Recurrent KAT6B/A::KANSL1 Fusions Characterize a Potentially Aggressive Uterine Sarcoma Morphologically Overlapping With Low-grade Endometrial Stromal Sarcoma.

With the widespread application of next-generation sequencing, the genetic landscape of uterine mesenchymal neoplasms has been evolving rapidly to include several recently identified fusion genes. Although chromosomal rearrangements involving the 10q22 and 17q21.31 loci have been reported in occasional uterine leiomyomas decades ago, the corresponding KAT6B::KANSL1 fusion has been only recently identified in 2 uterine tumors diagnosed as leiomyoma and leiomyosarcoma. We herein describe 13 uterine stromal neoplasms carrying a KAT6B::KANSL1 (n=11) and KAT6A::KANSL1 (n=2) fusion. Patient ages ranged from 33 to 81 years (median, 49 y). Tumor size was 2.6 to 23.5 cm (median, 8.2 cm). Nine tumors were myometrium-centered, and 3 had an intracavitary component. Original diagnoses were mostly low-grade endometrial stromal sarcoma (LG-ESS; 10 cases) with atypical features (limited CD10 expression, sex cord-like features, pericytic vasculature, and frequent myxoid changes). Treatment was hysterectomy±bilateral salpingo-oophorectomy (10), myomectomy (1), and curettage (2). Five patients were disease-free at 6 to 34 months, 3 (27%) died of disease at 2 to 47 months, and 3 were alive with disease at 2, 17, and 17 years. Histologically, most tumors showed variable overlap with LG-ESS, but they were generally well-circumscribed lacking the extensive permeative and angioinvasive growth typical of LG-ESS. They were composed of monotonous medium-sized oval and spindle cells arranged into diffuse sheets with prominent spiral-type arterioles and frequent pericytoma-like vascular pattern. Variable myxoid stromal changes were frequent. Mitotic activity ranged from 1 to >20 in 10 HPFs. Immunohistochemistry showed variable expression of CD10 (12/13), estrogen receptor (8/11), progesterone receptor (8/11), smooth muscle actin (9/11), desmin (4/12), h-caldesmon (2/10), calretinin (3/8), inhibin (1/7), WT1 (4/7), cyclin D1 (5/11; diffuse in only 1 case), and pankeratin (5/10). This series characterizes a KAT6B/A::KANSL1 fusion-positive uterine stromal neoplasm within the morphologic spectrum of LG-ESS but with atypical features. The relationship of these neoplasms to genuine LG-ESS remains unclear. This molecular subtype of uterine endometrial stromal sarcoma has the potential for an unfavorable clinical course despite the absence of widely invasive growth; nevertheless, analysis of more cases is necessary to delineate the phenotypic spectrum and biological potential of this tumor.

Intravascular adenomyomatosis: a morphologic variant of intravenous leiomyomatosis associated with endometriosis and potential for misdiagnosis.

Intravenous leiomyomatosis (IVL) is a quasi-malignant smooth muscle tumor involving lymphatic and venous spaces of the myometrium. Rare cases of IVL with admixed endometrial glands and stroma have been described, termed intravascular adenomyomatosis. We report four additional cases of intravascular adenomyomatosis and expand the clinicopathologic features of these rare tumors. Patients were 39-45 years old and presented with symptoms of dysmenorrhea, postmenopausal bleeding, or pelvic mass. All cases were associated with endometriosis. Three cases comprised intravascular bland smooth muscle tumors with plexiform features, and in some foci, the intravascular tumor contained endometrial type glands and stroma. In one case, there was extensive (>10) foci of intravascular adenomyomatosis without evidence of associated smooth muscle neoplasm but did have an endometrial polyp with adenomyomatous features. None of the cases had nuclear atypia, increased mitotic activity, or tumor cell necrosis. The endometrial stromal components were positive for CD10 and negative or weakly positive for desmin by immunohistochemistry. Two cases underwent molecular testing for JAZF1 and PHF1 rearrangements with negative results. Three patients had no evidence of disease at the time of the last follow-up, and one had persistent but stable disease 7 years after incomplete surgical removal and megestrol acetate treatment. Intravascular adenomyomatosis is a variant morphology rarely seen in IVL that lacks characteristic morphologic and molecular features of endometrial stromal sarcoma. Similar to IVL, prognosis is likely linked to completeness of surgical resection. In this study, we found that intravascular adenomyomatosis is frequently associated with endometriosis, a novel finding to add to the literature on this rare IVL variant.

