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We report 27 solitary fibrous tumors of the female genital tract emphasizing nonvulvar locations, variant histology, and prognostic factors. The patients ranged from 25 to 78 years (most were over 40), and tumors occurred in the vulva (7), vagina (2), cervix (2), corpus (6), fallopian tube/paratubal soft tissue (5), and ovary (5). They ranged from 1.5 to 39 (mean=10.5) cm and were typically solid, but 4 were predominantly cystic. All had a haphazard arrangement of spindled to ovoid cells, with most demonstrating alternating cellular and hypocellular areas and prominent vessels, but 13 lacked hypocellular areas, and 7 had focal diffuse growth with inconspicuous vasculature. Other patterns included corded (8), fascicular (5), trabecular (1), and nested (1). Microcysts (6), myxoid background (8), hyalinization (8), lipomatous differentiation (2), and multinucleated cells (6) were also present, and 10 tumors had necrosis. Vasculature included thin-walled branching “staghorn” (27), thick-walled (7), and hyalinized vessels (5) or dilated anastomosing vascular channels (3). Nuclear atypia ranged from mild (19), moderate (7), to severe (1), and mitoses from 0 to 24/10 HPF (mean=4). STAT6 was positive in all 25 tumors tested. One tumor showed dedifferentiation; the remainder were classified as benign (19) or malignant (7) based on mitotic rate (univariate stratification model) and as low risk (14), intermediate risk (8), or high risk (4) based on the Demicco multivariate risk stratification score. Follow-up (median=23 mo) was available for 16 patients. Six tumors recurred (2 intermediate risk, 3 high risk, and the dedifferentiated tumor), 5 in the abdomen; the dedifferentiated tumor metastasized to the lung. Multivariate risk stratification was superior to univariate classification, as 5 “benign” tumors were reclassified as intermediate risk using the multivariate model; of these, 2 recurred, and 1 patient died of disease. Upper female genital tract tumors occurred in older patients, were larger, and more frequently classified as high risk compared with those of the lower tract. A trend toward increased cellularity was also seen in the upper tract tumors. Only size (P=0.04), necrosis (P=0.04), and Demicco score (P=0.01) independently correlated with recurrence. Female genital tract solitary fibrous tumors demonstrate a wide range of variant morphologies and occur in diverse sites in addition to the vulva. Tumors were often misdiagnosed as other neoplasms; thus, awareness of solitary fibrous tumors occurring at these sites is crucial in prompting staining for STAT6 to establish this diagnosis. The Demicco risk stratification system effectively predicts behavior.

Supplemental Digital Content is available in the text.Dedifferentiated chordoma is a rare chordoma subtype characterized by a high-grade sarcoma juxtaposed to conventional chordoma. We identified a series of dedifferentiated chordomas, reviewed clinicopathologic features, performed next-generation sequencing in select cases, and analyzed all related English-language publications. Our series included 7 men and 3 women (age 15 to 80 y [median: 54 y]; <1% of >1000 chordomas surveyed). The tumor (2.8 to 24.5 cm [median: 5.8 cm] in size) presented de novo or as recurrence (including postradiotherapy) in sacrum (n=5), skull base (n=2), lumbar spine (n=1), thoracic/mediastinum (n=1), and lung (n=1; as metastasis). Histologically, the dedifferentiated component (3% to 95% [median: 60%]) was pleomorphic-to-fibrosarcomatous, juxtaposed to conventional (n=8) or chondroid (n=2) component. By immunohistochemistry, the conventional/chondroid component consistently expressed cytokeratin and brachyury, whereas the dedifferentiated component showed loss of both. We identified a sacral conventional chordoma with INI1 loss, with one of the lung metastases showing biphasic histology with loss of cytokeratin and brachyury in the dedifferentiated component. Sequencing identified tumor suppressor mutations in 4 tumors, including TP53mutations in the dedifferentiated component in 3 tumors. Of 7 patients with follow-up, 6 developed metastases; 4 died at 15 to 99 months (median: 24 mo) after dedifferentiated chordoma diagnosis. Collectively, of 87 dedifferentiated chordoma patients described in 1913-2020 (including 10 herein), the median overall survival was 20 months. In summary, dedifferentiated chordoma involves diverse sites and presents de novo, postradiotherapy, or as recurrence/metastasis months-to-years after initial diagnosis. The dedifferentiated component shows loss of brachyury and cytokeratin staining and harbors recurrent TP53mutations, implicating tumor suppressor dysregulation in chordoma dedifferentiation.

