Pleomorphic high grade endometrial stromal sarcoma with YWHAE gene amplification may be a novel variant with poor prognosis

Endometrial stromal neoplasms are classified by the World Health Organization (WHO) into endometrial stromal nodule (ESN), low grade (LGESS), high grade (HGESS), and undifferentiated uterine sarcoma (UUS). HGESS is subclassified based on molecular findings, YWHAE or BCOR. The HGESS with YWHAE::NUTM2A/B (alias YWHAE::FAM22A/B) fusion usually have relatively monomorphic (as with most fusion-associated malignancies) rounded to epithelioid cells with eosinophilic cytoplasm, vesicular nuclei, nucleoli, and mitotic figures >10/10 HPF. We present a 66-year-old woman with post-menopausal bleeding found to have a heterogeneous solid-cystic uterine mass on CT who underwent total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic lymph node dissection. A 15.0×9.0 cm variegated uterine mass with hemorrhage and necrosis was identified. Histologically, the tumor was hypercellular with haphazard fascicles, microcysts, and tongue-like destructive myometrial invasion. Tumor cells exhibited marked pleomorphism and high mitotic activity with atypical mitotic figures. There was extensive cyclin-D1 and subset CD10 immunopositivity. FISH showed YWHAE amplification but without rearrangement. Interestingly, we found only two other reported cases of pleomorphic HGESS with YWHAE gene amplification upon review of 259 cases from cBioPortal database, one of which was reported as carcinosarcoma with heterologous elements. Of note, all three YWHAE amplified cases were diagnosed at high-stage and succumbed to disease within six months. Our case appears to be the third case of YWHAE-amplified pleomorphic HGESS, possibly a new variant of uterine sarcoma with aggressive biologic behavior that needs further evaluation.     

Endometrial stromal sarcoma – the new genetic paradigm

Endometrial stromal sarcoma (ESS) is a gynaecological sarcoma that is composed of cells that resemble those of proliferative‐phase endometrial stroma. The 2014 World Health Organization tumour classification system separates ESS into low‐grade and high‐grade types, which are histologically, genetically and clinically distinct from undifferentiated uterine sarcoma (UUS). Low‐grade ESSs frequently contain chromosomal rearrangements that result in JAZF1–SUZ12 fusion or equivalent genetic fusions. Although most low‐grade ESSs show classic histological features that closely resemble those of proliferative‐phase endometrial stroma, there are several histological variants that are associated with the same genetic fusions as seen in the classic type. High‐grade ESS is defined by the presence of YWHAE–NUTM2A/B (YWHAE–FAM22A/B) fusions. High‐grade ESSs are clinically more aggressive than low‐grade ESSs, but are associated with a lower mortality rate than UUSs. The histological and immunophenotypic features of these different types of ESS, and their diagnostic considerations, are the subjects of this review.     

Colonic low‐grade endometrial stromal sarcoma and orthotopic endometrial stromal tumor with limited infiltration sharing the JAZF1‐SUZ12 gene fusion

Endometrial stromal tumors (ESTs) are composed of cells resembling endometrial stroma, and are divided into benign and malignant types based on morphology. Endometrial stromal nodule (ESN) is a benign localized tumor, and endometrial stromal sarcoma (ESS) is an infiltrative and potentially metastatic neoplasm. A series of genetic aberrations contribute to pathological diagnosis of ESTs. At present, subsets of ESN and ESS‐low grade (ESS‐LG) are characterized as JAZF1‐SUZ12/JJAZ1 gene fusion. The ESTs that show higher grade atypia but lack nuclear pleomorphism include YWHAE‐FAM22 ESS. Here we report an unusual case of ESTs. Sudden colonic perforation occurred to the patient, and emergency surgery was performed. Pathological findings suggested metastatic ESS. Thorough medical examination of the genital organs detected a 1 cm‐sized well‐demarcated uterine tumor. Microscopically, the tumor lacked infiltrative features, conforming to the definition of ESN. Both lesions demonstrated identical cytology and shared JAZF1‐SUZ12 gene fusion. Endometriosis was not found in any areas of the resected organs, strongly suggesting that the uterine orthotopic tumor metastasized. The current case uncovered the problems of differential diagnosis between ESN and ESS‐LG. We demonstrate detailed pathological features of the two lesions, and discuss the possibility of orthotopic EST with limited infiltration to develop into ESS‐LG.     

