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Leiomyomas are common hormone-responsive uterine neoplasms which can exhibit a variety of morphologic changes secondary to hormonal agents such as progestogens. They may increase in size during pregnancy as a result of hormonal stimulation but surprisingly the morphologic features of leiomyomas in pregnancy are not well described in the literature. In this report, we describe the morphologic features of a series of 29 uterine leiomyomas in pregnancy. The features include in decreasing order of frequency infarct-type necrosis, decidualization of the serosal surface, hyalinization, myxoid alteration of the stroma, edema (sometimes with cyst formation), and dystrophic calcification. We also report a feature which we term "deciduoid" change (seen in 10 of 29 leiomyomas) which takes the form of altered smooth muscle cells with an epithelioid morphology with abundant eosinophilic or clear cytoplasm. Furthermore, we show that the "deciduoid" cells commonly exhibit expression of sex cord markers inhibin and calretinin. We speculate on the pathogenesis of the "deciduoid" change which together with its "aberrant" immunophenotype may result in diagnostic problems and consideration of other neoplasms., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Uterine endometrial stromal sarcomas (ESS) with YWHAE::NUTM2 gene fusions are typically morphologically high-grade tumors composed of atypical round cells, sometimes associated with a low-grade fibromyxoid component; they are currently included in the category of high-grade ESS (HGESS). We report 5 morphologically pure low-grade endometrial stromal tumors harboring YWHAE::NUTM2 fusions, including 1 endometrial stromal nodule (ESN) and 4 low-grade endometrial stromal sarcomas (LGESS), an association only occasionally reported previously. Patients ranged from 30 to 51 (mean=43) years and tumors from 4.5 to 7.5 cm (mean=5.7). All were stage I at diagnosis (confined to the uterus). Microscopically, the 4 LGESS showed extensive "tongue-like" invasion of the myometrium, and the ESN was entirely confined to the endometrium with no myometrial invasion. All tumors were composed entirely of morphologically uniform bland ovoid cells resembling proliferative endometrial stroma. A fibromyxoid component was seen in 1 LGESS and the ESN; in the LGESS, this was the sole component. Atypical round cells characteristic of YWHAE::NUTM2 HGESS were not identified. Mitotic count ranged from <1 to 13 per 10 high-power fields (mean: 3). CD10 was positive in 2/4 (focal), estrogen receptor in 5/5 (focal=1; diffuse=4), progesterone receptor in 5/5 (focal=1; diffuse=4) and cyclin D1 was diffusely positive in 3/4. Follow-up was available in all 5 patients and ranged from 6 to 159 months (mean=72). Two patients with LGESS had recurrent disease at 15 and 155 months; 1 showed predominantly LGESS with rare round cells in the initial recurrence and pure HGESS in a subsequent recurrence, while the other patient's recurrent tumor was predominantly HGESS (90%) in a background of focal fibromyxoid LGESS (10%). Both patients rapidly progressed and died of disease within 5 months of high-grade recurrence. We show that rare cases of morphologically pure low-grade endometrial stromal tumors, some but not all with a fibromyxoid component, harbor YWHAE::NUTM2 fusions and may recur rapidly, with transformation to HGESS and aggressive behavior. Our findings suggest that at least a subset of YWHAE::NUTM2 HGESS evolves from LGESS. We suggest that cyclin D1 and CD10 staining should be performed in all LGESS. Diffuse staining for cyclin D1 and/or negative or focal staining for CD10 should suggest the possibility of a YWHAE::NUTM2 fusion, and appropriate molecular testing should be undertaken. Since no single morphological or immunohistochemical parameter is entirely sensitive for fusion status, we also suggest that testing for a YWHAE::NUTM2 gene fusion should be considered in all cases of LGESS and, if a fusion is present, this should raise the possibility of subsequent high-grade transformation and aggressive behavior, even though such cases should still be categorized as LGESS. Although seemingly rare, ESN and LGESS with YWHAE::NUTM2 fusions may be under-recognized due to a lack of routine fusion testing., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Gynecologic tract origin of inflammatory myofibroblastic tumor (IMT), a receptor tyrosine kinase fusion driven tumor with malignant potential, is uncommon and mostly involves the uterine corpus where misclassification as a smooth muscle tumor may occur due to overlapping morphologic features. With rare exception, uterine IMT involves ALK rearrangements and exhibits ALK immunoexpression. Molecularly confirmed vulvovaginal IMT has not been reported, but several low-grade mesenchymal tumors in this region exhibit myxoid stroma and/or inflammatory infiltrates that may resemble IMT. The aims of this study were to define the diagnostic specificity of ALK immunoexpression for IMT among a broad spectrum (107 cases) of vulvovaginal mesenchymal tumors in the differential diagnosis of IMT and to report the clinicopathologic features of vulvovaginal IMT identified in our archives or via retrospective ALK staining of otherwise classified vulvovaginal tumors. Review of archives from 5 different centers revealed a single case of vulvar IMT in a 62-yr-old woman. The 2.5 cm well-circumscribed tumor exhibited the typical microscopic features of IMT, namely a loose fascicular distribution of bland spindle cells within a myxoid stroma, accompanied by an infiltrate of plasma cells, lymphocytes, and eosinophils. The tumor cells exhibited expression for smooth muscle actin, desmin, h-caldesmon, and ALK. Break-apart fluorescence in situ hybridization confirmed the presence of ALK rearrangement. The patient did not receive any treatment and is alive without disease 32 mo later. No evidence of ALK expression was detected in any of the other 107 vulvovaginal tumors, which included 14 aggressive angiomyxomas, 2 superficial angiomyxomas, 12 angiomyofibroblastomas, 8 cellular angiofibromas, 15 smooth muscle neoplasms, 10 peripheral nerve sheath tumors, 20 fibroepithelial polyps, and a variety of other low grade mesenchymal tumors. Although vulvovaginal ALK- rearranged IMT is exceedingly rare, the behavior remains to be fully understood. ALK immunohistochemistry, which appears specific for IMT in this anatomic site, is advised in the evaluation of vulvovaginal mesenchymal tumors exhibiting myxoid stroma and/or an inflammatory infiltrate., Competing Interests: J.T.R. reports that his spouse receives salary and stock options from Merck & Co. The remaining authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

