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PDF file - 797K, Figure S1. Barrier phenotype of human brain microvascular endothelial cells and astrocytes in monocultures and co-cultures. Figure S2. alpha/beta-crystallin does not affect cell viability of TNBC cells in standard monolayer culture. Figure S3. alpha/beta-crystallin overexpression increases liver metastases in an orthotopic model of TNBC. Figure S4. Silencing alpha/beta-crystallin inhibits liver metastases in an orthotopic model of TNBC. Figure S5. alpha/beta-crystallin does not affect proliferation or apoptosis in primary mammary tumors and brain metastatic lesions determined at autopsy. Table S1. Patient characteristics Table S2. alpha/beta-crystallin expression in paired tumors. Table S3. Association of alpha/beta-crystallin expression with breast cancer subtype. Table S4. Incidence of metastases in mice in orthotopic models of TNBC .

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Purpose: We evaluated X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) protein in head and neck squamous cell carcinoma (HNSCC) patients in association with outcome.Experimental Design: XRCC1 protein expression was assessed by immunohistochemical (IHC) staining of pretreatment tissue samples in 138 consecutive HNSCC patients treated with surgery (n = 31), radiation (15), surgery and radiation (23), surgery and adjuvant chemoradiation (17), primary chemoradiation (51), and palliative measures (1).Results: Patients with high XRCC1 expression by IHC (n = 77) compared with patients with low XRCC1 expression (n = 60) had poorer median overall survival (OS; 41.0 months vs. OS not reached, P = 0.009) and poorer progression-free survival (28.0 months vs. 73.0 months, P = 0.031). This association was primarily due to patients who received chemoradiation (median OS of high- and low-XRCC1 expression patients, 35.5 months and not reached respectively, HR 3.48; 95% CI: 1.44–8.38; P = 0.006). In patients treated with nonchemoradiation modalities, there was no survival difference by XRCC1 expression. In multivariable analysis, high XRCC1 expression and p16INK4a-positive status were independently associated with survival in the overall study population (HR = 2.62; 95% CI: 1.52–4.52; P < 0.001 and HR = 0.21; 95% CI: 0.06–0.71; P = 0.012, respectively) and among chemoradiation patients (HR = 6.02; 95% CI: 2.36–15.37; P < 0.001 and HR = 0.26; 95% CI: 0.08–0.92, respectively; P = 0.037).Conclusions: In HNSCC, high XRCC1 protein expression is associated with poorer survival, particularly in patients receiving chemoradiation. Future validation of these findings may enable identification of HNSCC expressing patients who benefit from chemoradiation treatment. Clin Cancer Res; 17(20); 6542–52. ©2011 AACR.

Purpose: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs.Experimental Design: αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood–brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models.Results: In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin–dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models.Conclusion: αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. Clin Cancer Res; 20(1); 56–67. ©2013 AACR.

SUPPLEMENTARY TABLES, FIGURES AND FIGURE LEGENDS

One of the greatest barriers to curative treatment of neuroblastoma is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven neuroblastoma. GAS7 expression was also suppressed in MYCN-amplified neuroblastoma lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of neuroblastoma with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish neuroblastoma tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell–cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in neuroblastoma metastasis in the context of MYCN overexpression.Significance:Heterozygous deletion or MYCN-mediated repression of GAS7 in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma.See related commentary by Menard, p. 2815

Low-grade fibromyxoid sarcoma (LGFMS) is an uncommon mesenchymal tumor usually arising in the lower extremities and trunk. Only rare examples in the head and neck region have been reported. Fifteen cases of head and neck LGFMS were retrieved. MUC4 was performed on all cases. Results for smooth muscle actins, β-catenin, desmin, S100 protein, Epithelial membrane antigen (EMA) and STAT6 immunohistochemistry, as well as FUS rearrangement status, were recorded when available. Sites included neck (8), supraclavicular region (4) and orbit (1), parapharyngeal space (1) and lower lip (1). The age of the patients ranged from 3 to 97 years (median, 26 years). Tumors displayed classical morphologic features of LGFMS, as described. All cases (15/15) were positive for MUC4, and all cases tested (4/4) harbored FUS rearrangement. Variable positivity for EMA was identified in one case. Follow-up was available in 11 patients, ranging from 2 to 240 months (mean 71.4 months; median, 44 months). Three tumors recurred locally; none metastasized. In conclusion, although distinctly uncommon, LGFMS may arise in the head and neck region and should be distinguished from other more common spindle cell tumors in these locations. The morphologic, immunohistochemical and molecular genetic features of head/neck LGFMS are identical to those occurring elsewhere. The long-term metastatic risk of LGFMS in these locations remains to be fully elucidated.

Infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) commonly harbors the classic ETV6-NTRK3 translocation. However, there are recent reports of mesenchymal tumors with IFS-like morphology harboring fusions of other receptor tyrosine kinases or downstream effectors, including NTRK1/2/3, MET, RET, and RAF1 fusions as well as one prior series with BRAF fusions. Discovery of these additional molecular drivers contributes to a more integrated diagnostic approach and presents important targets for therapy. Here we report the clinicopathologic and molecular features of 14 BRAF-altered tumors, of which 5 had BRAF point mutations and 10 harbored one or more BRAF fusions. Of the BRAF fusion-positive tumors, one harbored two BRAF fusions (FOXN3-BRAF, TRIP11-BRAF) and another harbored three unique alternative splice variants of EPB41L2-BRAF. Tumors occurred in ten males and four females, aged from birth to 32 years (median 6 months). Twelve were soft tissue based; two were visceral including one located in the kidney (cCMN). All neoplasms demonstrated ovoid to short spindle cells most frequently arranged haphazardly or in intersecting fascicles, often with collagenized stroma and a chronic inflammatory infiltrate. No specific immunophenotype was observed; expression of CD34, S100, and SMA was variable. To date, this is the largest cohort of BRAF-altered spindle cell neoplasms with IFS-like morphology, including not only seven novel BRAF fusion partners but also the first description of oncogenic BRAF point mutations in these tumors.

Meningeal solitary fibrous tumor (SFT) is a rare tumor with high propensity to recur and metastasize, even late in the course of disease. The WHO 2021 classification of CNS tumors divides SFT in 3 grades, based on mitotic index and necrosis. We re-examined our cohort of 126 patients (57 F, 69 M; mean age 53.0 years) with SFT, confirmed by STAT6 nuclear positivity and/or NAB2::STAT6 fusion, with extended follow-up (median 7.6 years; range 4 days-26.6 years). Tumors included 76 grade 1, 36 grade 2 and 14 grade 3 according to 2021 WHO criteria, evaluated at primary resection (n=90), recurrence (n=35), or metastasis (n=1). Fifty-six patients had one or more post-surgical events, the earliest event being local recurrence (n=41) or metastasis (n=15). Forty patients died (29 of disease; 9 of other causes; 2 unknown). Overall survival (OS), and progression-free survival (PFS, recurrence and/or metastasis) from time of primary resection (n=90) were not significantly associated with grade; however, risk of metastasis differed significantly (5-year estimates: 4.1%, 15.3%, and 37.8% for grades 1, 2, and 3 SFT, respectively; p=0.005). NAB2::STAT6 fusion status was known in 101 cases (51 = ex5-7-ex16-17, 26 = ex4_ex2-3; 12 = ex2-3_exANY/other and 12 =no fusion). Disease specific 5-year survival in primary tumors with molecular data (n = 75) was 80.0% in patients whose tumors harbored ex5-7_ex16-17 compared to 93.3% in all others combined (p=0.014). Targeted TERT promoter mutation testing was performed in 98 patients, revealing patients with tumors lacking TERT promoter mutation (n = 88) were younger at time of surgery than those harboring a mutation (n=10; p = 0.022), and none with a mutation harboring concurrent ex5-7_ex16-17 fusion (p = 0.0009). In summary, WHO 2021 grade is associated with risk of metastasis. Patients whose tumors harbor ex5-7_ex16-17 fusion have a higher risk of dying from the disease.