PGR Gene Fusions Identify a Molecular Subset of Uterine Epithelioid Leiomyosarcoma With Rhabdoid Features.

Genetic aberrations among uterine epithelioid leiomyosarcomas are unknown. Following identification of an index case with NR4A3-PGR fusion demonstrating monomorphic morphologic features, we interrogated additional uterine tumors demonstrating similar histology and sought to describe the morphologic and immunohistochemical characteristics of PGR-rearranged sarcomas. Targeted next-generation RNA sequencing was performed on RNA extracted from formalin-fixed paraffin-embedded tissue of the index case. Fluorescence in situ hybridization using custom probes flanking PGR and NR4A3 genes was applied to 17 epithelioid leiomyosarcomas, 6 endometrial stromal tumors, and 3 perivascular epithelioid cell tumors. NR4A3-PGR fusion (n=4) and PGR rearrangement (n=2) were detected in 6 (35%) epithelioid leiomyosarcomas. Median patient age was 45 years, and all presented with FIGO stage I or II tumors, 2 being alive with disease at 75 and 180 months. All tumors were centered in the cervical stroma or myometrium and consisted of cells with abundant eosinophilic cytoplasm (epithelioid), including many displaying dense intracytoplasmic inclusions (rhabdoid). Myxoid matrix and hydropic change imparted a microcystic growth pattern in 4 tumors. Five also showed a minor spindle cell component which was low-grade in 3, consisting of bland spindle cells with low mitotic activity. High-grade spindle cell morphology was seen in 2 tumors, exhibiting a storiform pattern of atypical spindle cells associated with brisk mitotic activity. Desmin, estrogen receptor, and progesterone receptor were positive in all 6 tumors, while CD10 and HMB45 were negative. PGR rearrangements define a genetic subset of epithelioid leiomyosarcomas with often biphasic morphology consisting of epithelioid and rhabdoid as well as spindle cell components.

Undifferentiated Uterine Sarcomas Represent Under-Recognized High-grade Endometrial Stromal Sarcomas.

Undifferentiated uterine sarcoma is a diagnosis of exclusion with limited molecular genetic data available. Recent recognition of high-grade endometrial stromal sarcomas with diverse genotypes suggests that some tumors classified as undifferentiated uterine sarcomas may represent misdiagnosed high-grade endometrial stromal sarcomas. Archival material from 10 tumors diagnosed as undifferentiated uterine sarcomas in 2009 to 2017 were collected. BCOR immunohistochemistry and fluorescence in situ hybridization (FISH) using break-apart probes flanking BCOR, ZC3H7B, CCNB3, YWHAE, NUTM2, JAZF1, and BCORL1 were performed. Tumors lacking or harboring gene rearrangement with no known fusion partner by FISH were subjected to targeted RNA sequencing. Morphology was correlated with FISH and sequencing results. BCOR expression was moderate to strong in ≥50% of cells in 8 tumors, while weak in <5% cells and negative in 2. FISH detected mutually exclusive ZC3H7B-BCOR and YWHAE-NUTM2 fusions in 3 uniform undifferentiated uterine sarcomas; 2 pleomorphic tumors harbored YWHAE rearrangement with no known partner. Targeted RNA sequencing of 5 FISH-negative uniform undifferentiated uterine sarcomas detected BRD8-PHF1 and YWHAE-NUTM2B fusions and BCOR internal tandem duplication in 4 of them. Tumors with YWHAE-NUTM2 fusions and BCOR genetic abnormalities showed morphology characteristic of high-grade endometrial stromal sarcomas. No fusions were detected by sequencing in the tumor with YWHAE rearrangement only by FISH. Most tumors classified as undifferentiated uterine sarcomas represent misdiagnosed high-grade endometrial stromal sarcomas. BCOR expression in ≥50% of cells may help triage tumors for molecular confirmation of high-grade endometrial stromal sarcoma-related genetic abnormalities. Novel YWHAE rearrangements may define a subset of true undifferentiated pleomorphic sarcomas.

Low-grade Endometrioid Stromal Sarcoma of the Paratestis: A Novel Report With Molecular Confirmation of JAZF1/SUZ12 Translocation.