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., Competing Interests: Conflicts of Interest and Source of Funding: Supported by P50 CA 140146-01 (to C.R.A.), P50 CA217694 (to C.R.A.), P30 CA008748 (to C.R.A.). This study was supported in part by the research fund from the Ministry of Science and Technology, Taiwan (MOST 109-2326-B-002-010-MY3) to J.-C.L. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

High-grade endometrial stromal sarcoma (HGESS) is an uncommon tumor accounting for <1% of all uterine malignancies. Currently this designation is largely reserved for neoplasms harboring YWHAE-NUTM2A/B and ZC3H7B-BCOR translocations. Here, we report a novel CIQTNF1-ERBB4 translocation in a uterine neoplasm arising in a 49-yr-old woman with morphology suggestive of HGESS. Histologic examination of the 5 cm polypoid uterine corpus mass showed a neoplasm composed of a monotonous population of cells with moderately atypical ovoid to spindle shaped nuclei with easily identifiable mitotic activity and prominent vasculature with focal intravascular extension. Immunohistochemistry showed variable positivity with desmin, estrogen receptor, progesterone receptor, AE1/3 and cyclin D1, and molecular testing showed a translocation between CIQTNF1 on chromosome 17 and ERBB4 on chromosome 2. This represents the first report of this translocation in a uterine neoplasm and adds to the growing list of translocations identified in uterine sarcomas. Although the morphology is suggestive of HGESS, this neoplasm is currently best termed an ERBB4 -rearranged uterine sarcoma until additional cases are reported to more fully characterize these neoplasms., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

We report a spindle cell sarcoma arising in the uterine corpus of a 26-yr-old patient. The patient underwent a simple hysterectomy and the uterine corpus contained a 9 cm tumor showing nodular and "finger-like" myometrial invasion. Histologically, the tumor was composed of a monomorphic population of atypical spindle cells which contained widespread foci of cytologically benign adipocytes. Immunohistochemistry revealed diffuse strong positivity for CD10, CD56, and CD99 and diffuse weak positive staining with ER and WT1 while smooth muscle markers, S100, TLE1, and cyclin D1 were negative. Total RNA sequencing identified an in-frame fusion between exon 6 of MEIS1 and exon 12 of NCOA2. Copy number analysis revealed few aberrations with no deletions or amplifications identified. No adjuvant therapy was given and the patient is disease-free 9 yr after initial diagnosis. This case represents the second report of a uterine sarcoma harboring a MEIS1-NCOA2/1 gene fusion and expands the morphologic spectrum of recently reported spindle cell sarcomas arising in the genitourinary tract harboring MEIS1-NCOA2/1 gene fusions. This is the first reported case of such tumors with an adipocytic component., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

