of the mesenchymal tumors that enter into the differential diagnosis of perineurioma.

Superficial low-grade fibromyxoid sarcoma (Evans tumor): a clinicopathologic analysis of 19 cases with a unique observation in the pediatric population.

Low-grade fibromyxoid sarcoma (LGFMS), usually a deeply situated mass in adults, is uncommon in superficial soft tissue and in children. Nineteen superficial LGFMS from our files were studied for clinicopathologic features, the latter including tumor size, growth pattern, cellularity, collagen rosettes, vascularity, nuclear atypia, mitotic rate, necrosis, and immunophenotype. The patients included 12 males and 7 females who ranged in age from 2 to 70 years (mean, 29 years). There were 7 children. Tumor locations included the lower extremity (8), buttock (3), trunk (3), vulva/inguinal region (2), upper extremity (2), and unspecified subcutis (1). Clinical and histologic submitting diagnoses were mainly benign except for 3 cases, submitted as low-grade sarcoma, with only one as superficial LGFMS. The mean tumor size was 4.2 cm (range, 1.6-18 cm). Of 15 with evaluable resections, 5 had focal ink on tumor and 2 of these had known negative wider reexcisions. The tumors were relatively well circumscribed with low to moderate cellularity. The tumors alternated from myxoid zones with prominent curvilinear vasculature to collagenous fascicular zones. Collagen rosettes with peripheral round epithelioid cells and focal ischemic necrosis were present in 6 cases each. Mitotic rate was low (mean 1.6/50 HPF). Tumor cells were positive for vimentin and some were focally positive for actins, CD68, and EMA. CD34, keratins, and S-100 protein were negative. Follow-up (mean, 44 months; range, 10-84 months) on 16 patients demonstrated 14 with no evidence for disease, 2 with local recurrences at 5 and 16 months, but no metastases. Superficial LGFMS is more common than previously recognized and may affect children at a higher rate (7 of 19, 37%) than that for deep LGFMS. The prognosis is good and appears to be better than that for deep LGFMS.

Epithelioid sarcoma-like hemangioendothelioma.

We are reporting seven histologically identical cases of a distinctive, low-grade vascular tumor that closely mimics an epithelioid sarcoma because of growth in solid sheets and nests, the eosinophilia of the rounded to slightly spindled neoplastic cells, and the diffuse, strong cytokeratin expression. Termed epithelioid sarcoma-like hemangioendothelioma, all were diagnosed by the submitting pathologist or another expert consultant as epithelioid sarcoma. Although none displayed architectural evidence of vascular differentiation in the form of multicellular vascular channels, some displayed subtle cytologic features of vascular differentiation and all displayed immunohistochemical evidence of endothelial differentiation. The patients (four male; three female) ranged in age from 17 to 54 years (median 23 years). Ranging in size from 1 to 3.5 cm, they occurred in the extremities (n = 5), scalp (n = 1), and chest wall (n = 1), both in deep (n = 3) and superficial (n = 3) soft tissue or both (n = 1). The tumors were characterized by sheets, ill-defined nodules, or fascicles of deeply eosinophilic cells set within a desmoplastic stroma. Multicellular vascular channel formation and/or hemorrhage were absent in all cases. In four cases intracytoplasmic vacuolization suggestive of intracytoplasmic vascular lumen formation was noted. The typical neoplastic cell was large and rounded in shape but modulated in areas to a spindled or multipolar shape. Mitotic activity was low (<5 mitotic figures/50 high power fields), nuclear pleomorphism was mild to moderate, and necrosis was absent. The tumors were positive for cytokeratin (6 of 6), vimentin (6 of 6), CD31 (5 of 6), FLI-1 (6 of 6), but negative for CD34 (0 of 6). Within a follow-up period of 3–72 months (median 39 months), two patients experienced a local recurrence and one patient regional soft tissue metastases, but no distant ones. Two patients presented with multifocal lesions suggestive of regional metastases. Currently, two patients are alive with disease and five are disease free. Epithelioid sarcoma-like hemangioendothelioma appears to be a largely unrecognized epithelioid vascular tumor with an indolent course. Despite its similar clinical and histologic features, it differs from epithelioid sarcoma by the presence of endothelial markers and the absence to date of distant metastases. Its distinction from other epithelioid vascular lesions is discussed. We think this tumor fits best into the family of “hemangioendothelioma” or vascular lesions of intermediate malignancy.