Tumors with Müllerian-like serous or mucinous phenotypes originating in the testis and its adnexa are rare neoplasms that have been increasingly recognized in recent years. Cystadenomas with or without ovarian-type stroma, borderline tumors, and adenocarcinomas are the main documented types. Although a handful cases of putative endometrioid adenocarcinomas have been reported, to our knowledge no case of endometrial stromal-type neoplasm has ever been reported in the literature. A 59-year-old man presented with a 2 cm left intrascrotal mass that was found on sonographic examination to arise from the epididymal tail with prominent vascularization. He was otherwise healthy without significant clinical history, endocrinopathy, or external hormone therapy. His testicular tumor markers (beta-HCG, AFP) were normal. Histologic examination of the resection showed a multinodular tumor closely associated with the epididymis and composed of monotonous rounded to ovoid cells with scanty cytoplasm and prominent spiral-like arterioles and capillaries. Mitotic activity was high. No other tumor component was seen. Immunohistochemistry revealed strong and diffuse expression of vimentin, CD10, estrogen receptor, and progesterone receptor. Molecular examination (performed on paraffin-embedded tumor tissue using a 517 gene fusion next-generation sequencing assay) showed a JAZF1/SUZ12 translocation, which was then confirmed by fluorescence in situ hybridization (FISH). These findings are consistent with a low-grade endometrioid stromal sarcoma originating in the paratestis. This report represents a novel addition to the growing spectrum of Müllerian-analog testicular adnexal neoplasms.

BCOR Internal Tandem Duplication in High-grade Uterine Sarcomas.

Endometrial stromal sarcomas (ESSs) are mesenchymal uterine tumors characterized by recurrent genetic events, most commonly chromosomal rearrangements, that create oncogenic gene fusions. High-grade endometrial stromal sarcomas (HG-ESSs), as defined in the 2014 World Health Organization Classification, typically contain oncogenic YWHAE-NUTM2 fusions; however, although not well characterized, there are tumors morphologically overlapping with HG-ESS that do not contain the YWHAE-NUTM2 fusions. These fusions are also found in certain pediatric primitive sarcomas, including clear cell sarcoma of the kidney and soft tissue undifferentiated round cell sarcoma of infancy. A subset of these same pediatric sarcomas lack YWHAE-NUTM2 fusions and instead have internal tandem duplications (ITDs) involving exon 15 of BCOR (BCOR ITD). We investigated the presence of BCOR ITD by targeted sequencing in a series of 31 uterine sarcomas, comprising 5 low-grade ESS, 13 uterine sarcomas diagnosed as HG-ESS, and 13 undifferentiated uterine sarcomas. BCOR ITD were present in 1 uterine sarcoma diagnosed as HG-ESS and 2 undifferentiated sarcomas with uniform nuclear features, all of which lacked any of the recurrent chromosome translocations known to occur in ESS. These 3 high-grade sarcomas with BCOR ITD affected young patients (average age, 24) and morphologically were composed of nonpleomorphic spindle cells admixed with epithelioid and round cell areas. Focal myxoid stroma was present in 2 cases. Mitotic activity was brisk, necrosis was present, and there was lymphovascular involvement in all cases. The 3 uterine sarcomas with BCOR ITD exhibited diffuse cyclin D1 immunohistochemical expression and there was diffuse BCOR expression in the 2 cases tested. Long-term follow-up in 2 patients revealed 1 to be tumor-free after 22 years and the other to die of disease after 8 years. In conclusion, BCOR ITD is an oncogenic alternative to YWHAE-NUTM2 fusion in high-grade uterine sarcomas with uniform nuclear features. We propose that neoplasms with the morphology described and BCOR ITD be regarded as a unique subtype of high-grade uterine sarcoma, possibly within the family of endometrial stromal neoplasia.

Myxoid Mesenchymal Tumors of the Uterus: An Update on Classification, Definitions, and Differential Diagnosis.

Tumors with a predominant myxoid stroma are rare in the uterus. When encountered, however, they pose a diagnostic challenge. Traditionally myxoid leiomyosarcoma has been the most important consideration in this category, given its adverse prognosis and deceptively bland morphology. Conventional features of malignancy are variably present; in contrast, an infiltrative tumor border is a consistent pathologic characteristic. More recently, previously under-recognized lesions have been identified, in part due to our growing knowledge of their underlying molecular alterations: uterine inflammatory myofibroblastic tumor frequently harbors ALK rearrangements and a novel ZC3H7B-BCOR gene fusion has been described in a subset of myxoid high-grade endometrial stromal sarcomas. These tumors need to be distinguished from myxoid leiomyosarcoma, as by comparison have a less aggressive course and are amenable to targeted treatments. In addition, uterine mesenchymal tumors with malignant potential need to be distinguished from benign tumors and epithelial and mixed malignancies. This review aims to discuss our current understanding of the most common uterine myxoid neoplasms: their clinical features, their distinguishing histopathologic, immunohistochemical, and molecular features and the clues and pitfalls in their diagnosis.

BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology.

Recognition of high-grade endometrial stromal sarcoma is important because of its aggressive clinical behavior. Morphologic features of YWHAE-NUTM2 high-grade endometrial stromal sarcoma may overlap with other uterine sarcoma types. BCOR immunoexpression was studied in these tumors and their morphologic mimics to assess its diagnostic utility. BCOR immunohistochemical staining was performed on archival tissue from 28 high-grade endometrial stromal sarcomas with classic morphology (20 YWHAE-NUTM2, 5 ZC3H7B-BCOR, 3 BCOR-ZC3H7B), 3 high-grade endometrial stromal sarcomas with unusual morphology and unknown gene rearrangement status, 66 low-grade endometrial stromal sarcomas, 21 endometrial stromal nodules, 38 uterine leiomyosarcomas, and 19 uterine leiomyomas. Intensity of nuclear staining and percentage of positive tumor cells were recorded. Strong diffuse nuclear BCOR staining (defined as >95% of tumor cells) was seen in the round cell component of all 20 (100%) classic YWHAE-NUTM2 high-grade endometrial stromal sarcomas and the 3 unusual high-grade endometrial stromal sarcomas which prompted FISH studies confirming YWHAE rearrangement in 2 tumors. Genomic PCR confirmed the presence of BCOR exon 16 internal tandem duplication in the third case. Diffuse BCOR staining was strong in three and weak in one BCOR-rearranged high-grade endometrial stromal sarcoma while absent in the remaining four BCOR-rearranged tumors. BCOR staining was weakly positive in <5% of tumor cells in 4 of 66 (6%) low-grade endometrial stromal sarcomas and 1 of 18 (6%) endometrial stromal nodules and weakly to moderately positive in <5-40% of tumor cells in 6 of 31 (19%) leiomyosarcomas. No BCOR staining was seen in the remaining low-grade endometrial stromal sarcomas, endometrial stromal nodules, leiomyosarcomas, or any of the leiomyomas. BCOR immunohistochemical staining is a highly sensitive marker for YWHAE-NUTM2 high-grade endometrial stromal sarcoma with both classic and unusual morphology and identifies a subset of high-grade endometrial stromal sarcoma with BCOR alterations, including BCOR rearrangement and internal tandem duplication.

Primary extragenital endometrial stromal sarcoma of the lung: first reported case and review of literature.

BACKGROUND: Endometrial stromal sarcomas arising in extrauterine and extraovarian sites, in the absence of a primary uterine lesion are quite rare, especially in the absence of endometriosis. They usually present as an abdominal or pelvic mass lesion. CASE PRESENTATION: In 2007, a 45-year-old woman underwent total hysterectomy for in situ squamous cell carcinoma of the cervix. In 2014, an upper left pulmonary lobectomy was performed for a mass, which was provisionally diagnosed as primary carcinosarcoma of the lung. A second histological revision of the lung surgical specimen was performed in the Pathology Unit of our Institute. After extensive immunohistochemical analyses, the preferred diagnosis was spindle-cell sarcoma, consistent with high-grade extragenital endometrial stromal sarcoma (EESS). A review of all slides of the hysterectomy specimen confirms the original diagnosis: no evidence of stromal tumor was found. Afterwards, the patient developed multiple and metachronous pulmonary lesions and a scapular soft tissue mass, which showed the same morphophenotypic features of the first lung mass. The patient was treated with antiblastic therapy, surgical resection and radioablation, when appropriate. To date, the patient has no signs or symptoms. CONCLUSIONS: The authors present the first case of primary EESS arising in the lung with no association with endometriosis published to date. Detailed clinical history and follow-up are also described. Moreover, extensive literature review is reported, along with differential diagnoses, immunohistochemical and molecular findings, pathogenetic hypotheses and treatment options. The knowledge of EESS potential extrauterine location and of its peculiar morphophenotypic aspects are required for a correct diagnosis, and for choosing the most suitable treatment.