Background. Follicular dendritic cell (FDC) sarcoma is a rare neoplasm arising from follicular dendritic cells (FDCs). It can be nodal or extranodal. Histological diagnosis of extranodal FDC sarcoma in the head and neck region is challenging and a significant percentage are misdiagnosed. Objectives. To report clinicopathological features of head and neck extranodal FDC sarcoma cases and discuss differential diagnoses. Methods. Seven head and neck extranodal FDC sarcomas were retrieved and clinicopathological features were noted. Results. Two tumors each involved parapharyngeal space and tonsil while remaining cases involved the parotid, soft tissue of neck and oropharynx. Age range was 12 to 79 years (mean and median age were 40 and 44 years respectively) and there was a male predilection (6 males: 1 female). All showed spindle to ovoid cells arranged in fascicles, whorls and/or storiform pattern. Mitoses ranged from 3 to 20/mm2. All tumors expressed CD21 and CD23. Two patients died of their disease at 9 and 16 months. Both had tumors larger than 5 cm with ≥10 mitoses/mm2. Three patients were alive at 12, 44 and 184 months. Conclusions. There was a distinct male predominance in our cohort. FDC sarcoma should be included in the differential diagnosis of spindle cell extranodal neoplasms in the head and neck with a whorled growth pattern and intratumoral lymphocytes. Head and neck region tumors show similar clinicopathologic characteristics as their counterparts at other locations with potential for aggressive behavior especially in tumors greater than 5 cm in size and with high mitotic rates.

AIMS PRRX1-NCOA1-rearranged fibroblastic tumour is a recently described, rare mesenchymal tumour. Only four cases have been previously reported. The aim of this article is to report six additional cases of this unusual mesenchymal neoplasm, with an emphasis on its differential diagnosis. METHODS AND RESULTS The six cases were from three females and three males (age, 20-49 years; median, 42 years). Three tumours were located on the abdominal wall; two from the shoulder/axillary areas, and one on the lateral hip. All presented as slow-growing subcutaneous nodules, ranging from 26 to 55 mm (median, 40 mm). The tumours consisted of circumscribed, variably cellular nodules composed of relatively bland plump spindled to epithelioid cells arranged singly, in cords, and occasionally in nests, embedded in hyalinised and collagenous stroma. Small hypocellular myxoid zones with ropey collagen fibres were present, as were irregularly dilated, gaping, crescent-shaped or staghorn-like thin-walled vessels, best appreciated at the periphery. Immunohistochemistry for CD34, S100, MUC4 and STAT6 was consistently negative. RNA-sequencing revealed PRRX1-NCOA1 fusions in all cases. Of the four cases with limited follow-up (1.5-4 months), none recurred following local surgical excision. CONCLUSIONS The morphological features of PRRX1-NCOA1-rearranged fibroblastic tumour overlap with those of RB1-deficient soft-tissue tumours, solitary fibrous tumour, and low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. This differential diagnosis can be resolved with a combination of careful morphological study and the application of a panel of immunostains, although molecular genetic study is most definitive. The natural history of PRRX1-NCOA1-rearranged fibroblastic tumour appears to be quite favourable, although longer-term study of a larger number of cases is warranted.

