FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology.

Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.

Intra-Abdominal Epithelioid Neoplasm With EWSR1::CREB Fusions Involving the Kidney: A Clinicopathologic and Molecular Characterization With an Emphasis on Differential Diagnosis.

Soft tissue neoplasms, harboring fusions between EWSR1 and FUS with genes encoding CREB transcription factors family (ATF1, CREB1, and CREM), are an emerging heterogeneous group of mesenchymal tumors that differ significantly in morphology, immunophenotypes, and behavior. Recently, EWSR1/FUS::CREB fusions have been recognized to define a group of aggressive neoplasms of epithelioid morphology with multiple growth patterns and a striking predilection for mesothelial-lined cavities. These neoplasms presenting as a primary neoplasm of intra-abdominal visceral organs are rare, which could elicit a wide range of differential diagnoses because of their diverse morphologies and immunohistochemical profiles. We report 3 cases of intra-abdominal epithelioid neoplasms with EWSR1::CREB fusions involving the kidney. This study included 2 female patients and 1 male patient, with age at presentation ranging from 17 to 61 years (mean: 32 years). All the patients underwent radical nephrectomy without adjunctive therapies. Grossly, the tumors were large, and all were solitary masses with sizes ranging from 5.6 to 30.0 cm (mean: 14.5 cm). Histologically, the neoplasms showed infiltrating and indistinct borders and were composed predominantly of monomorphic round-to-epithelioid cells with variable amounts of pale-to-clear cytoplasm, arranged in cords, nests, and sheets and embedded in a sclerotic hyalinized stroma with variable lymphoid cuffing either intermixed or at the periphery. Notably, a hemangiopericytomatous growth pattern was commonly seen. Nuclear atypia was mild, and mitotic activity was scarce. Immunohistochemically, all 3 cases were at least focally positive for epithelial membrane antigen and keratin AE1/AE3, with 2 tumors showing focal MUC4 expression and 1 case displaying diffuse CD34 and focal CAIX positivity. Targeted RNA sequencing identified EWSR1::CREM fusion in 2 cases and EWSR1::ATF1 fusion in 1 case. Subsequent fluorescence in situ hybridization analysis confirmed the RNA sequencing results. On follow-up, 1 patient developed multiple spinal bone metastases 5 months after the surgery while the other 2 patients were free of disease 9 and 120 months after diagnosis, respectively. Our findings demonstrate that intra-abdominal epithelioid neoplasms with EWSR1::CREB fusions may rarely occur primarily in the kidney and should be included in the differential diagnosis of primary renal epithelioid mesenchymal neoplasms.

Numerous multinucleated giant cells in cutaneous epithelioid angiosarcoma and pulmonary metastasis: A unique observation with potential diagnostic pitfalls.

The histopathologic diagnosis of poorly differentiated cutaneous angiosarcoma can be challenging. We report a case of cutaneous epithelioid angiosarcoma with numerous multinucleated giant cells (MGCs) developing pulmonary metastasis. A 79-year-old man presented with a red-purple plaque on the scalp. A skin biopsy revealed epithelioid cell proliferation, admixed with numerous MGCs, and background hemorrhage. Vascular spaces were focally present and lined by atypical endothelial cells, including MGCs. Immunohistochemically, tumor cells, including MGCs, were positive for CD31, D2-40, and ERG. The patient received radiation therapy and chemotherapy, after which a follow-up CT scan revealed symptomless pneumothorax and pulmonary metastases. The patient received palliative partial lung resection, and the specimen revealed histopathological and immunohistochemical features similar to the primary cutaneous lesion. Our report expands the morphologic spectrum of cutaneous epithelioid angiosarcoma. Cutaneous angiosarcoma is an aggressive neoplasm; thus, awareness of this rare manifestation is important.

Primary gallbladder melanoma: A systematic review of literature.