This review covers the significant new developments in the pathological classification of gynecological tumors. Many of these were included in the updated World Health Organization Classification of Female Genital Tract Tumours, published in 2020. Topics include the compelling evidence that a large majority of extrauterine high-grade serous carcinomas arise from the fallopian tube; the Cancer Genome Atlas (TCGA) Classification of endometrial carcinomas; the discovery that most so-called synchronous endometrial and ovarian endometrioid carcinomas represent metastasis from the endometrium to the ovary; and the division of cervical, vaginal, and vulval carcinomas into clinically meaningful HPV-associated and HPV-independent types. Newly described tumor types are covered, including endometrial and ovarian mesonephric-like adenocarcinoma, uterine sarcoma types associated with specific molecular abnormalities, and gastric (gastrointestinal)-type adenocarcinomas of the endometrium and vagina. Important molecular events in ovarian sex cord-stromal tumors are also discussed., (International Journal of Gynecology & Obstetrics© 2021 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Herein we evaluated a series of 21 embryonal rhabdomyosarcomas of the uterine corpus (ucERMS), a rare neoplasm, to characterize their morphology, genomics, and behavior. Patients ranged from 27 to 73 (median 52) years and tumors from 4 to 15 (median 9) cm, with extrauterine disease noted in two. Follow-up (median 16 months) was available for 14/21 patients; nine were alive and well, four died of disease, and one died from other causes. Most tumors (16/21) showed predominantly classic morphology, comprised of alternating hyper- and hypocellular areas of primitive small cells and differentiating rhabdomyoblasts in a loose myxoid/edematous stroma. A cambium layer was noted in all; seven had heterologous elements (six with fetal-type cartilage) and eight displayed focal anaplasia. The remaining five neoplasms showed only a minor component (≤20%) of classic morphology, with anaplasia noted in four and tumor cell necrosis in three. The most frequent mutations detected were in DICER1 (14/21), TP53 (7/20), PI3K/AKT/mTOR pathway (7/20), and KRAS/NRAS (5/20). Copy-number alterations were present in 10/19 tumors. Overall, 8/14 DICER1-associated ucERMS showed concurrent loss of function and hotspot mutations in DICER1, which is a feature more likely to be seen in tumors associated with DICER1 syndrome. Germline data were available for two patients, both DICER1 wild type (one with concurrent loss of function and hotspot alterations). DICER1-associated ucERMS were more likely to show a classic histological appearance including heterologous elements than DICER1-independent tumors. No differences in survival were noted between the two groups, but both patients with extrauterine disease at diagnosis and two with recurrences died from disease. As no patients had a known personal or family history of DICER1 syndrome, we favor most DICER1-associated ucERMS to be sporadic., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Müllerian adenosarcoma is an uncommon biphasic malignant tumor most often occurring in the uterine corpus and derived from native surface endometrium. We report a case of intramural uterine adenosarcoma arising in association with adenomyosis, in the absence of tumor involving the surface endometrium. This is an extremely rare phenomenon, with only 8 other published cases of uterine corpus adenosarcoma in the absence of surface endometrial involvement, 5 originating in adenomyosis and 3 in adenomyomas. We review these cases. The current FIGO staging system for uterine adenosarcoma assumes origin from the surface endometrium and does not address the rare occurrence of intramural tumors without a surface endometrial component. Such tumors are problematic to stage and could potentially be overtreated, particularly if there is deep myometrial involvement., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 by the International Society of Gynecological Pathologists.)