Endometrial stromal sarcoma with endometrioid adenocarcinoma of the uterus: a case report.

Endometrial stromal sarcoma (ESS) is a rare malignant neoplasm of the uterus. We report the first case of undifferentiated ESS (UES) coexistent with grade 1 endometrioid adenocarcinoma in a 73-year-old female who presented with irregular vaginal bleeding for 4 days after menopause 20 years. Imaging examination including Magnetic Resonance Imaging (MRI) demonstrated multi-node reflection in uterine cavity without metastatic lesions, and the endometrium essentially normal. Grossly, a grey-red breakable polypoid tumor of 4.5×3.0×2.0 cm was recognized in the posterior uterine wall with surrounding slight rough endometrium. Microscopically, the tumor was composed of a larger component of undifferentiated stromal sarcoma that was distinct from a smaller endometrioid adenocarcinoma. The separate components of the tumor could be supported in immunohistochemical studies. There was no sign of recurrence for postoperative 6 months.

SMARCA4 (BRG1) loss of expression is a useful marker for the diagnosis of ovarian small cell carcinoma of the hypercalcemic type (ovarian rhabdoid tumor): a comprehensive analysis of 116 rare gynecologic tumors, 9 soft tissue tumors, and 9 melanomas.

Ovarian small cell carcinoma of the hypercalcemic type (SCCOHT)/ovarian rhabdoid tumor is a rare and highly malignant tumor that typically occurs in young women. Up until now the diagnosis has been made on the basis of morphology without any specific immunohistochemical (IHC) markers. However, several authors have shown recently that SCCOHTs are characterized by inactivation of the SMARCA4 gene (encoding the BRG1 protein) resulting in a loss of BRG1 protein expression in IHC. We evaluated BRG1 and INI1 expression in 12 SCCOHTs and in a series of 122 tumors that could mimic SCCOHT morphologically: 9 juvenile granulosa cell tumors, 47 adult granulosa cell tumors, 33 high-grade ovarian serous carcinomas, 9 desmoplastic round cell tumors, 13 Ewing sarcomas (5 from the pelvis and 8 from soft tissues), 1 round cell sarcoma associated with CIC-DUX4 translocation from soft tissue (thigh), 1 case of high-grade endometrial stromal sarcoma of the ovary, and 9 melanomas. Forty-four adult granulosa cell tumors were interpretable by IHC. All 12 SCCOHTs were devoid of BRG1 expression and expressed INI1. All other interpretable 119 tumors showed BRG1 nuclear positivity, with variable staining proportions, ranging from 10% to 100% of positive cells (mean: 77%, median: 80%), variable intensities (weak: 5%, moderate: 37%, strong: 58%), and distributions: diffuse in 82 cases (70%) and heterogenous in 36 cases (30%). BRG1 positivity was heterogenous in desmoplastic round cell tumors and adult granulosa cell tumors. Overall, BRG1 is a useful diagnostic marker in SCCOHT, showing the absence of expression in SCCOHT. Nevertheless, the possible heterogeneity and the variable intensity of this staining warrant caution in the interpretation of BRG1 staining in biopsy specimens.

Fibromyxoid variant of endometrial stromal sarcoma with atypical bizarre nuclei.

Endometrial stromal sarcoma (ESS) is the second most common malignant uterine mesenchymal tumor. It affects women primarily in the perimenopausal age group. ESSs are morphologically heterogeneous. The distinction between uterine smooth muscle tumors such as cellular leiomyoma and myxoid leiomyosarcoma and low-grade ESS can be problematic when stromal sarcomas show prominent smooth muscle differentiation and abundant myxoid stroma, respectively. We herein present a rare case of fibromyxoid variant of ESS, which was misdiagnosed as hydropic leiomyoma on intraoperative frozen section examination. Grossly, the uterine mass consisted of intracavitary and intramural portions. The intracavitary portion with extensive hydropic degeneration mimicked a hydropic leiomyoma. In contrast, the intramural portion displayed an obvious tongue-like myometrial invasion. Histologically, the tumor consisted of both cellular (20%) and myxoid (80%) areas. In the cellular areas, oval to spindle-shaped tumor cells with bland nuclear features were found to surround concentrically a rich vascular network of arterioles, a characteristic of ESS. In addition, two relatively well-circumscribed nodular lesions showing atypical bizarre nuclei were identified in the myxoid area. Immunohistochemically, the tumor cells were diffusely and strongly positive for CD10. The present case indicates a wide morphological spectrum of ESS. Fibromyxoid variant of ESS should be considered in the differential diagnosis of intracavitary and/or intramural uterine mesenchymal tumors with myxoid differentiation. It is important to avoid confusion between fibromyxoid ESS and myxoid leiomyosarcoma because of the differences in their clinical course, treatment, and prognosis.