YAP1-TFE3-fused hemangioendothelioma is an extremely rare malignant vascular tumor. We present the largest multi-institutional clinicopathologic study of YAP1-TFE3-fused hemangioendothelioma to date. The 24 cases of YAP1-TFE3-fused hemangioendothelioma showed a female predominance (17 female, 7 male) across a wide age range (20-78 years old, median 44). Tumors were most commonly located in soft tissue (50%), followed by bone (29%), lung (13%), and liver (8%), ranging from 3 to 115 mm in size (median 40 mm). About two-thirds presented with multifocal disease, including 7 cases with distant organ metastasis. Histopathologically, we describe three dominant architectural patterns: solid sheets of coalescing nests, pseudoalveolar and (pseudo)vasoformative pattern, and discohesive strands and clusters of cells set in a myxoid to myxohyaline stroma. These patterns were present in variable proportions across different tumors and often coexisted within the same tumor. The dominant cytomorphology (88%) was large epithelioid cells with abundant, glassy eosinophilic to vacuolated cytoplasm, prominent nucleoli and well-demarcated cell borders. Multinucleated or binucleated cells, prominent admixed erythrocytic and lymphocytic infiltrates, and intratumoral fat were frequently present. Immunohistochemically, ERG, CD31, and TFE3 were consistently expressed, while expression of CD34 (83%) and cytokeratin AE1/AE3 (20%) was variable. CAMTA1 was negative in all but one case. All cases were confirmed by molecular testing to harbor YAP1-TFE3 gene fusions: majority with YAP1 exon 1 fused to TFE3 exon 4 (88%), or less commonly, TFE3 exon 6 (12%). Most patients (88%) were treated with primary surgical resection. Over a follow-up period of 4-360 months (median 36 months) in 17 cases, 35% of patients remained alive without disease, and 47% survived many years with stable, albeit multifocal and/or metastatic disease. Five-year progression-free survival probability was 88%. We propose categorizing YAP1-TFE3-fused hemangioendothelioma as a distinct disease entity given its unique clinical and histopathologic characteristics in comparison to conventional epithelioid hemangioendothelioma.

Myxoid pleomorphic liposarcoma is a recently defined subtype of liposarcoma, which preferentially involves the mediastinum of young patients and shows mixed histological features of conventional myxoid liposarcoma and pleomorphic liposarcoma. While myxoid pleomorphic liposarcoma is known to lack the EWSR1/FUS-DDIT3 fusions characteristic of the former, additional genetic data are limited. To further understand this tumor type, we extensively examined a series of myxoid pleomorphic liposarcomas by fluorescence in situ hybridization (FISH), shallow whole genome sequencing (sWGS) and genome-wide DNA methylation profiling. The 12 tumors occurred in 6 females and 6 males, ranging from 17 to 58 years of age (mean 33 years, median 35 years), and were located in the mediastinum (n = 5), back, neck, cheek and leg, including thigh. Histologically, all cases consisted of relatively, bland, abundantly myxoid areas with a prominent capillary vasculature, admixed with much more cellular and less myxoid foci containing markedly pleomorphic spindled cells, numerous pleomorphic lipoblasts and elevated mitotic activity. Using sWGS, myxoid pleomorphic liposarcomas were found to have complex chromosomal alterations, including recurrent large chromosomal gains involving chromosomes 1, 6-8, 18-21 and losses involving chromosomes 13, 16 and 17. Losses in chromosome 13, in particular loss in 13q14 (including RB1, RCTB2, DLEU1, and ITM2B genes), were observed in 4 out of 8 cases analyzed. Additional FISH analyses confirmed the presence of a monoallelic RB1 deletion in 8/12 cases. Moreover, nuclear Rb expression was deficient in all studied cases. None showed DDIT3 gene rearrangement or MDM2 gene amplification. Using genome-wide DNA methylation profiling, myxoid pleomorphic liposarcomas and conventional pleomorphic liposarcomas formed a common methylation cluster, which segregated from conventional myxoid liposarcomas. While the morphologic, genetic and epigenetic characteristics of myxoid pleomorphic liposarcoma suggest a link with conventional pleomorphic liposarcoma, its distinctive clinical features support continued separate classification for the time being.

Infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) commonly harbors the classic ETV6-NTRK3 translocation. However, there are recent reports of mesenchymal tumors with IFS-like morphology harboring fusions of other receptor tyrosine kinases or downstream effectors, including NTRK1/2/3, MET, RET, and RAF1 fusions as well as one prior series with BRAF fusions. Discovery of these additional molecular drivers contributes to a more integrated diagnostic approach and presents important targets for therapy. Here we report the clinicopathologic and molecular features of 14 BRAF-altered tumors, of which 5 had BRAF point mutations and 10 harbored one or more BRAF fusions. Of the BRAF fusion-positive tumors, one harbored two BRAF fusions (FOXN3-BRAF, TRIP11-BRAF) and another harbored three unique alternative splice variants of EPB41L2-BRAF. Tumors occurred in ten males and four females, aged from birth to 32 years (median 6 months). Twelve were soft tissue based; two were visceral including one located in the kidney (cCMN). All neoplasms demonstrated ovoid to short spindle cells most frequently arranged haphazardly or in intersecting fascicles, often with collagenized stroma and a chronic inflammatory infiltrate. No specific immunophenotype was observed; expression of CD34, S100, and SMA was variable. To date, this is the largest cohort of BRAF-altered spindle cell neoplasms with IFS-like morphology, including not only seven novel BRAF fusion partners but also the first description of oncogenic BRAF point mutations in these tumors.