Ins(10;19) in an endometrial stromal sarcoma

A 37-year-old woman with a history of bilateral mesenchymal cystic hamartomata of the lung was subsequently found to have low-grade endometrial stromal sarcoma. Cytogenetic analysis of the uterine tumor revealed, in all metaphases, an unusual derivative chromosome generated by the insertion of chromosome 19 into chromosome 10 at the level of its centromere [ins(10;19)(p11;p13q13)].     

Neues in der WHO-Klassifikation 2014 der Tumoren des Corpus uteri

The 2014 World Health Organization (WHO) classification of uterine tumors revealed simplification of the classification by fusion of several entities and the introduction of novel entities. Among the multitude of alterations, the following are named: a simplified classification for precursor lesions of endometrial carcinoma now distinguishes between hyperplasia without atypia and atypical hyperplasia, the latter also known as endometrioid intraepithelial neoplasia (EIN). For endometrial carcinoma a differentiation is made between type 1 (endometrioid carcinoma with variants and mucinous carcinoma) and type 2 (serous and clear cell carcinoma). Besides a papillary architecture serous carcinomas may show solid and glandular features and TP53 immunohistochemistry with an “all or null pattern” assists in the diagnosis of serous carcinoma with ambiguous features. Neuroendocrine neoplasms are categorized in a similar way to the gastrointestinal tract into well differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas (small cell and large cell types). Leiomyosarcomas of the uterus are typically high grade and characterized by marked nuclear atypia and lively mitotic activity. Low grade stromal neoplasms frequently show gene fusions, such as JAZF1/SUZ12. High grade endometrial stromal sarcoma is newly defined by cyclin D1 overexpression and the presence of the fusion gene YWHAE/FAM22 and must be distinguished from undifferentiated uterine sarcoma. Carcinosarcomas (malignant mixed Mullerian tumors MMMT) show biological and molecular similarities to high-grade carcinomas.     

Heterologous and rare homologous sarcomas of the uterine corpus: a clinicopathologic review

Pure sarcomas of the uterine corpus are uncommon, constituting less than 3% of all malignancies at this site, and most of them are leiomyosarcomas and endometrial stromal sarcomas. Rare histotypes of homologous sarcomas and heterologous sarcomas are occasionally encountered, and the absence of significant accumulated experience with these histotypes at this location may potentially raise diagnostic and patient management difficulties. In this article, the clinicopathologic attributes of all earlier reported sarcomas of the uterine corpus other than leiomyosarcomas and endometrial stromal sarcomas are summarized. Included are embryonal rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, angiosarcoma, alveolar soft part sarcoma, malignant perivascular epithelioid cell tumors (PEComas), osteosarcoma, chondrosarcoma, liposarcomatous tumors, malignant extrarenal rhabdoid tumors, Ewing sarcoma/primitive neuroectodermal tumor, and other rare histotypes. Embryonal rhabdomyosarcoma (20%), Ewing sarcoma/primitive neuroectodermal tumor (17%), angiosarcoma (14%), and pleomorphic rhabdomyosarcoma (13%) appeared to be more common than the others, although there was no single overwhelmingly prevalent histotype in the group. A subset, including embryonal rhabdomyosarcoma, alveolar soft part sarcoma, and PEComas, peak in the premenopausal years, but most of the others were observed in postmenopausal women. Favorable outcomes have been reported for the patients diagnosed with alveolar soft part sarcoma, and the prognosis for their counterparts with PEComa remains a matter of debate. Multimodal therapeutic approaches to contemporary patients with embryonal rhabdomyosarcomas have resulted in significantly improved outcomes. Unfortunately, most of the other sarcomas have been associated with rapid tumor progression and unfavorable patient outcomes. The differential diagnosis for these sarcomas is often extensive and varies by histotype, but their accurate diagnosis fundamentally requires the careful exclusion of biphasic malignancies.     

An endometrial stromal sarcoma with clonal cytogenetic abnormalities

Cytogenetic analysis of a low-grade metastatic endometrial stromal sarcoma in a 58-year-old woman revealed translocations involving both homologues of chromosome 7 with chromosomes 13 and 17, respectively, and an interstitial deletion of the long arm of chromosome 11. The karyotype of the tumor was 46,XX,t(7;13)(q11.1;p13),t(7;17)(p21;q12),del(11)(q13q21).     