Aims: Uterine sarcomas can be grouped into tumours with pathognomonic genetic fusions such as low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS), and inflammatory myofibroblastic tumour (IMT), and tumours lacking genetic fusions such as leiomyosarcoma (LMS) and undifferentiated uterine sarcoma (UUS). Members of the latter group frequently harbour TP53 mutations. The aim of this study was to evaluate TP53 mutations by the use of immunohistochemistry in fusion-positive uterine sarcomas., Methods and Results: We performed p53 immunohistochemical staining on 124 uterine sarcomas harbouring genetic fusions and 38 fusion-negative LMSs and UUSs. These included 41 HGESSs with YWHAE, BCOR and BCORL1 fusions/rearrangements, 13 IMTs with ALK fusion, 12 sarcomas with NTRK1/3 fusion, three sarcomas with PDGFB fusion, and 55 LGESSs with JAZF1, SUZ12 and PHF1 fusions/rearrangements. All HGESSs, LGESSs, IMTs and sarcomas with PDGFB fusion showed wild-type p53 expression. Among NTRK1/3-positive sarcomas, a TPR-NTRK1-positive sarcoma with nuclear pleomorphism showed mutation-type p53 expression. The remaining 11 NTRK1/3-positive sarcomas showed wild-type p53 expression, except for the subclonal p53 mutation-type staining in a minor pleomorphic focus of an NTRK3-positive sarcoma. Twenty-one of 27 (78%) LMSs and six of nine (67%) UUSs showed mutation-type p53 expression., Conclusion: p53 immunohistochemistry may be considered in the initial work-up of a uterine sarcoma, as mutation-type staining would make a fusion-positive sarcoma very unlikely. Mutation-type p53 expression, however, can be seen in a small subset of NTRK1/3-positive sarcomas showing pleomorphic round/ovoid cell histology, which may represent a mechanism of progression in these tumours., (© 2020 John Wiley & Sons Ltd.)

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., (© 2020 John Wiley & Sons Ltd.)

Mullerian adenosarcoma is a biphasic neoplasm composed of benign or atypical Müllerian epithelium and a malignant mesenchymal component that is usually, but not always, of low grade. Focal architectural or cytologic atypia of the epithelial component resembling atypical hyperplasia may uncommonly be present and foci of adenocarcinoma have been rarely reported. Whether the coexistence of these 2 tumor components is a result of independent primaries (collision tumor), adenocarcinoma arising from the epithelial component of the adenosarcoma, an unusual form of carcinosarcoma or some other mechanism is uncertain. To establish the diagnostic criteria and clinical significance of the coexistence of adenocarcinoma in close association with Müllerian adenosarcoma, we conducted a multi-institutional study of these rare tumors. Twenty-six patients were identified with "mixed" adenosarcoma and adenocarcinoma; they ranged in age from 43 to 87 years (median: 66 y). Tumors occurred in the uterine corpus (n=22), ovary (n=2), and the pelvis (n=2). All but 6 had International Federation of Gynecology and Obstetrics (FIGO) stage I disease. All extrauterine tumors were associated with endometriosis. The tumor size ranged from 2 to 25 cm (median: 7.9 cm). The sarcomatous component was of low grade in 18 and high grade in 8 (the majority demonstrating rhabdomyoblastic differentiation); 9 had stromal overgrowth. Twenty-five carcinomas were endometrioid in type (23 FIGO grade 1; 3 FIGO grade 2) and 1 carcinoma was dedifferentiated with FIGO grade 1 endometrioid adenocarcinoma component; 33% of the uterine neoplasms were associated with adjacent endometrial hyperplasia. Next-generation sequencing in 2 tumors identified similar molecular abnormalities in the sarcomatous and carcinomatous components supporting a clonal relationship. Of 10 patients with available follow-up (median: 18 mo), 8 had no evidence of disease and 2 died of recurrent sarcoma at 7 and 8 months. Endometrioid adenocarcinomas that arise in close spatial association with Müllerian adenosarcoma appear to be clonally related to the sarcoma. Unlike carcinosarcomas, these tumors are usually early stage at presentation. The prognosis appears to be driven by the sarcomatous component. These tumors should be distinguished from carcinosarcomas, dedifferentiated endometrial carcinomas, and corded and hyalinized endometrioid carcinomas., Competing Interests: Conflicts of Interest and Source of Funding: D.I.L. reports current full-time employment at Foundation Medicine which is a whole subsidiary of Roche. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The landscape of uterine sarcomas has greatly expanded in recent years to include neoplasms with recurrent gene fusions, such as BCOR and YWHAE translocated high-grade endometrial stromal sarcomas. Sophisticated molecular techniques have also resulted in the description of "new" entities associated with recurrent kinase fusions involving NTRK and RET as well as COL1A1-PDGFB rearranged uterine sarcomas. These rare neoplasms will be discussed in this review, highlighting that some of the underlying molecular events are clinically actionable and potentially susceptible to targeted therapy. While relatively few of these neoplasms have been described to date, likely being previously lumped under the spectrum of undifferentiated uterine sarcoma, the number of cases will expand in the future given their recognition and the increasing availability of molecular testing. These neoplasms have overlapping morphology (often with a "fibrosarcoma-like" appearance) and immunohistochemical features, and are characterized by variable clinical outcomes. Although immunohistochemistry may assist in some cases, a definitive subclassification requires confirmatory molecular studies. As these molecular assays may not be routinely available in most laboratories, referral to reference centers may be needed. In order to assist the pathologist, we suggest a diagnostic algorithm for routine practice when dealing with a malignant or potentially malignant uterine spindle cell neoplasm., (© 2020 Wiley Periodicals LLC.)