Spindle cell rhabdomyosarcoma (RMS) is an aggressive sarcoma type with a predilection for the head and neck and frequent transactivating MYOD1mutations. Malignant peripheral nerve sheath tumors (MPNST) show heterologous (most often rhabdomyoblastic) differentiation in 10% of cases; such tumors have been referred to as malignant “Triton” tumors. MPNST frequently harbors inactivating mutations in SUZ12or EED, resulting in PRC2 dysfunction and loss of histone H3 lysine 27 trimethylation (H3K27me3), most often seen in sporadic and radiation-associated, high-grade tumors; immunohistochemistry (IHC) for H3K27me3 is a useful diagnostic marker. We recently encountered a tumor showing H3K27me3 loss but with otherwise typical features of spindle cell RMS. The purpose of this study was to evaluate H3K27me3 in spindle cell RMS and further investigate putative spindle cell RMS with loss of H3K27me3. IHC for H3K27me3 was performed on 50 tumors diagnosed as spindle cell RMS. Targeted sequencing of all exonic and selected intronic regions of ~450 genes was performed on the tumors with H3K27me3 loss using hybrid capture with a custom probe set and massively parallel (next-generation) sequencing (NGS). Of the 50 patients, 32 were male and 18 were female with a median age of 33 years (range, 6 wk to 77 y). Tumors most often involved head and neck (N=23), extremities/limb girdles (N=11), and trunk wall (N=5). Three cases (6%) showed loss of H3K27me3; based on all available evidence, we believe at least 2 of these cases in fact represent MPNST with complete heterologous rhabdomyoblastic differentiation: a deep-seated groin mass in a 76-year-old female and a paratesticular mass in a 22-year-old male (neither of whom had a history or signs of type 1 neurofibromatosis). The tumors showed similar histologic appearances: fascicular architecture, marked nuclear atypia, eosinophilic cytoplasm, and a high mitotic rate; rhabdomyoblasts were not apparent. One tumor showed focal areas with scant myxoid stroma and alternating hypocellularity and hypercellularity. By IHC, the tumors showed diffuse staining for desmin, myogenin, and MyoD1, whereas S100 protein and SOX10 were negative. NGS on 2 tumors revealed (1) 2-copy deletion of NF1, CDKN2A, and SUZ12and a TP53mutation with arm-level loss of 17p; and (2) 2-copy deletion of CDKN2Aand an NF1mutation with loss of 17q11, findings characteristic of MPNST. NGS on the third tumor showed no distinctive alterations. MPNST may occasionally show complete heterologous rhabdomyoblastic differentiation without histologic evidence of residual conventional MPNST, closely mimicking spindle cell RMS. IHC for H3K27me3 reliably distinguishes MPNST from spindle cell RMS.