Primary gallbladder melanoma (PGM) is a rare malignancy with only sporadic cases reported in the English literature. We performed a systematic review of the cases published in the PubMed, Science Direct and Google Scholar databases with the aim of describing the reported clinicopathologic features of PGM. Thirty-six articles reporting on 39 patients were reviewed. There was a male predominance, with 23 (64 %) of 36 patients being males. The mean age at presentation was 55 ±16 years. Pain in the right upper quadrant was reported in 20/27 (74 %). The average size of the tumor was 3.5 × 1.9 × 1.4 cm. Gallbladder calculi were reported in 7/27 (26 %). A cholecystectomy was performed in 34/38 (89.5 %). Grossly, the tumor mostly (96.5 %) had polypoid appearances and on microscopic examination, the tumor were predominantly comprised of epithelioid cells 12/17 (70.6 %). Mitotic figures and prominent nucleoli were reportedly found in 8/8 (100 %) and 3/3 (100 %) respectively. Junctional melanocytic components were present in 13/21 (61.9 %). Tumor cells were reportedly immunoreactive for S-100 and HMB-45 in all tested cases. Metastasis were reported in 25/36 (69.4 %), with lymph nodes being the most common site (n = 8), followed by brain (n = 6) and liver (n = 4) for metastasis. At a mean follow-up period of 19 +/- 3 months, 16 (48.5 %) of the 33 patients with available survival data were alive and 17/33 (51.5 %) were dead of disease. There is a lack of unified criteria for the diagnosis of PGM, and future studies should aim to resolve this.

A rare case of primary cutaneous malignant perivascular epithelioid cell tumor and review of the literature.

A 77-year-old female presented with a 6-month history of a 2-cm pink exophytic tumor on the right anterior shin, which had grown rapidly and began to bleed over the last 4 weeks. A shave biopsy showed a dermal proliferation of epithelioid spindled cells, arranged in nests and trabeculae associated with thin-walled capillary vessels. The cells showed pleomorphic nuclei with vacuolated nuclear chromatin and occasional prominent nucleoli. Mitotic figures (7/10 high-power fields [HPFs]), including atypical forms, were present in the specimen. Immunohistochemical staining was negative for SOX10 and stained positive for MiTF. The histopathologic findings were consistent with a malignant perivascular epithelioid cell tumor (PEComa). A malignant PEComa is a rare entity of mesenchymal-derived cells with both melanocytic and myocytic differentiation. A PEComa is considered to be malignant by fulfilling two of the following criteria: size greater than 5 cm, vascular invasion, necrosis, mitotic figures greater than 1 per 50 HPF, infiltrative growth pattern, high nuclear grade, and hypercellularity. PEComas show immunohistochemical positivity to myocytic markers such as SMA, pan-muscle actin, muscle myosin, calponin, and h-caldesmon as well as melanocytic markers such as HMB-45, Melan-A, tyrosinase, and MiTF.

Undifferentiated sarcoma of bone with a round to epithelioid cell phenotype harboring a novel EWSR1-SSX2 fusion identified by RNA-based next-generation sequencing.

Due to the increased application of RNA-based next-generation sequencing techniques on bone and soft tissue round cell sarcomas new fusions are frequently found, thereby expanding the molecular landscape of these tumors. In this report, we describe and discuss the finding of an undifferentiated sarcoma of the bone with a round to epithelioid cell phenotype harboring a novel EWSR1-SSX2 fusion. Treatment of this new bone tumor entity according to the Euro Ewing 2012 protocol led to complete pathologic response.

Expanding the spectrum of mesenchymal neoplasms with NR1D1-rearrangement.

Undifferentiated mesenchymal neoplasms can be morphologically subclassified based on cell shape; epithelioid tumors may be diagnostically challenging, particularly since they can show morphologic and immunohistochemical overlap with epithelial neoplasms. Following the recent report of an NR1D1::MAML1 gene fusion in an undifferentiated pediatric neoplasm, we performed a retrospective archival review and identified four additional cases of undifferentiated mesenchymal neoplasms with NR1D1-rearrangement. All four tumors occurred in adult women. The tumors involved superficial and/or deep soft tissues of the extremities or abdomen. Morphologically, they showed a spectrum of overlapping features. In addition to epithelioid cells, two cases also had a prominent spindle cell component. Two cases also had admixed polygonal cells containing prominent cytoplasmic vacuoles with amorphous debris. The immunophenotype was nonspecific but all cases had at least focal keratin expression; this was extensive in two tumors. Targeted RNA-sequencing revealed two cases each with NR1D1::MAML1 and NR1D1::MAML2 gene fusions. One patient developed lung and liver metastases, and one patient required amputation due to multifocal disease and underlying bone involvement. This study confirms undifferentiated NR1D1-rearranged sarcoma represents a distinct mesenchymal neoplasm with an epithelioid morphology and potential for aggressive behavior. Further, we offer new insight into the spectrum of clinical, morphologic, immunohistochemical, and molecular findings possible in these rare neoplasms. An awareness of this entity is especially important given the potential for misclassification as a carcinoma.