Background: The uterus is one of the most dynamic organs in the human body, and this dynamic homeostasis is supported by endometrial stem/progenitor cells (ES/PCs), which are heterogeneous in their phenotype and degree of differentiation. ES/PCs are generally localized in the endometrial stroma, the site of origin for adenosarcoma and endometrial stromal sarcoma (ESS). Subsets of ESSs and adenosarcomas harbor SUZ12 or DICER1 gene alterations, two genes with roles in embryonic stem cell biology. However, the possible contribution of ES/PCs to tumorigenesis is unexplored., Method: We examined the expression of eleven ES/PC markers, along with three proteins expressed in the mature endometrial stroma (ER, PR and CD10) in 60 uterine tumors (24 low-, 11 high-grade ESS, 25 adenosarcomas). Protein expression profiles were assessed by unsupervised hierarchical clustering. miRNA expression profiles were examined in a subset of adenosarcoma with/without DICER1 mutations, using the NanoString platform., Results: ES/PC markers were variably expressed, and the tumors exhibited limited immunophenotypic resemblance to different ES/PCs. Within the ESSs, the ES/PC marker clustering pattern was prognostic for both overall and disease-free survival. Comparing adenosarcomas and ESSs, most high-grade ESSs clustered with one another, while low-grade ESSs and adenosarcomas tended to cluster with one another. Among the adenosarcomas, the miRNA expression profiles were varied with respect to the DICER1 mutation status, with pathway analysis pointing to dysregulated signal transduction and stem cell biology., Conclusions: ESSs and adenosarcomas exhibit varying immunophenotypic resemblance to ES/PCs. These expression profiles have prognostic implications and may be genetically driven., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Surface epithelial changes involving endometrioid carcinomas of the uterine corpus mimicking papillary syncytial metaplasia or cervical microglandular hyperplasia are relatively common. There have been rare reports of surface epithelial changes in endometrioid carcinomas mimicking ovarian serous borderline tumor or low-grade serous carcinoma. We report an endometrioid carcinoma of the uterine corpus with striking morphologic mimicking of an ovarian serous borderline tumor with only a minimal amount of conventional endometrioid carcinoma. The tumor was diffusely positive for estrogen receptor, negative for WT1, and showed wild-type immunoreactivity with p53. Targeted sequencing revealed a KRAS mutation (G12V/D/A), but no BRAF mutation. This close mimicry of a serous borderline tumor by a uterine endometrioid carcinoma has not been emphasized in the literature and this case is unique because the features involved almost the entire neoplasm. In reporting this case, we review surface changes in endometrioid carcinomas of the uterine corpus.

Embryonal rhabdomyosarcomas (ERMS) account for 2-3% of cancers in pediatric and adolescent populations. They are rarer in adults. We and others have reported that ERMS arising in the uterine cervix may harbor mutations in the gene encoding the microRNA biogenesis enzyme, DICER1, but a large series of cases has not been published. In the uterus, distinguishing ERMS from adenosarcoma can be very challenging, even for expert pathologists, and DICER1 alterations have been identified in a variable subset of uterine adenosarcomas. We hypothesized that DICER1 genetic testing may be useful in distinguishing between ERMS and adenosarcoma. We conducted a central pathology review-based study of 64 tumors initially thought to be uterine ERMS or adenosarcoma; 19 neoplasms had a consensus diagnosis of ERMS, 27 of adenosarcoma and for 18, no consensus diagnosis was reached. The median age at diagnosis was 30 years (range 2.5-69) for ERMS, 57.5 years (range 27-82) for adenosarcoma, and 65.5 years (range 32-86) for no consensus cases. In our series, the DICER1 mutation prevalence differed between the three groups: DICER1 alterations were present in 18/19 (95%) ERMS, 7/27 (26%) adenosarcomas (p < 0.001), and 4/18 (22%) no consensus cases. A germline alteration was present in 6/12 ERMS patients tested versus 0/6 adenosarcoma patients. Thus, although DICER1 mutations are near ubiquitous in uterine ERMS and are significantly less common in uterine adenosarcoma, DICER1 testing is only of value in distinguishing between the two neoplasms when a DICER1 mutation is absent, as this is helpful in excluding ERMS. On review of the clinical and radiological features of the single DICER1 wild-type cervical ERMS, this was thought most likely to be of vaginal origin. Given the significant prevalence of DICER1 germline pathogenic variants in uterine ERMS, all patients with this diagnosis should be referred to a genetics service.