Maxillofacial central giant cell lesions (CGCLs) are often locally aggressive tumors in young patients that may be histologically very similar to or quite distinct when compared with giant cell tumors (GCTs) of long bones. It has been well established that GCTs express high levels of receptor activator of nuclear factor-kappa B ligand (RANKL) and are amenable to treatment with denosumab. To assess the predictive value of morphology, we evaluated CGCLs with GCT-like or non–GCT-like histology for RANKLexpression by RNA in situ hybridization. Tumors were classified by clinical and radiographic criteria as aggressive or nonaggressive and histopathologically as resembling GCT or non–GCT-like. RNA in situ hybridization for RANKLmRNA was performed and scored semiquantitatively based on the magnification at which the signal was first detected. There were 17 patients (M:F=8:9) with a median age of 15 years. Nine patients were children under 18 years of age. In 10 patients, tumors were characterized as GCT-like and in 7, non–GCT-like; 6 occurred in the setting of a known associated syndrome. Of the sporadic tumors, 9/11 (82%) were classified as aggressive. Fifteen of 17 (88%) tumors strongly expressed RANKL(8/9 aggressive, 2/2 nonaggressive; 10/10 GCT-like and 5/7 non–GCT-like). Two patients with clinically aggressive CGCL, GCT-like histology and high tumor RANKLexpression were identified as candidates for a trial of denosumab with notable clinical response. CGCLs demonstrate strong and diffuse RANKLmRNA expression in mononuclear stromal cells, regardless of histology or presence of an associated syndrome. Denosumab may be clinically beneficial in aggressive CGCLs.

The distinction of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) from its benign counterpart, lipoma, may represent a challenge. MDM2DNA amplification is used as the gold standard as MDM2 immunohistochemistry lacks specificity and sensitivity. Herein, we investigate the diagnostic utility of MDM2RNA in situ hybridization (RNA-ISH) and compare the test with MDM2 immunohistochemistry and MDM2DNA fluorescence in situ hybridization (FISH) in benign and malignant lipomatous neoplasms. We evaluated 109 neoplasms including 27 lipomas, 25 spindle cell lipomas, 32 ALTs/WDLs, and 25 dedifferentiated liposarcomas (DDL). The validation cohort included 14 lipoma-like neoplasms that lacked unequivocal features of ALT/WDL and in which MDM2 immunohistochemistry was either equivocal, negative or falsely positive. Immunohistochemistry, automated RNA-ISH and DNA-FISH for MDM2 were performed. Tumors with diffuse nuclear staining or >50 dots per cell on RNA-ISH were considered positive. All lipomas and lipoma variants were negative for RNA-ISH while all ALTs/WDLs and DDLs were positive. Eighty percent (24/30) and 92% (22/24) of ALTs/WDLs and DDLs were positive for MDM2 immunohistochemistry. Lipomas and its variants were negative for MDM2amplification; 92% and 100% of ALTs/WDLs and DDLs showed MDM2DNA amplification. The mean percentage of ALT/WDL tumor cells showing MDM2RNA-ISH positivity was 73% compared with 24% on MDM2 immunohistochemistry. RNA-ISH correctly classified all 10 ALTs/WDLs and all 4 lipomas in the validation cohort. The performance of MDM2RNA-ISH and MDM2DNA-FISH are equivalent. MDM2RNA-ISH can be of diagnostic value in histologically challenging lipomatous neoplasms. The automated MDM2RNA-ISH assay should allow for more widespread use of MDM2 testing and for a more sensitive and specific diagnosis of ALT/WDL.

Supplemental Digital Content is available in the text.The evolving classification of round cell sarcomas is driven by molecular alterations. EWSR1-PATZ1fusion positive spindle and round cell sarcoma is one such new tumor entity. Herein, we report 2 EWSR1-PATZ1fusion positive spindle and round cell sarcomas with overlapping histologic features and polyphenotypic differentiation. The intra-abdominal tumors affected female patients, 31-and 53-year old. Both tumors showed sheets and nests of round to spindle cells, fine chromatin, tiny conspicuous nucleoli, moderate cytoplasm, and thick bands of intratumoral fibrosis. On immunohistochemistry, both tumors showed positivity for CD99, desmin, myogenin, MyoD1, S100, Sox10, CD34, and GFAP and were negative for keratin. Fluorescence in situ hybridization revealed rearrangement at EWSR1locus. Next-generation sequencing–based RNA fusion assay revealed EWSR1-PATZ1fusion in both cases. EWSR1-PATZ1fusion positive spindle and round cell sarcomas show abundant intratumoral fibrosis and polyphenotypic differentiation, thus mimicking a range of tumors including desmoplastic small round cell tumor. The precise classification of this spindle and round cell sarcoma and its relationship to the Ewing sarcoma family of tumors remains to be determined.