Inflammatory leiomyosarcoma (ILMS), defined as "a malignant neoplasm showing smooth muscle differentiation, a prominent inflammatory infiltrate, and near-haploidization", is a very rare soft tissue tumor with a generally favorable prognosis. The morphologic features of "histiocyte-rich rhabdomyoblastic tumor" (HRRMT) are similar to those of ILMS, although this lesion shows by definition a skeletal muscle phenotype. Recent gene expression profiling and immunohistochemical studies have also suggested that ILMS and HRRMT may be related. We studied the clinicopathologic, immunohistochemical and genetic features of four cases previously classified as ILMS and nine classified as HRRMT. Tumors from both groups tended to occur in the deep soft tissues of the extremities of young to middle-aged males and exhibited indolent behavior. Morphologically, all were well-circumscribed, often encapsulated, and showed a striking histiocyte-rich inflammatory infiltrate admixed with variably pleomorphic tumor cells showing spindled and epithelioid to rhabdoid morphology, eosinophilic cytoplasm, and prominent nucleoli, but few, if any, mitotic figures. Immunohistochemically, the tumor cells expressed desmin, alpha-smooth muscle actin, and the rhabdomyoblastic markers PAX7, MyoD1, and myogenin. H-caldesmon expression was absent in all cases, using the specific h-CD antibody. Karyotypic study (1 HRRMT) and genome-wide copy number analysis (7 HRRMT, OncoScan SNP assay), revealed near-haploidization in four cases, with subsequent genome doubling in one, an identical phenotype to that seen in ILMS. We propose reclassification of ILMS and HRRMT as "inflammatory rhabdomyoblastic tumor", a name which accurately describes the salient morphologic and immunohistochemical features of this distinctive tumor, as well as its intermediate (rarely metastasizing) clinical behavior.

Extraskeletal Ewing sarcoma presenting as intra-abdominal or pelvic disease in adult female patients is very rare and may lead to diagnostic difficulty due to clinical and histologic overlap with Mullerian adenocarcinomas, which are far more common. We report a case of an intra-abdominal Ewing sarcoma in a postmenopausal female patient whose clinical and radiological presentation closely resembled that of peritoneal carcinomatosis. Biopsy of an omental nodule revealed numerous histologic features suggestive of a Mullerian carcinoma, including gland-like rosettes, strong, diffuse PAX8 immunoreactivity and cytokeratin expression. After excluding other differential diagnostic considerations, the possibility that this might represent an intra-abdominal Ewing sarcoma was entertained. Reverse transcriptase polymerase chain reaction testing demonstrated the presence of an EWSR1-ERG fusion transcript, confirming the diagnosis. The differential diagnostic considerations when dealing with this unusual clinical scenario and the uncommon yet important pitfall of PAX8 immunoreactivity in Ewing sarcoma are discussed.