Malignant Pigmented Epithelioid Angiomyolipoma of the Kidney in a Child with Tuberous Sclerosis Complex.

INTRODUCTION: Pigmented epithelioid angiomyolipoma is a variant of epithelioid angiomyolipoma (EAML) that has not previously been described in children with tuberous sclerosis. CASE PRESENTATION: A 15-year-old boy with tuberous sclerosis had a rapidly enlarging renal mass associated with a left lung nodule. Microscopically it was a pigmented EAML, confirmed by immunohistochemistry. DISCUSSION/CONCLUSION: The pigmented variant of EAML can arise and metastasize from the kidney of a teenager with tuberous sclerosis.

Trends of lymph node sampling and metastasis in pediatric and young adult patients with clear cell, epithelioid, and synovial sarcomas.

BACKGROUND: Clear cell sarcoma of soft tissue (CCS), epithelioid sarcoma, and synovial sarcoma are rare tumors historically identified as high risk for lymph node metastasis. This study investigates incident nodal metastasis and associated survival in children and young adults with these subtypes. PROCEDURE: Using the National Cancer Database (2004-2015), we created a retrospective cohort of 1303 patients (aged ≤25 years) who underwent local control therapy for CCS, epithelioid sarcoma, and synovial sarcoma. Kaplan-Meier curves estimated overall survival (OS) by subtype. Stratifying on subtype, Cox regressions assessed OS by lymph node sampling status and nodal metastasis. RESULTS: There were 103 (7.9%) patients with CCS, 221 (17.0%) with epithelioid sarcoma, and 979 (75.1%) with synovial sarcoma. Lymph node sampling was more frequent in patients with CCS (56.3%) and epithelioid sarcoma (52.5%) versus synovial sarcoma (20.5%, p < .001). Synovial sarcoma metastasized to lymph nodes less frequently than CCS or epithelioid sarcoma (2.1% vs. 14.6% and 14.9%, p < .001). Across all subtypes, lymph node metastasis was associated with inferior OS (HR 2.02, CI 1.38-2.95, p < .001). Lymph node sampling was associated with improved OS in CCS (HR 0.35, CI: 0.15-0.78, p = .010), inferior OS in synovial sarcoma (HR 1.60, CI: 1.13-2.25, p = .007), and no statistical association with OS in epithelioid sarcoma. CONCLUSIONS: Lymph node metastasis is rare in children and young adults with synovial sarcoma. Lymph node sampling procedures were not consistently performed for patients with CCS or epithelioid sarcoma, but improved OS supports routine lymph node sampling in children and young adults with CCS.

Uterine PEComatosis With TSC1 Mutation in a Patient With Tuberous Sclerosis: Case Report and Literature Review.

Uterine PEComatosis is a rare phenomenon characterized by the presence of multiple perivascular epithelioid cell tumors (PEComas) and/or microscopic proliferations of perivascular epithelioid cells. Herein, we report a case of PEComatosis arising in a 49-yr-old woman with a known history of tuberous sclerosis. Targeted next-generation sequencing revealed a TSC1 stopgain mutation (p.Q732X) in all tested nodules, with single-copy TSC1 loss or copy-neutral TSC1 loss of heterozygosity. To our knowledge, this is the second report of TSC1 inactivation in uterine PEComa and the first report of confirmed TSC1 abnormalities in PEComatosis.

Epithelioid hemangioma involving large arteries in the skin.

Epithelioid hemangioma (EH) is a benign vascular lesion, typically consisting of small vascular channels lined by epithelioid endothelial cells and associated with a dense lymphocytic infiltrate with eosinophils. Here, we report a rare case of EH involving large arteries. The patient presented with a 9-month history of an asymptomatic nodule on the forehead, which was thought to be an epidermal inclusion cyst. Skin biopsy revealed large arteries with clusters of epithelioid cells in the vascular walls and lumen. Scattered eosinophils were noted in the walls. Adjacent areas showed groups of small-caliber vessels lined by prominent endothelial cells and associated with a dense lymphoid infiltrate with eosinophils. No significant cytologic atypia was noted. Given the presence of the classic small-vessel involvement, along with CD31 reactivity for the epithelioid cells in the large vessels, the findings are classified as EH involving large arteries, which is an uncommon subtype. There have only been a handful of such cases reported in the literature.