Perivascular epithelioid cell tumor (PEComa), mesenchymal tumors morphologically characterized by epithelioid cells, coexpress melanocytic and muscle markers. Herein, we describe a heretofore-undescribed tuberous sclerosis complex (TSC)-related neoplasm, morphologically resembling a soft tissue fibroma-like lesion, but showing an immunophenotype resembling PEComa. We identified 3 soft tissue fibroma-like lesions in individuals with TSC. We also evaluated 6 TSC-related periungual fibroma as well as a range of non-TSC fibroma-like lesions (n=19). Immunohistochemistry for HMB-45, desmin, smooth muscle actin, TFE3, and S100 was performed on the TSC-related fibromas. Periungual fibromas and non-TSC fibroma-like lesions were also stained for HMB-45. All 3 TSC patients were female, ranging in age from 4 to 51 years (mean, 26.7 y). Two tumors were located in extremities and 1 on the chest wall. The tumors showed elongated to stellate spindle-shape cells, prominent collagenous background, and lacked mitotic activity and cytologic atypia. Immunohistochemically, all 3 tumors were positive for HMB-45; smooth muscle actin or desmin was positive in both tumors tested. TFE3 was negative. All patients were alive with no evidence of disease with median follow-up of 55 months (range, 6 to 131 mo). Non-TSC fibroma-like lesions and oral and periungual fibromas were negative for HMB-45. Fibroma-like PEComa, a newly recognized soft tissue tumor with a strong association with TSC, mimics soft tissue fibroma but shows reactivity with melanocytic markers.

Giant cell tumor (GCT) of bone is a locally aggressive benign neoplasm characterized by an abundance of osteoclastic giant cells that are induced by the neoplastic mononuclear cells; the latter express high levels of receptor activator of nuclear factor κ-B ligand (RANKL). Denosumab, a RANKL inhibitor, which is clinically used to treat GCT, leads to a marked alteration in the histologic appearance of the tumor with giant cell depletion and new bone deposition, leading to substantial histologic overlap with other primary tumors of bone. Most significantly, denosumab-treated GCT (tGCT) with abundant bone deposition may mimic de novo osteosarcoma, or GCT that has undergone malignant transformation. To histologically characterize tGCT, we identified 9 cases of GCT biopsied or resected after denosumab treatment. tGCT cases included 16 specimens from 9 patients including 6 female and 3 male individuals aged 16 to 47 (median 32) years. Duration of treatment varied from 2 to 55 months. We compared these tumors with malignant neoplasms arising in GCTs (n=9). The histology of tGCT was variable but appeared to relate to the length of therapy. All tGCTs showed marked giant cell depletion. Early lesions were highly cellular, and the combination of cellularity, atypia, and haphazard bone deposition caused the lesion to resemble high-grade osteosarcoma. Unlike de novo high-grade osteosarcoma or malignancies arising in GCT, however, tGCT showed less severe atypia, reduced mitotic activity, and lack of infiltrative growth pattern. Tumor in patients on prolonged therapy showed decreased cellularity and abundant new bone, deposited as broad, rounded cords or long, curvilinear arrays. The latter morphology was reminiscent of low-grade central osteosarcoma, but, unlike low-grade central osteosarcoma, tGCT was negative for MDM2 and again lacked an infiltrative growth pattern. Overall, tGCT may have a wide range of morphologic appearances. Because the treated tumors bear little resemblance to their pretreatment counterparts, careful attention to the history of denosumab administration is crucial to avoid a misdiagnosis with an important impact on therapy. Unlike malignant GCTs, tGCTs lack significant nuclear atypia, mitotic activity, and infiltration of preexisting bone, but instead show a unique pattern of intralesional bone deposition.