Myxoid endometrial stromal sarcoma of the uterus

A rare case of a myxoid type of endometrial stromal sarcoma of the uterus in a 41-year-old woman is reported. A tumor was found in the myometrium and was well circumscribed, measuring 9 x 7 x 7 cm in size. The tumor was mainly composed of a hypocellular area with tumor cells separated by prominent myxoid stroma. The tumor cells were spindle-shaped and resembled endometrial stromal cells. Numerous small thin-walled vessels were seen throughout the tumor. Immunohistochemically, the tumor cells were diffusely stained for estrogen and progesterone receptors and CD10, and focally and weakly for HHF35, alpha-smooth muscle actin and desmin, but not stained for h-caldesmon. These results indicated that the tumor originated from endometrial stromal cells. The tumor had an increased mitotic activity (MIB-1 labeling index: 1-10%), and focally showed nuclear pleomorphism. Thus, this tumor had a malignant potential and was diagnosed as a myxoid type of low-grade endometrial stromal sarcoma. The patient is currently well with no evidence of local recurrence or metastasis 21 months after the operation. This case indicates a wide morphological spectrum of endometrial stromal tumor. A myxoid endometrial stromal sarcoma should be considered in the different diagnosis of the intramural myxoid tumors in the uterus.     

Uterine sarcomas

A wide variety of sarcomas occur in the uterus but two subtypes - leiomyosarcoma and endometrial stromal sarcoma - account for a majority of those more routinely encountered. Using the 2003 World Health Organization classification, this review focuses on six uterine sarcomas: endometrial stromal sarcoma, undifferentiated endometrial sarcoma, leiomyosarcoma, rhabomyosarcoma, angiosarcoma and liposarcoma. The epidemiological, clinical, pathological and molecular features are presented along with therapeutic approaches. Familiarity with molecular aspects of these tumors and application of novel technologies in their assessment should be encouraged as they may provide alternate therapies resulting in improved survival for the patient. Clinical information necessary for accurate diagnosis of these lesions is emphasised. A multidisciplinary approach to management of patients with uterine sarcomas is essential for optimal management.     

Cytogenetic and molecular aberrations in endometrial stromal tumors

Endometrial stromal tumors (ESTs) are rare uterine mesenchymal tumors, comprising <10% of all uterine mesenchymal neoplasms. The latest World Health Organization classification divides endometrial stromal tumors into 3 categories based on morphologic features: endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma, and undifferentiated endometrial sarcoma. Specific cytogenetic aberrations and molecular genetic alterations have recently been identified in endometrial stromal tumors, providing insights into their molecular biology, potential diagnostic markers, and possible therapeutic targets. Currently, recurrent chromosomal rearrangements resulting in gene fusion play a substantive role in the pathogenesis of endometrial stromal nodules, endometrial stromal sarcomas, and a small subset of undifferentiated endometrial sarcomas. Loss of heterozygosity of tumor suppressor genes and deregulation of the Wnt signaling pathway have also been implicated in EST tumorigenesis. In this review, we summarize the recent advances in the molecular pathology of endometrial stromal tumors.     

Uterine tumor resembling ovarian sex cord tumor: report of a case with t(X;6)(p22.3;q23.1) and t(4;18)(q21.1;q21.3).

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor of reproductive-age and postmenopausal women. We present the first case of UTROSCT with cytogenetic analysis. The tumor occurred in a 34-year-old woman who presented with menorrhagia and a uterine mass. Histologic examination showed tumor with features of sex cord-like epithelium and abundant fibromuscular stroma without an endometrial stromal sarcoma component. The tumor cells expressed cytokeratin, CD99, vimentin, desmin, smooth muscle actin, and estrogen and progesterone receptors. The majority of the cells analyzed by cytogenetic studies showed two balanced chromosomal translocations: t(X;6)(p22.3;q23.1) and t(4;18)(q21.1;q21.3). Several known tumor-related genes (bcl-2, MALT-1, FVT1, SCCA1, SCCA2, and DCC at 18q21; RAP1 at 4q21; and STL at 6q23) and a gonadal-development related gene (H-Y regulator gene at Xp22.3) are located at or near the translocation breakpoints. The tumor cells of sex cord-like elements were strongly and diffusely immunoreactive for bcl-2 antibody. These cytogenetic and immunohistochemical data may suggest potential molecular mechanisms of tumorigenesis of UTROSCT.     

Distinction of endometrial stromal sarcomas from 'hemangiopericytomatous' tumors using a panel of immunohistochemical stains.