Primary cutaneous epithelioid mesenchymal neoplasm with ACTB-GLI1 fusion: a case report.

Mesenchymal tumors harboring GLI1 gene abnormalities are a rare but distinctive group of neoplasms whose clinicopathologic features are currently evolving. In particular, examples of this tumor with ACTB-GLI1 gene fusion, tentatively termed ACTB-GLI1 epithelioid mesenchymal neoplasm (EMN), show a distinctive monomorphic round-to-epithelioid morphology, nested to trabecular pattern of growth, and S100+/SOX10-/SMA- immunophenotype. We report the first case of this entity arising exclusively in the skin. A 69-year-old man with no prior history of neoplasia presented with a 1.5-cm raised lesion on the left buttock. Histopathologic examination revealed a diffuse dermal proliferation of small, monomorphic, round-to-ovoid cells with hyperchromatic nuclei, focally enlarged nucleoli, and minimal eosinophilic to clear-staining cytoplasm. These cells were arranged in confluent nests and trabeculae in a background of fibrocollagenous to focally myxoid stroma. Immunohistochemical analysis revealed strong positivity for S100 and CD56, and negativity for SOX-10, SMA, Melan-A, HMB-45, and a variety of other markers. Based on the morphology and immunophenotype, molecular studies were performed, which revealed the presence of an ACTB-GLI1 fusion transcript, confirming the diagnosis. Given the morphologic overlap of this tumor with other cutaneous round cell neoplasms and its potential for malignant behavior, ACTB-GLI1 EMN is an important entity for pathologists to recognize.

♣Evaluation of clinicopathological profiles and development of a risk model in renal epithelioid angiomyolipoma patients: a large-scale retrospective cohort study.

BACKGROUND: To identify the malignant potential and prognostic indicators of renal epithelioid angiomyolipoma (eAML), clinicopathological and molecular features as well as the drug efficacy of 67 eAML cases were analyzed. MATERIALS AND METHODS: Sixty-seven renal eAML patients were enrolled and the immunohistochemical features of these patients were examined. FFPE slides of all patients were re-examined. 21 patients with metastasis received Everolimus 10 mg orally once daily. Responses were evaluated with RECIST criteria by three authors. A risk stratification model was constructed using the following factors: pT3 and pT4, presence of necrosis, mitotic count ≥ 2; the presence of atypical mitoses; severe nuclear atypia, SMA negative, Ki-67 ≥ 10%. RESULTS: The average percentage of the epithelioid component was 85.6% (range 80-95%). Immunohistochemically, Ki-67 ≥ 10% and negative SMA staining were significantly correlated with malignant characteristics (Ki-67: p < 0.001; SMA: p = 0.001). Survival analysis suggested that pT3-pT4 stage, presence of necrosis, severe nuclear atypia, presence of atypical mitoses, mitotic count ≥ 2, Ki-67 ≥ 10% and negative SMA expression were significantly associated with poorer PFS and OS (p < 0.05). The risk model sufficiently discriminated recurrence/metastasis (AUC = 0.897) and cancer-specific mortality (AUC = 0.932) of renal eAML patients in different risk groups. 21 patients had received Everolimus targeted therapy after recurrence/metastasis. The best response for Everolimus treatment was 8/21 (38.1%) partial responses (PR), 9/21 (42.9%) stable disease (SD) and 4/21 (19.0%) progressive disease (PD). CONCLUSION: The risk stratification model could well distinguish eAML patients at high risk of recurrence/metastasis. Everolimus targeted treatment showed good efficacy in patients with recurrence/metastasis.

Snot what you think: Mucus or myxoid matrix with epithelioid cells and bubbly cytoplasm?

A case of progressive nasal obstruction in a 63 year old man is described. FNA cytology yielded dominant myxoid matrix with charateristic epithelioid cells, round nuclei with nucleoli, and eosinophilic, granular or vacuolated cytoplasm to allow a diagnosis tto be made.

Superficial CD34-positive fibroblastic tumor (SCPFT): A review of pathological and clinical features.