Supplemental Digital Content is available in the text.Loss of expression of the SMARCB1 (INI1/BAF47/SNF5) tumor-suppressor protein, originally identified in pediatric malignant rhabdoid tumors, has been noted in significant percentages of epithelioid sarcomas of classical and proximal-type and in myoepithelial carcinomas. Epithelioid sarcoma and myoepithelial carcinoma are very rare in the vulvar region, and few of these cases have been evaluated for SMARCB1 protein loss by immunohistochemistry (IHC) or for SMARCB1gene alterations by molecular genetic techniques. We studied the clinicopathologic, IHC, and molecular genetic features of 14 SMARCB1-deficient vulvar neoplasms. All available routinely stained sections were reexamined, and IHC analysis for wide-spectrum cytokeratins, high–molecular weight cytokeratins, epithelial membrane antigen, S100 protein, CD34, smooth muscle actin, desmin, and SMARCB1 was performed. Multiplex ligation-dependent probe amplification and DNA sequencing of the SMARCB1gene was performed on 12 cases with sufficient available tissue. The 14 vulvar tumors occurred in adult women (mean age 46 y, range 22 to 62 y) and measured 1.1 to 8.8 cm in size (mean 4.7 cm). Tumors were classified as classical-type epithelioid sarcoma (N=1), proximal-type epithelioid sarcoma (N=6), myoepithelial carcinoma (N=4), and “SMARCB1-deficient vulvar sarcoma, not otherwise specified” (N=3) on the basis of combined histopathologic and IHC findings. One myoepithelial carcinoma showed divergent rhabdomyoblastic differentiation. All tested cases showed partial or complete SMARCB1deletions (homozygous: 9 cases; heterozygous: 3 cases). One case with a heterozygous deletion also showed a c.528delC mutation in exon 5. Fluorescence in situ hybridization for EWSR1rearrangement was performed for 3 cases classified as myoepithelial carcinoma and was negative. Follow-up (13 patients, range 5 to 72 mo, mean 31 mo) data showed 3 patients dead of disease, 1 alive with unresectable metastatic disease, 1 alive with radiographic evidence of extensive lymph nodal disease, and 8 alive without disease. We conclude that SMARCB1-deficient vulvar neoplasms chiefly comprise epithelioid sarcoma and myoepithelial carcinoma, although some defy easy classification. No association was seen between clinical behavior and the type of SMARCB1alteration.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare, aggressive malignant neoplasm characterized by small nests and linear arrays of epithelioid cells embedded in a dense collagenous matrix. Very few primary SEFs of bone have been reported. Recognition is critical, as the dense extracellular collagenous matrix can be interpreted as osteoid, leading to misdiagnosis as-osteosarcoma. MUC4 and SATB2 are 2 recently characterized immunohistochemical markers for SEF and osteosarcoma, respectively. In reports to date, osteosarcomas are positive for SATB2 and negative for MUC4, whereas soft tissue SEFs have shown the opposite immunohistochemical profile (SATB2−/MUC4+). The purpose of this study was to characterize the clinicopathologic and immunohistochemical features of 8 primary SEFs of bone. The patients presented at a wide range of ages (25 to 73 y; median 52 y). Tumors mostly involved long bones of the extremities, with 3 cases involving the femur, 2 involving the ulna, and 1 involving the humerus. Other sites of involvement included the second rib (1) and the C6 vertebra (1). Follow-up information was available for 7 patients, 3 of whom developed metastases within 2 years of diagnosis. The other 4 patients were free of local recurrence or metastases at 1, 5, 12, and >84 months of follow-up, respectively. Radiographically, the tumors were predominantly lytic and poorly marginated. Histologically, 6 tumors showed pure SEF morphology, and 2 showed hybrid SEF/low-grade fibromyxoid sarcoma morphology. Focal dystrophic mineralization was seen in 1 case but was limited to areas of necrosis. None of the tumors showed the lace-like pattern of mineralization typical of osteosarcoma. The majority (6/8) of the tumors strongly expressed MUC4. SATB2 was negative in all but 1 case, which showed variable weak to moderate staining in ∼50% of nuclei. In general, the combination of morphology, MUC4 expression, and the absence of SATB2 expression was highly useful in arriving at the correct diagnosis.