We present our experience with ten well-characterized malignant tenosynovial giant cell tumors, including detailed immunohistochemical analysis of all cases and molecular cytogenetic study for CSF1 rearrangement in a subset. Cases occurred in 7 M and 3 F (mean age: 52 years; range: 26-72 years), and involved the ankle/foot (n = 1), finger/toe (n = 3), wrist (n = 1), pelvic region (n = 3), leg (n = 1), and thigh (n = 1). There were eight primary and two secondary malignant tenosynovial giant cell tumors. Histologically, all cases showed definite areas of typical tenosynovial giant cell tumor. The malignant areas varied in appearance. In some cases, isolated malignant-appearing large mononuclear cells with high nuclear grade and mitotic activity were identified within otherwise-typical tenosynovial giant cell tumor, as well as forming larger masses of similar-appearing malignant cells. Occasionally, these nodules of malignant large mononuclear cells showed transition to pleomorphic spindle cell sarcoma, with varying degrees of collagenization and myxoid change. One malignant tenosynovial giant cell tumor was composed of sheets of monotonous large mononuclear cells with high nuclear grade, growing in a hyalinized, osteoid-like matrix, with areas of heterologous osteocartilaginous differentiation. Mitotic activity ranged from 2 to 34 mitoses per 10 HPF (mean 18/10 HPF). Geographic necrosis was observed in four cases. The malignant-appearing large mononuclear cells were consistently positive for clusterin and negative for CD163, CD68, and CD11c. Desmin was positive in a small minority of these cells. Areas in malignant tenosynovial giant cell tumor resembling pleomorphic spindle cell sarcoma or osteo/chondrosarcoma showed loss of clusterin expression. RANKL immunohistochemistry was positive in the large mononuclear cells in eight cases. Two cases showed an unbalanced rearrangement of the CSF1 locus. Follow-up (nine patients; range 0.5-66 months; mean 20 months) showed three patients dead of disease, with three other living patients having lung and lymph node metastases; three patients were disease-free. We conclude that malignant tenosynovial giant cell tumors are highly aggressive sarcomas with significant potential for locally destructive growth, distant metastases, and death from disease. The morphologic and immunohistochemical features of these tumors and the presence of CSF1 rearrangements support origin of malignant tenosynovial giant cell tumor from synoviocytes.

Adamantinoma represents a distinct group of bone tumors showing both mesenchymal and epithelial differentiation most commonly involving the tibial diaphysis. Most adamantinomas contain a fibro-osseous component and an epithelial component consisting of squamous or basaloid cells. Adamantinomas are considered malignant neoplasms requiring en bloc excision that frequently recur locally and can rarely metastasize. Rare adamantinomas show an epithelial component consisting predominantly of monomorphic spindle cells, which, combined with an epithelial immunophenotype, can mimic monophasic synovial sarcoma. Synovial sarcoma is very rare in bone. It is considered a high-grade sarcoma that typically necessitates chemotherapy. However, the relationship between spindle cell adamantinoma and intraosseous synovial sarcoma has not been investigated. The current study was prompted by identification of a presumed spindle cell adamantinoma of the tibia with diffuse keratin expression that harbored a SS18 gene region rearrangement. FISH of eight additional bone tumors initially classified as spindle cell adamantinoma based on clinicoradiopathologic findings revealed one additional case with SS18 rearrangement. Histologically, both intraosseous synovial sarcoma and spindle cell adamantinoma demonstrated uniform fusiform nuclei with scant cytoplasm, short fascicles and low mitotic activity. The adamantinomas, but not the synovial sarcomas, were more likely to show overt epithelial differentiation in the form of pseudoglands or squamous nests. Immunohistochemistry of all cases, irrespective of SS18 status, showed diffuse keratin positivity in the spindle cell component, and less consistent EMA positivity. Clinical follow-up was available in both intraosseous synovial sarcomas, one of which recurred and the other metastasized. Two of the six spindle cell adamantinomas with follow-up metastasized. The above findings highlight the morphologic and immunophenotypic overlap between spindle cell adamantinoma and intraosseous synovial sarcoma of the tibia. Investigation of SS18 status to exclude synovial sarcoma is suggested prior to rendering a diagnosis of spindle cell adamantinoma.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor often arising in the lower extremities. Only rare examples in the abdominal cavity, pelvis, and retroperitoneum have been reported.cases of abdominopelvic and retroperitoneal LGFMS were retrieved. MUC4, Actin, ALK, β-catenin, desmin, DOG1, KIT, S100 protein, and STAT6 testing was performed, and a subset was tested for FUS rearrangement.Sites included intra-abdominal/abdominal wall (four cases), retroperitoneum (three cases), pelvis (three cases), small bowel (two cases), and kidney (one case) (median size, 15 cm; age range, 5-61 years). Tumors harbored spindled cells with mild to moderate atypia, displaying alternating myxoid nodules and hyalinized areas. All cases were positive for MUC4, and five (of five) cases tested harbored FUS rearrangement. Variable positivity for DOG1 (four of 10) and actin (two of 10) was identified. Six tumors recurred, and one patient developed metastasis.LGFMS arising in these central locations exhibits similar clinicopathologic features to its counterpart in the extremities. LGFMS at these sites may show limited immunoreactivity for DOG1 and actin.