So-called squamous morules are closely associated with endometrioid proliferative lesions, in the endometrium and the ovary. Morules have an unusual immunophenoptype, typically exhibiting nuclear staining with β-catenin, positivity with CDX2, CD10, and p16 and are negative with hormone receptors and p63. We report the previously undescribed occurrence of consistent SATB2 nuclear positivity within morules. Nuclear positivity was present in 38/43 (88%) cases of morules (24 focal; 14 diffuse) while all cases of nonmorular squamous metaplasia in endometrioid proliferative lesions (n=13) were SATB2 negative, except for occasional positive nuclei in 1 case. We also observed that the stromal cells of atypical polypoid adenomyoma typically exhibited diffuse nuclear immunoreactivity with SATB2 while the stromal cells of other endometrial polypoid lesions (endometrial polyp, adenomyoma, adenosarcoma) were usually negative, although there was focal weak staining in occasional cases. Pathologists should be aware of this previously undescribed phenomenon which represents a further example of the unusual immunophenotype of so-called squamous morules. The reasons underlying SATB2 nuclear positivity in squamous morules and the stroma of atypical polypoid adenomyoma are unknown.

Mesenchymal neoplasms of the uterus (corpus and cervix) encompass a heterogeneous group of tumors with differing morphologies, immunophenotypes and molecular alterations. With the advent of modern molecular techniques, such as next generation sequencing, newly defined genetic abnormalities are being reported in this group of neoplasms. Herein we report the clinicopathological and molecular features of a series of 13 spindle cell sarcomas of the uterus and vagina (10 cervix, 2 uterine corpus, 1 vagina) with morphology resembling fibrosarcoma. After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement. All the NTRK fusion-positive sarcomas were located in the cervix and exhibited diffuse staining with Trk while all the other neoplasms were negative. CD34 was diffusely positive in all 3 of the COL1A1-PDGFB fusion sarcomas. The latter molecular abnormality is identical to that commonly found in dermatofibrosarcoma protuberans and has not been reported previously in uterine mesenchymal neoplasms. We suggest that uterine sarcomas with a morphology resembling fibrosarcoma (and in which leiomyosarcoma and the known molecularly confirmed high-grade endometrial stromal sarcomas have been excluded) can be divided into 3 groups:- an NTRK fusion group, a COL1A1-PDGFB fusion group and a group containing neither of these molecular abnormalities which, on the basis of positive staining with S100, could be tentatively classified as malignant peripheral nerve sheath tumor, although additional molecular studies may identify specific genetic alterations necessitating a nomenclature change. We suggest a diagnostic algorithm when reporting such neoplasms. Identification of these newly described fusion-associated sarcomas is important given the potential for targeted treatments.

Mutations of CTNNB1 have been implicated in tumorigenesis in many organs. However, tumors harboring a CTNNB1 translocation are extremely rare and this translocation has never been reported in a uterine mesenchymal neoplasm. We report a novel translocation t(2;3)(p25;p22) involving the GREB1 (intron 8) and CTNNB1 (exon 3) in a uterine tumor resembling ovarian sex cord tumor (UTROSCT), which exhibited extrauterine metastasis. The translocation detected by RNA-sequencing was validated by RT-PCR, and resulted in nuclear expression of β-catenin. Juxtapositioning with GREB1, which is overexpressed in response to estrogens, resulted in overexpression of a truncated and hypophosphorylated nuclear β-catenin in the primary and recurrent tumors. This accumulation of nuclear β-catenin results in a constitutive activation of the Wnt/β-catenin signaling pathway with a major oncogenic effect. The CTNNB1 gene fusion, promoted by an estrogen-responsive gene (GREB1), could be a potential driver of tumorigenesis in this case and a therapeutic target with adapted inhibitors. RT-PCR and immunohistochemistry performed on 11 additional UTROSCTs showed no CTNNB1 fusion transcript or nuclear β-catenin immunoreactivity., (© 2018 Wiley Periodicals, Inc.)