Endometrial stromal tumours revisited: an update based on the 2014 WHO classification.

Endometrial stromal tumours (EST) are rare tumours of endometrial stromal origin that account for less than 2% of all uterine tumours. Recent cytogenetic and molecular advances in this area have improved our understanding of ESTs and helped refine their classification into more meaningful categories. Accordingly, the newly released 2014 WHO classification system recognises four categories: endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS) and undifferentiated uterine sarcoma (UUS). At the molecular level, these tumours may demonstrate a relatively simple karyotype with a defining chromosomal rearrangement (as in the majority of ESNs, LGESSs and YWHAE-rearranged HGESS) or demonstrate complex cytogenetic aberrations lacking specific rearrangements (as in UUSs). Herein we provide an update on this topic aimed at the practicing pathologist.

Endometrial stromal tumors: the new WHO classification.

Endometrial stromal tumors are rare uterine mesenchymal neoplasms that have intrigued pathologists for years, not only because they commonly pose diagnostic dilemmas, but also because the classification and pathogenesis of these tumors has been widely debated. The current World Health Organization recognizes 4 categories of endometrial stromal tumor: endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS). uterine sarcoma. These categories are defined by the presence of distinct translocations as well as tumor morphology and prognosis. Specifically, the JAZF1-SUZ12 (formerly JAZF1-JJAZ1) fusion identifies a large proportion of ESN and LG-ESSs, whereas the YWHAE-FAM22 translocation identifies HG-ESSs. The latter tumors appear to have a prognosis intermediate between LG-ESS and UUS, which exhibits no specific translocation pattern. This review (1) presents the clinicopathologic features of endometrial stromal tumors; (2) discusses their immunophenotype; and (3) highlights the recent advances in molecular genetics which explain their pathogenesis and lend support for a new classification system.

Prognostic significance of steroid receptor positivity and adjuvant progestogen use in endometrial stromal sarcoma.

BACKGROUND: The prognostic significance of oestrogen and progesterone receptors (ER/PR) in endometrial stromal sarcoma (ESS) has conflicting reports in the literature, and the routine use of adjuvant progestogen is of uncertain efficacy. AIMS: To examine the prognostic significance of ER/PR positivity and of primary adjuvant progestogen use with outcome in ESS. MATERIALS AND METHODS: All women with a diagnosis of ESS in our tertiary institution and associated private practices over the last 23 years were included. Primary variables were ER/PR positivity and adjuvant progestogen use. Other variables included high-grade disease and extrauterine disease. The primary outcome was survival, and the secondary outcome was recurrence-free survival (both overall and at 5 years). Survival was calculated using the Kaplan-Meier method. Univariate analyses were performed with t-test for means and chi-squared test for proportions, and multivariate analysis was used to control for age. RESULTS: 35 women were included. ER/PR positivity was associated with a survival benefit (OR death 0.22, P = 0.02), but primary adjuvant progestogen was not. High-grade disease (OR 13, P = 0.02) and extrauterine disease (OR 8.7, P = 0.04) were associated with decreased survival. No variable significantly affected recurrence-free survival. Eight of ten cases of recurrence treated with progestogen have survived more than 3 years. CONCLUSIONS: ER/PR positivity appears to be useful for prognosis, but routine administration of primary adjuvant progestogen is not supported. There may be a role for progestogen in ER/PR positive tumours with recurrence or incomplete surgical clearance, but further research is required.

High-grade endometrial stromal sarcomas: a clinicopathologic study of a group of tumors with heterogenous morphologic and genetic features.