Nodular fasciitis (NF) is a clonal self-limited neoplastic proliferation characterized by rearrangements of the USP6 locus in most examples. To our knowledge well-documented malignant behavior has never been previously observed in NF. In this report we present an unusual case of NF with classical histologic features that showed a protracted clinical course characterized by multiple recurrences and eventual metastatic behavior over a period of 10 years. Molecular analyses revealed the presence and amplification of the novel PPPR6-USP6 gene fusion, which resulted in USP6 mRNA transcriptional upregulation. These findings further support the oncogenic role of the USP6 protease in mesenchymal neoplasia and expand the biologic potential of NF. © 2016 Wiley Periodicals, Inc.

There is a group of tumors which has been thought to include ‘histiocyte-like', ‘fibroblast-like'and ‘myo-fibroblast-like' cells that has been repeatedly expanded and collapsed over several decades as our methods of examining these tumors has advanced. In this review, we examine the history and present state of malignant fibrous histiocytoma.

Background: Myxoid liposarcomas account for approximately one third of all liposarcomas and typically present as a slow-growing, deep-seated tumor in the lower extremity. Although approximately one-third of patients develop metastases and eventually die from their tumors, prognostic factors for recurrence have not been thoroughly studied. The effects of radiotherapy and perioperative allogeneic blood transfusions on tumor recurrence in primary myxoid liposarcomas were investigated. Patients and Methods: A retrospective review of 47 primary myxoid liposarcomas treated at a single institution was completed. Morphologic diagnoses were confirmed by soft tissue pathologists without prior knowledge of the clinical features, treatment, or outcome. Associations among treatment factors and recurrence were examined. Results: Four (9%) and fourteen (30%) patients developed local recurrences and distant metastases, respectively. The median follow-up time was 54 months. There were no local recurrences among those who received radiotherapy, thus producing a significant decrease in local recurrence in those patients who received radiotherapy ( p [Cox model]=0.010). The receipt of ≥3 blood transfusions correlated with an increase in tumor local recurrence ( p [Cox model]=0.030). Conclusions: Radiotherapy and perioperative blood transfusion quantity may have an effect on tumor recurrence and warrant further investigation. Mini -Abstract: Radiotherapy and perioperative blood transfusion quantity have a significant effect on myxoid liposarcoma recurrence.

AIMS: The majority of adenoid cystic carcinomas (AdCCs), regardless of anatomical site, harbour the MYB-NFIB fusion gene. The aim of this study was to characterize the repertoire of somatic genetic events affecting known cancer genes in AdCCs. METHODS AND RESULTS: DNA was extracted from 13 microdissected breast AdCCs, and subjected to a mutation survey using the Sequenom OncoCarta Panel v1.0. Genes found to be mutated in any of the breast AdCCs and genes related to the same canonical molecular pathways, as well as KIT, a proto-oncogene whose protein product is expressed in AdCCs, were sequenced in an additional 68 AdCCs from various anatomical sites by Sanger sequencing. Using the Sequenom MassARRAY platform and Sanger sequencing, mutations in BRAF and HRAS were identified in three and one cases, respectively (breast, and head and neck). KIT, which has previously been reported to be mutated in AdCCs, was also investigated, but no mutations were identified. CONCLUSIONS: Our results demonstrate that mutations in genes pertaining to the canonical RAS pathway are found in a minority of AdCCs, and that activating KIT mutations are either absent or remarkably rare in these cancers, and unlikely to constitute a driver and therapeutic target for patients with AdCC.