Endometrial stromal sarcomas are low-grade malignant tumors that may pose a diagnostic challenge, especially when they are present in an extrauterine site. Owing to the presence of an arborizing vasculature and cells with an undifferentiated appearance, endometrial stromal sarcomas can be confused with several soft-tissue neoplasms. We studied 17 endometrial stromal sarcomas, eight hemangiopericytomas, 14 solitary fibrous tumors, and 16 synovial sarcomas immunohistochemically, detecting the following antigens: CD10, estrogen receptor, progesterone receptor, bcl-2, CD34, smooth muscle antigen, epithelial membrane antigen and cytokeratin (AE1/AE3). Most endometrial stromal sarcomas stained positively for CD10 (16/17), estrogen receptor (17/17), progesterone receptor (15/17), and bcl-2 (17/17). Staining with antismooth muscle antigen was seen in 11 of 17 cases of endometrial stromal sarcoma, with more intense staining seen in areas showing smooth muscle differentiation. Staining with AE1/3 was seen in four of 17 endometrial stromal sarcomas, with two of the positive cases containing epithelioid cells. None of the endometrial stromal sarcomas expressed epithelial membrane antigen or CD34. More than half of the hemangiopericytomas (4/8) and solitary fibrous tumors (9/14) cases demonstrated CD10 expression either focally or in a patchy cytoplasmic and membranous pattern. Hemangiopericytomas, solitary fibrous tumors, and synovial sarcomas did not express estrogen receptor. Four of eight hemangiopericytomas and seven of 14 solitary fibrous tumors also showed patchy progesterone receptor expression. CD34 expression was identified in six of eight hemangiopericytomas and 13 of 14 solitary fibrous tumors, but we did not find expression of CD34 in synovial sarcoma. Differences between endometrial stromal sarcoma and other soft-tissue tumors were detected for all of the immunohistochemical markers (P<0.05), except anti-bcl-2 and AE1/3. Antibodies against CD10 mark a substantial number of hemangiopericytomas and solitary fibrous tumors (albeit not diffusely) and should always be combined with antiestrogen receptor and CD34 when the differential diagnosis includes endometrial stromal sarcoma. Unlike estrogen receptor antibodies, progesterone receptor antibodies show at least focal nuclear staining in most hemangiopericytomas, solitary fibrous tumors and rare synovial sarcomas, and are not useful for this differential diagnosis. All endometrial stromal sarcomas expressed bcl-2, mostly in a diffuse pattern, but this did not distinguish between endometrial stromal sarcoma and mimics. We therefore recommend the use of a small antibody panel comprising anti-CD10, anti-estrogen receptor, and anti-CD34 to distinguish endometrial stromal sarcomas from tumors with a predominant hemangiopericytomatous growth pattern.     

An update in pathologic diagnosis of uterine mesenchymal tumours

Recent discovery of new disease-defining molecular alterations and development of novel targeted therapies has dramatically changed the classification and management of uterine mesenchymal neoplasms. This review discusses diagnostic updates in endometrial stromal sarcoma, PEComa, uterine tumor resembling ovarian sex cord tumor (UTROSCT), inflammatory myofibroblastic tumor, NTRK fusion uterine sarcoma, COL1A1-PDGFB fusion sarcoma, and SMARC-deficient uterine sarcoma. Key clinical, morphologic, immunophenotypic, and molecular features are reviewed, with emphasis on common differential diagnoses and pitfalls, and their impact on prognosis or management. Where applicable, the role of novel targeted therapies is discussed. A stepwise approach to uterine mesenchymal neoplasms can achieve a proper diagnosis and guide appropriate clinical management in most cases. Nonetheless, given the rarity of these tumors, their overlapping pathologic features, and rapid evolution in their classification and management, we advocate a low threshold for diagnostic consultation.     

Endometrial stromal tumors: Diagnostic updates and challenges

Endometrial stromal tumors are rare uterine mesenchymal tumors of endometrial stromal origin. They are classified into endometrial stromal nodule, low-grade endometrial stromal sarcoma, high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma by the current (2020) WHO classification. Correct diagnosis of endometrial stromal tumors is critical for proper patient management. However, due to infrequent encounters, overlapping morphological features and immunohistochemical profiles, the differential diagnoses among endometrial stromal lesions and their morphologic mimics are often challenging. Partially with our own experience, here we review and summarize the tumor morphology, immunohistochemical phenotype, as well as molecular feature of endometrial stromal tumors and key differential diagnoses, emphasizing the newest developments and their utilization in daily practice.     