Superficial CD34-positive fibroblastic tumor (SCPFT) is a recently described rare mesenchymal tumor of borderline malignancy. It generally involves superficial soft tissue, with a predilection to the lower extremities. Microscopically this tumor is characterized by a fascicular and storiform growth pattern, spindled to epithelioid cells, nuclear atypia with pleomorphism, and eosinophilic granular, and fibrillar to glassy cytoplasm. Strong diffuse immunoreactivity for CD34 is very characteristic of this entity. Due to under-recognition, this tumor is generally underreported. Additionally, cases of recurrence are rarely reported in the literature. We will comprehensively review the English language literature on all reported cases of SCPFT, with emphasis on recurrence.

Hyalinizing epithelioid tumors with OGT-FOXO fusions. A case report of a non-acral soft tissue mass harboring a novel FOXO4 gene rearrangement.

Recurrent fusions between OGT and members of the Forkhead box (FOXO) family of genes have been recently described in three cases of hyalinizing epithelioid acral soft tissue tumors in young adults showing co-expression for EMA and CD34. Despite the lack of an established myoepithelial lineage by immunohistochemistry, these lesions have been labeled as myoepithelioma-like due to their epithelioid phenotype and sclerotic background. In this study, we report a novel FOXO4-OGT fusion identified by targeted RNA sequencing in an unclassified shoulder soft tissue mass in a 40-year-old male. The tumor showed nodular foci of increased cellularity in a uniformly hyalinized background. The neoplastic cells were mainly epithelioid and focally spindled, with eosinophilic cytoplasm and indented nuclei with mild atypia. The tumor lacked significant mitotic activity and necrosis. Immunohistochemically, the tumor showed variable positivity for EMA, pan-CK, CD34, ERG and FLI1, while it was negative for CD31, S100, SOX10, desmin, and MUC4. INI1 expression was retained. Due to its unusual histology and conflicting immunoprofile, TruSight RNA fusion panel sequencing was performed which revealed a fusion between FOXO4 exon 2 to OGT exon 2. This is the first example of a soft tissue lesion harboring OGT-related fusions occurring in a non-acral location and associated with FOXO4 gene. Its line of differentiation and biologic potential remain uncertain.

A unique epithelioid vascular neoplasm of bone characterized by EWSR1/FUS-NFATC1/2 fusions.

An increasing number of epithelioid vascular lesions, in particular tumors from the benign and low-grade end of the spectrum, have been characterized by recurrent gene fusions. As a result, the detection of these molecular markers have improved the classification of diagnostically challenging cases. However, despite the significant progress, there are occasional lesions that do not fit in known histologic or molecular groups. Herein, we present five such unclassified epithelioid vascular lesions, which occurred in the bone and showed a distinct morphology composed of alternating vasoformative and solid growth and mild to moderate nuclear pleomorphism. The variegated morphologic appearance resembled that of composite hemangioendothelioma, being distinct from both epithelioid hemangioma and epithelioid hemangioendothelioma, and consistently showed cytologic atypia. Due to their unusual morphologic appearance and negative molecular work-up, targeted transcriptome sequencing was performed in two cases showing the presence of NFATC2 fusions with either EWSR1 or FUS genes. Three additional bone tumors with EWSR1 gene rearrangements were identified by FISH screening of a large cohort of 45 fusion-negative epithelioid vascular neoplasms, one fused to NFATC2 while two others to NFATC1. There were three females and two males, with a wide age range at presentation, mean of 44 years. The lesions occurred in the pelvis, maxillary sinus, and humerus. Two patients presented with polyostotic disease, both located in the pelvic bones. Two patients had available follow-up, one developed two local recurrences in the humerus over a 15-year period, while the other showed no recurrence 4 years subsequent to an en-bloc resection. Tumors were positive for CD31 and ERG, while negative for EMA, CK, synaptophysin, and chromogranin. FISH confirmed this abnormality in all cases, none of them being associated with gene amplifications. Further studies are needed to establish the pathogenetic relationship of this rare molecular subset with other epithelioid vascular tumors and to determine its clinical behavior.

Micronodular PEComas of the appendix.