Do leiomyomas of deep soft tissue exist? An analysis of highly differentiated smooth muscle tumors of deep soft tissue supporting two distinct subtypes.

There is a prevailing view that leiomyomas of deep soft tissue are rare or nonexistent, but there are limited data on this subject in the form of large clinical studies with long follow-up information. We reviewed 36 consultation cases that had been diagnosed as leiomyoma or probable leiomyoma based on absence of nuclear atypia, necrosis, and no/minimal mitotic activity. Follow-up information was obtained to determine whether these stringent histologic criteria could identify a biologically benign group of smooth muscle tumors of deep soft tissue. The tumors occurred in two distinct locations. The first (n = 13) occurred in deep somatic soft tissue of the lower extremity (7), upper extremity (2), trunk (2), axilla (1), and back (1) and affected the sexes equally (7 male, 6 female). Composed of a circumscribed mass of mature smooth muscle cells, they were frequently calcified with a mean mitotic activity of <1 mitosis/50 high power fields (HPF) (range 1–4 mitoses/50 HPF). Estrogen receptor and progesterone receptor proteins were negative in the three cases tested. No tumors recurred or metastasized (mean follow-up 58.7 months, range 5–97 months). The second group (n = 23) occurred within the retroperitoneum (20) or abdominal cavity (3) of women (1 male, 22 female). Resembling uterine leiomyomas, they were always distinct from the uterus, occasionally multiple (n = 4), and sometimes occurred up to years after hysterectomy (n = 3). Four cases occurred with synchronous uterine leiomyomas. In the six cases tested, five of six were positive for the estrogen receptor protein and all were positive for progesterone receptor protein. Mean mitotic activity was 1 mitosis/50 HPF (range <1–10 mitoses/50 HPF). None developed metastasis within the follow-up period (mean 42.5 months, range 6–120 months); one tumor with a positive margin recurred at 10 months. We conclude that clinically benign smooth muscle tumors of deep soft tissue are rare but can be identified using stringent histologic criteria. They comprise two distinct subtypes: leiomyomas of somatic soft tissue and retroperitoneal–abdominal leiomyomas. The latter probably arise from hormonally sensitive smooth muscle. Although similar to uterine leiomyomas, they are located at sites removed from the uterus and are likely independent soft tissue primaries rather than parasitic leiomyomas of the uterus. We suggest that these two groups of smooth muscle tumors be diagnostically approached in a site-specific fashion.

FISH for MYC amplification and anti-MYC immunohistochemistry: useful diagnostic tools in the assessment of secondary angiosarcoma and atypical vascular proliferations.

Background: Secondary angiosarcoma and benign but microscopically atypical vascular proliferations (herein referred to as atypical vascular lesion or AVL) are rare consequences of radiation therapy and/or chronic lymphedema most commonly seen in breast cancer patients. Differentiating angiosarcoma from AVL can be difficult due to overlapping clinical and microscopic features. Recently, amplification of MYC has been associated with 55–100% of secondary angiosarcomas but is reportedly absent in AVL. We examined a series of secondary angiosarcoma and AVL for MYC amplification by fluorescence in situ hybridization (FISH) and expression by immunohistochemistry to investigate the diagnostic utility for discriminating angiosarcoma from AVL.

Synovial sarcoma of the upper digestive tract: a report of two cases with demonstration of the X;18 translocation by fluorescence in situ hybridization.