The existence of a "high-grade endometrial stromal sarcoma" category of tumors has been a controversial subject owing to, among other things, the difficulty in establishing consistent diagnostic criteria. Currently, the recommended classification for such tumors is undifferentiated uterine/endometrial sarcoma. Interest in this subject has recently increased markedly with the identification of recurrent molecular genetic abnormalities. At Mayo Clinic, a group of neoplasms has been observed that morphologically resemble, either cytologically or architecturally, classic "low-grade" endometrial stromal sarcoma but feature obvious deviations, specifically, 17 tumors with unequivocally high-grade morphology. These high-grade tumors displayed 3 morphologic themes: (1) tumors with a component that is identical to low-grade ESS that transitions abruptly into an obviously higher-grade component; (2) tumors composed exclusively of high-grade cells with uniform nuclear features but with a permeative pattern of infiltration; (3) tumors similar to the second group but with a different, yet characteristic, cytomorphology featuring enlarged round to ovoid cells (larger than those found in low-grade ESS) with smooth nuclear membranes and distinct chromatin clearing but lacking prominent nucleoli. We collected clinicopathologic data, applied immunohistochemical studies, and also tested tumors by fluorescence in situ hybridization for abnormalities in JAZF1, PHF1, YWHAE, and CCND1. Tumors from these 3 groups were found to be immunohistochemically and genetically distinct from one another. Most notable was the fact that category 3 contained all the cases that tested positive for YWHAE rearrangement, did not show any classic translocations for JAZF1, PHF1, or CCND1, often presented at a high stage, and behaved aggressively. This study demonstrates the morphologic, immunophenotypic, and molecular genetic heterogeneity that exists within "undifferentiated endometrial sarcomas" as currently defined and lends credence to the effort of subclassifying some tumors as truly "high-grade endometrial stromal sarcomas." Our study also shows that, in the context of undifferentiated endometrial sarcomas, recognition of cytomorphologic features on routine hematoxylin and eosin-stained sections may be used to select tumors with specific molecular genetic changes-that is, translocations involving YWHAE. Our conclusions will help further efforts towards proper sub-classification of these tumors which will aid in diagnosis and potentially affect clinical management.

Endometrial stromal sarcoma involving the urinary bladder: a study of 6 cases.

Endometrial stromal sarcoma (ESS) involving the urinary bladder is very rare, with no prior series reported. We identified 6 cases of low-grade ESS involving the bladder at our institution (1998 to 2013), 5 of them consults. The median age at bladder involvement was 60 years (range, 44 to 77 y). One patient presented with bladder involvement at initial diagnosis of ESS. The remaining 5 cases with bladder involvement presented 7 to 30 years (mean 18 y) after a known diagnosis of ESS (n=2) or after a remote history of hysterectomy with an uncertain diagnosis (n=3). The location of bladder involvement included dome (n=1), trigone (n=2), diffuse (n=1), and unknown (n=2). Two cases demonstrated worm-like infiltrating tumor nests classic of low-grade ESS with little stromal reaction with retraction artifact mimicking vascular invasion. One case originating from the ovary showed focal glandular differentiation in the bladder, resembling endometriosis. Two cases had abundant keloidal collagen formation, arranged haphazardly or in a sunburst pattern. One case showed primitive cells infiltrating entirely hyalinized stroma, after chemotherapy given for a misdiagnosis of urothelial carcinoma. CD31 was negative in all cases, except for 1 case with obvious large vessel invasion. The differential diagnosis included a large nested variant of urothelial carcinoma, carcinoid tumor, synovial sarcoma, solitary fibrous tumor, Ewing sarcoma/primitive neuroectodermal tumors, and endometriosis. CD10 was strongly positive in 5 cases, and 1 case had very focal, moderate staining. Estrogen receptor showed strong and diffuse staining in all 6 cases. Progesterone receptor showed moderate to strong staining in 5 cases and focal staining in 1 case. One case showed PAX8 expression, and 2 cases showed p16 nuclear and cytoplasmic expression. CD56 showed weak to strong staining in 4 cases. Two cases had diffuse synaptophysin, and 1 case had focal p63 positivity. GATA-3, CD34, and CD99 were negative in all cases. The Ki-67 index was 1% to 10% (mean 4%). The mitotic count was 0 to 3/10 HPF (mean <1/10 HPF). Two patients had metastases to pelvic lymph nodes, and 1 had possible lung metastasis. Three patients were treated with Megace and 1 with Arimidex after surgery. Follow-up averaged 19 years (0 to 33 y) after the initial diagnosis of ESS or hysterectomy and 3.5 years (0 to 11 y) after bladder surgery. ESS involving the bladder is extremely rare with a very long interval from onset to bladder involvement. In female patients, low-grade spindle cell lesions involving the bladder should include ESS in the differential diagnosis.