The clinical and pathologic features of 8 primary myoepitheliomas of bone were analyzed. There were 5 female and 3 male patients who ranged in age from 16 to 49 (mean, 33.5) years. Three tumors arose in the ilium, 2 in the tibia, and 1 each in the maxilla, sacrum, and L1 vertebral body. Microscopically, the tumors had a solid, lobulated, reticular, or storiform growth pattern and were predominantly composed of spindle-shaped cells arranged in intersecting fascicles with eosinophilic cytoplasm. The round to polygonal epithelioid cells were arranged randomly or formed small clusters and contained variable amounts of eosinophilic or clear cytoplasm. Immunohistochemically, all the tumors were positive for vimentin and S100 protein, and 7 were positive for epithelial membrane antigen. No tumors were positive for keratin (AE1.3CAM5.2). Smooth muscle actin was positive in 3 tumors and negative in 4, whereas desmin was negative in all 7 tumors tested. Nuclear staining for p63 was negative in 3 tested tumors. Staining for GFAP and CD34 was performed on 4 and 5 tumors, respectively, and all showed no expression. Fluorescence in situ hybridization for EWSR1rearrangement was performed in 7 tumors. Five tumors (71) showed the presence of EWSR1gene rearrangement, and 2 were negative. Cytogenetic studies conducted on 1 tumor showed 46,XY,t(1;22)(q21;q12) associated with EWSR1-PBX1fusion. Surgical procedures included curettage in 3 patients, resection in 3 patients, and 2 patients only had an open biopsy. Follow-up information was available for 4 patients; all remain free of disease with no recurrence. Although experience with primary myoepithelioma of bone is limited, histologically, banal tumors appear to behave in a benign manner, and conservative surgery appears to be sufficient treatment. Immunohistochemical and molecular analyses are helpful in their accurate identification.

Distinguishing chondrosarcoma from chondroblastic osteosarcoma can be difficult and highly subjective, especially on a small biopsy specimen. This distinction is critical in determining the most accurate prognosis and appropriate treatment modality, as adjuvant chemotherapy with surgery is standard treatment for osteosarcoma, whereas chondrosarcoma is generally treated by surgical excision alone. Cartilaginous neoplasms have recently been shown to frequently (56) harbor gene mutations in the metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2(IDH1>IDH2), whereas other mesenchymal tumors lack these genetic aberrations. We investigated whether the presence of IDH12mutations can be used to distinguish chondrosarcoma from chondroblastic osteosarcoma. Tumors including 25 predominantly high-grade chondrosarcomas and 65 osteosarcomas (44 chondroblastic osteosarcomas and 21 mixed osteosarcomas with a chondroblastic component) were evaluated, and a total of 59 cases (66) were suitable for genotyping. Mutational analysis was performed using a multiplexed polymerase chain reaction genotyping platform to query for hotspot mutations in the genes IDH1at codon R132. IDH1-negative cases underwent Sanger sequencing of IDH2exon 4. No osteosarcomas (036) and 61 of chondrosarcomas (1423) harbored a somatic mutation in IDH12, with the majority (86) of mutations found in the IDH1gene. IDH12mutation analysis appears to be a promising biomarker for the distinction of chondrosarcoma from chondroblastic osteosarcoma. A positive result strongly favors the diagnosis of chondrosarcoma over chondroblastic osteosarcoma. The presence of IDH12mutations can also help confirm the diagnosis of dedifferentiated chondrosarcoma when the tumor displays osteosarcomatous differentiation.