Two cases of synovial sarcoma that arose in the upper digestive tract are reported. One case was a polypoid mass that arose at the gastroesophageal junction; the other was a large intramural mass that arose in the wall of the stomach. Both cases had a classic biphasic pattern. In the stomach tumor, the biphasic morphology was focal and there was an abrupt transition to poorly differentiated synovial sarcoma. The tumors had immunohistochemical features that were consistent with synovial sarcoma. Ultrastructural evaluation of the gastroesophageal tumor supported the diagnosis. The diagnostic X;18 translocation was demonstrated by fluorescence in situ hybridization on sections from paraffin-embedded tissue in 86% and 50% of interphase nuclei from the gastroesophageal and gastric tumor, respectively. The translocation was present in equal frequency in the epithelial and spindle cells in the biphasic areas and the poorly differentiated areas of the gastric tumor, indicating that the development of the more aggressive subclone was probably due to genetic mutations not encompassing the SYT-SSX gene fusion product. We are aware of only five reported cases of synovial sarcoma arising in the digestive tract, all in the proximal esophagus. These cases are the first reported arising in the gastroesophageal junction and stomach and the only cases of synovial sarcoma of the digestive tract in which the diagnostic translocation was demonstrated. Sarcomatoid carcinoma (carcinosarcoma) and gastrointestinal stromal tumor are the main differential diagnoses for synovial sarcoma in this site. Synovial sarcoma of the digestive tract may be underdiagnosed, and its recognition may have important clinical implications. Fluorescence in situ hybridization is helpful in making this distinction.

Identical Allelic Losses in Mature Teratoma and Other Histologic Components of Malignant Mixed Germ Cell Tumors of the Testis

Teratomas of the testis in post-pubertal patients are histologically diverse tumors that often coexist with other types of germ cell tumors. Using laser capture microdissection and loss of heterozygosity analysis, we investigated the clonality of mature teratoma and its relationship to other components of malignant mixed germ cell tumors to gain potential insight into the histogenetic relationship of teratoma with other germ cell tumor components. All 16 patients had mature teratoma as one component of their mixed germ cell tumors. The other histological subtypes included immature teratoma, seminoma, embryonal carcinoma, yolk sac tumor, and choriocarcinoma. Laser-assisted microdissection was performed on the formalin-fixed, paraffin-embedded tissue. Polymerase chain reaction was used to amplify genomic DNA at specific loci on chromosome 1p36.2 (D1S508), 2q22-32 (D2S156), 9p21-22 (D9S162), 11p13 (D11S903), 12q22-23 (D12S1051), and 18q21 (D18S46). Fourteen of 16 (88%) cases showed allelic loss in one or more components of the mixed germ cell tumors. Fourteen of 16 mature teratomas showed allelic loss in at least one of six microsatellite polymorphic markers analyzed. The frequency of allelic loss in mature teratoma was 50% (7 of 14) with D1S508, 33% (5 of 15) with D2S156, 58% (7 of 12) with D9S162, 43% (6 of 14) with D11S903, 20% (3 of 15) with D12S1051, and 33% (5 of 15) with D18S46. Completely concordant allelic loss patterns between mature teratoma and all of the other germ cell tumor components were seen in 10 of 14 tumors in which mature teratoma showed loss of heterozygosity. Our data support the common clonal origin of mature teratoma with other components of malignant mixed germ cell tumors of the testis.

Cutaneous and subcutaneous fibrohistiocytic tumors of intermediate malignancy : An update

Abstract:The fibrohistiocytic tumors of intermediate malignancy are uncommon mesenchymal tumors, which typically occur in the skin and subcutis and which may pose significant problems for the dermatopathologist. This article reviews the clinical, histopathologic, and genetic features of dermatofibrosarcoma protuberans, giant cell fibroblastoma, angiomatoid (malignant) fibrous histiocytoma, plexiform fibrous histiocytoma, and soft tissue giant cell tumor (of low malignant potential). The differential diagnosis of these tumors with a variety of benign and fully malignant cutaneous soft tissue neoplasms is discussed.