¹8F-Fluorodeoxyglucose uptake and clinicopathological features of recurrent or metastatic endometrial stromal sarcoma.

AIM: Maximum standardized uptake value on (18) F-fluorodeoxyglucose positron emission tomography was evaluated as a predictive surrogate marker in developing treatment strategies for recurrent or metastatic endometrial stromal sarcoma. METHODS: Clinical information was obtained from records of patients with recurrent or metastatic endometrial stromal sarcoma who underwent surgery or biopsy following (18)F-fluorodeoxyglucose positron emission tomography. Pathological features - including estrogen receptor, progesterone receptor and Ki-67 expression - were immunohistochemically evaluated. We classified lesions as 'positron emission tomography positive' if the maximum standardized uptake value was 3.0 or higher. Clinicopathological features were compared between patients with positive and negative positron emission tomography findings by using the χ(2)-test. RESULTS: Among eight recurrent and one metastatic endometrial stromal sarcoma patients, four (44%) had positron emission tomography-positive findings. Two positron emission tomography-positive patients were estrogen receptor negative and the five positron emission tomography-negative patients were estrogen receptor positive (P = 0.073). The Ki-67 index was 10% or higher in the four positron emission tomography-positive patients, but less than 5% in the five positron emission tomography-negative patients (P = 0.003). Three patients with positron emission tomography-positive tumors received more aggressive treatment (e.g. cytotoxic chemotherapy and additional surgery) than did those with positron emission tomography-negative tumors. One patient who died of disease had positron emission tomography-positive tumors, was negative for estrogen and progesterone receptors, and had a 20% Ki-67 index. CONCLUSION: (18)F-Fluorodeoxyglucose uptake was associated with tumor biology of recurrent or metastatic endometrial stromal sarcoma. (18)F-fluorodeoxyglucose-positron emission tomography was useful for developing treatment strategies for recurrent or metastatic endometrial stromal sarcoma.

Endometrial stromal sarcoma arising in vagina.

Endometrial stromal sarcoma (ESS) arising in the vagina is an extremely rare extrauterine endometrial stroma sarcoma, with only 4 cases reported in the literature up to date. Here we report a case of neoplasm originating from vagina. A 32-year-old woman complained of intermittent vaginal bleeding especially after intercourse. A mass with a diameter of 1.0 cm was found in the middle and upper segments of the right posterior vaginal wall. Biopsy showed ESS. Total abdominal hysterectomy, unilateral salpingo-oophorectomy (right) and partial vaginectomy were performed. No ESS lesion was found in endometrium. The patient received six courses of platinum-containing combination chemotherapy after surgery and was free of tumor 18 months after the diagnosis of ESS. The diagnosis of ESS relies on pathologic examination. CD10 is the most useful immunohistochemical marker for the diagnosis of this tumor. The mainstay treatment of ESS is surgery. Local excision and ovarian retaining may be considered in premenopausal women.

Intravascular adenomyomatosis: expanding the morphologic spectrum of intravascular leiomyomatosis.

Intravascular leiomyomatosis (IVL) is characterized by the presence of smooth muscle in venous and lymphatic spaces within the myometrium. Although the intravascular component usually consists solely of typical smooth muscle or variants of smooth muscle differentiation, we report 5 cases in which the intravascular component also included endometrioid glandular and stromal elements. We propose the term "intravenous adenomyomatosis" to describe this unusual variant of IVL. The mean age of the patients in this series was 50.2 years, slightly older than that of patients with conventional IVL. In addition to intravenous adenomyomatosis, both adenomyosis and leiomyomas were identified in all of our cases, supporting the hypothesis that the intravascular smooth muscle component in IVL is derived from associated myometrial pathology rather than from vessel walls. In our series, intravenous adenomyomatosis had a similar benign clinical behavior to most cases of IVL with no metastatic or recurrent disease identified at follow-up in 4 cases for which follow-up information was available. The main differential diagnoses are adenomyosis with vascular involvement, low-grade endometrial stromal sarcoma (ESS), including ESS with smooth muscle and glandular differentiation, and adenosarcoma with lymphovascular invasion. The possibility of intravenous adenomyomatosis should be borne in mind when considering these diagnoses, particularly ESS and adenosarcoma, which have different implications for patient management and prognosis.