Translocation t(12;22)(q13;q12.2–12.3) in a clear cell sarcoma of tendons and aponeuroses

Cytogenetic analysis of a short-term culture from a clear cell sarcoma revealed a complex karyotype with the mainline of 49,XY,t(7;18)(p11.2;q21.3), + der(7)t(7;18)(p11.2;q21.3), + 8, + der(8;17)(q10;q10),t(12;22)(q13;q12.2–12.3),add(13)(p13). An apparently identical translocation t(12;22) has been described recently in four clear cell sarcomas, indicating that this constitutes a primary cytogenetic change specific for this type of tumor. In our case, the breakpoint on chromosome 22 could be assigned to band 22q12.2 or 22q12.3. Together with the present case, trisomy or tetrasomy 8 has been found in six of nine clear cell sarcomas, suggesting that, as in Ewing's sarcoma and myxoid liposarcoma, trisomy/tetrasomy 8 represents a nonrandom secondary aberration. We conclude that the finding of the specific translocation t(12;22) may prove to be an important marker in the differential diagnosis of clear cell sarcoma from some other soft tissue sarcomas and malignant melanoma. © 1993 Wiley-Liss, Inc.     

CD10 is a sensitive and diagnostically useful immunohistochemical marker of normal endometrial stroma and of endometrial stromal neoplasms

AIMS: The CD10 antigen is expressed in acute lymphoblastic leukaemia and follicle centre cell lymphoma. A recent study investigating the expression of CD10 in a wide range of non-haematopoietic neoplasms found positive staining in a small number of endometrial stromal sarcomas as well as in normal endometrial stroma. The present study aimed to ascertain whether CD10 positivity is indeed found in normal endometrial stroma and endometrial stromal neoplasms. Staining of a range of tumours which can be confused morphologically with endometrial stromal neoplasms was also undertaken to ascertain whether antibodies against CD10 are of value in a diagnostic sense. METHODS AND RESULTS: Neoplasms included in the study were endometrial stromal nodule (n=1), low-grade endometrial stromal sarcoma (ESS) (n=13), high-grade ESS (n=6), mixed endometrial stromal-smooth muscle tumour (n=1), uterine cellular leiomyoma (n=10), uterine leiomyosarcoma (n=5), adult granulosa cell tumour (AGCT) (n=10), undifferentiated endometrial carcinoma (n=6), uterine carcinosarcoma with an endometrial stromal component (n=1) and type II uterine mesenchymal tumour with sex cord-like elements (n=1). Cases of proliferative (n=5), secretory (n=5) and atrophic (n=3) endometrium were also stained. There was positive staining of stroma but not of glands in all cases of non-tumorous endometrium. There was positive staining of the endometrial stromal nodule and of all low-grade ESS. Staining in these varied but was often diffuse and of moderate to strong intensity. There was positive staining of four of six high-grade ESS, but this was usually focal. There was also positive staining of the endometrial stromal component in the mixed endometrial stromal-smooth muscle tumour and in the uterine carcinosarcoma. Most cellular leiomyomas were completely negative although three exhibited weak positivity. There was some positivity, usually focal or weak, of three of five leiomyosarcomas. Most AGCT and undifferentiated carcinomas were completely negative although one case of each exhibited focal staining. There was focal staining of the type II uterine mesenchymal tumour with sex cord-like elements. CONCLUSION: CD10 is a reliable and sensitive immunohistochemical marker of normal endometrial stroma. Positivity, which is often strong and/or diffuse is found in endometrial stromal nodules and low-grade ESS. Positive staining with CD10, when strong and diffuse, may be useful in distinguishing these tumours from histological mimics, especially cellular leiomyoma and AGCT which are generally negative. In this situation, CD10 should be used as part of a panel which might include desmin and alpha-inhibin depending on the differential diagnosis considered. Positive staining with CD10 in a high-grade uterine sarcoma which is negative with muscle markers might indicate endometrial stromal differentiation and identify a group of neoplasms which it is correct to diagnose as high-grade ESS rather than undifferentiated uterine sarcoma.     

Uterine stromal sarcoma cell line. A cytogenetic and electron microscopic study.

Uterine sarcomas constitute approximately 3% of all malignant uterine corpus tumors. Of these, the tumors that originate solely in the stromal elements of the uterine wall are relatively infrequent and have not been well characterized cytogenetically. We report data from a low-grade endometrial stromal sarcoma both at the time of resection and after months in long-term tissue culture. Cytogenetic analysis showed a clonal population of cells with an abnormal karyotype of 46,XX,del(5)(q31.1),der(7)t(6;7)(p21;p22) which remained unchanged in long-term culture. Electron microscopy suggests that these cells are similar to other neoplastic cells in having immature-appearing nuclei surrounded by a relatively mature cytoplasm (with well-developed organelles). Determination of the specificity of these observations must await study of additional stromal sarcomas.