AIMS: Perivascular epithelioid cell tumours (PEComas) of the appendix have been reported very rarely. In this study, we describe three cases of a distinctive micronodular proliferation in the appendix consistent with a variant of PEComa. Although known as 'granular degeneration of smooth muscle' in prior reports, we reappraise its clinicopathological, immunohistochemical and ultrastructural features which support a change in classification. METHODS AND RESULTS: Patients were two females (aged 33 and 41 years) and one male (aged 41). None had a history of tuberous sclerosis. Histologically, each case demonstrated a multifocal nodular proliferation towards the distal tip of the appendix, composed of epithelioid cells with abundant granular eosinophilic to clear cytoplasm. By immunohistochemistry, the lesional cells were positive for muscle markers [smooth muscle actin (SMA) and desmin], melanocytic markers (HMB45, melan A), cathepsin K and the lysosomal marker NKI-C3 in each case. MITF was positive in two of three cases. None expressed S100 protein. Electron microscopy in one case revealed striated electron-dense structures consistent with pre-melanosomes. Follow-up, available in one case, showed no recurrence at 5 years. CONCLUSIONS: We propose the term 'micronodular PEComa' for this appendiceal lesion to reflect more accurately its histological and immunohistochemical characteristics, which include consistent positivity for both muscle and melanocytic markers. Micronodular PEComa seems to follow an indolent course, consistent with its uniformly low-grade histological features, and appears to be unassociated with tuberous sclerosis.

Primary sclerosing epithelioid fibrosarcoma of the spine: a single-institution experience.

AIMS: To present our experience on spinal sclerosing epithelioid fibrosarcoma (SEF) and review the existing literature pertaining to SEF of the spine. METHODS AND RESULTS: Six cases of spinal SEF were reviewed, and a literature search of all primary SEFs of the spine was performed. All tumours occurred in adults (median age, 41 years) and were located all along the spine, the lumbar vertebrae being the most commonly involved. All patients presented with pain that they had experienced for months. The mean tumour size at diagnosis was 52 mm. Five tumours showed a spectrum of microscopic features consistent with pure SEF, and one showed a hybrid morphology with areas of low-grade fibromyxoid sarcoma. All were diffusely and strongly positive for mucin 4. Two cases were initially misdiagnosed as epithelioid haemangioendothelioma and aggressive chondroblastoma. Fluorescence in-situ hybridisation showed rearrangements of either FUS or EWSR1 in four cases. Reverse transcription polymerase chain reaction showed the presence of FUS-CREB3L1 and EWSR1-CREB3L1 fusion transcripts in two cases and one case, respectively. Of five patients with follow-up data available, two developed one or more local recurrences and three patients had metastatic disease. Distant metastases were mainly to other osseous locations, followed by lungs and lymph nodes. At last follow-up, three patients had died of disease and one was alive with multiple metastases. CONCLUSIONS: SEF is an aggressive sarcoma that can involve the spine. It is important to recognise the spine as the primary location of SEF, in order to avoid misdiagnosis as more common primary spinal neoplasms, which can impact on therapeutic approaches.

Uterine plexiform tumourlets: multifocal and solitary cases with subsets expressing melanocytic markers.

AIMS: Uterine plexiform tumourlets are traditionally regarded as microscopic epithelioid leiomyomas. They are typically solitary incidental findings, but may be multifocal (plexiform leiomyomatosis). We aim to report novel immunohistochemical and morphological findings, specifically the presence of spindled and epithelioid cell nodules, in these lesions. METHODS AND RESULTS: Three cases of plexiform leiomyomatosis and 16 solitary plexiform tumourlets were included. Two cases of plexiform leiomyomatosis and four solitary plexiform tumourlets demonstrated spindled and epithelioid cell nodules which, in one of the former cases, formed expansile masses up to 15 mm. The nodules demonstrated mild cytological atypia and occasional mitotic activity, and they were associated with a myxoid stroma and a lymphohistiocytic infiltrate which imparted a granulomatous appearance to the microscopic lesions. The plexiform tumourlets (solitary and multifocal) consistently expressed desmin, smooth muscle actin, ER and PR, and they commonly co-expressed melanocytic and perivascular epithelioid cell (PEC) markers HMB45, MiTF and cathepsin K. The spindled and epithelioid cell nodules were generally negative for myoid markers and hormone receptors, but expressed p16, cyclin D1 and TFE3. All lesions tested were negative for cytokeratin, S100, melanA, inhibin, EMA, ALK and BCOR; fluorescence in-situ hybridisation was negative for ALK, TFE3 and BCOR rearrangements in one of the larger spindled and epithelioid cell nodules. CONCLUSIONS: Plexiform tumourlets commonly co-express myoid and melanocytic markers and may represent part of the spectrum of gynaecological PEC-related lesions. Some cases are associated with spindled and epithelioid cell nodules that could potentially mimic other uterine myxoid neoplasms.