This article provides practical recommendations developed from the International Society of Gynecological Pathologists Endometrial Carcinoma Project to address 4 issues that may arise in the diagnosis of uterine corpus low-grade endometrioid carcinoma: (1) The distinction between atypical hyperplasia and low-grade endometrioid carcinoma. (2) The distinction between low-grade endometrioid carcinoma and serous carcinoma. (3) The distinction between corded and hyalinized or spindle cell variants of low-grade endometrioid carcinoma and carcinosarcoma. (4) The diagnostic criteria for mixed endometrial carcinomas, a rare entity that should be diagnosed only after exclusion of a spectrum of tumors including morphologic variants of endometrioid carcinoma, dedifferentiated endometrial carcinoma, carcinosarcoma, and endometrial carcinomas with ambiguous morphology.

Inflammatory myofibroblastic tumor (IMT) is a myofibroblastic/fibroblastic neoplasm of intermediate malignant potential. It is frequently characterized by genetic fusion of ALK with a variety of partner genes, which results in the activated ALK signaling pathway that can be targeted with kinase inhibitors. IMTs can occur in the gynecologic tract, with the uterus (corpus and cervix) being the most frequent site. Recent studies suggest that IMTs in the gynecologic tract are underrecognized, and a low-threshold for performing ALK immunohistochemistry has been proposed. The aim of this study was to evaluate the specificity of ALK immunohistochemistry for IMTs among uterine mesenchymal and mixed epithelial/mesenchymal tumors. We performed ALK immunohistochemistry on 14 molecularly confirmed uterine IMTs and 260 other uterine pure mesenchymal and mixed epithelial/mesenchymal tumors. Cases showing any positive cytoplasmic and/or membranous staining of the tumor cells were considered to be ALK positive. All 14 IMTs were confirmed to harbor ALK genetic fusion by RNA sequencing, and ALK immunostaining in the form of granular cytoplasmic positivity with paranuclear accentuation was observed in all 14 cases. ALK was negative (complete absence of staining) in all the other pure mesenchymal tumors and in all mixed epithelial/mesenchymal tumors examined. Our findings show that ALK is a highly specific diagnostic immunohistochemical marker for ALK fusion in uterine mesenchymal tumors. In the work-up of uterine mesenchymal tumors, particularly smooth muscle tumors showing myxoid stromal changes, a diagnosis of IMT should be strongly considered if ALK positivity is observed.

Mesonephric adenocarcinoma most commonly arises in the cervix and is presumed to be derived from normal or hyperplastic mesonephric remnants. It is characterized by recurrent KRAS mutations and lack of PIK3CA/PTEN alterations. Adenocarcinomas of the uterine corpus and ovary characterized by morphologic and immunophenotypic similarities to mesonephric adenocarcinoma have been reported. The pathogenesis of these tumors, which have been designated "mesonephric-like adenocarcinomas" is unknown, and it has been debated whether these represent mesonephric adenocarcinomas that arise in the endometrium/ovary or endometrioid adenocarcinomas that closely mimic mesonephric adenocarcinoma. The relationship at the molecular level between mesonephric adenocarcinomas and mesonephric-like adenocarcinomas is unknown. The aim of this study was to examine the molecular alterations in mesonephric-like adenocarcinomas to identify driver mutations and potential therapeutically targetable mutations, and to determine the relationship between mesonephric-like adenocarcinomas and mesonephric adenocarcinomas using targeted next-generation sequencing. Seven mesonephric-like adenocarcinomas (4 ovarian, 3 uterine corpus) underwent targeted next-generation sequencing to detect mutations, copy number variations and structural variants in exonic regions of 300 cancer genes, and 113 selected intronic regions across 35 genes. All 7 tumors (100%) harbored canonical activating KRAS mutations (4 G12D, 3 G12V). PIK3CA activating mutations were identified in 3 of 7 (43%) cases. There were no alterations in PTEN, ARID1A, or TP53 in any of the tumors. In copy number analysis, 5 of 7 (71%) tumors exhibited 1q gain, which was accompanied by 1p loss in 2 cases. In addition, 4 of 7 (57%) tumors had chromosome 10 gain, which was accompanied by gain of chromosome 12 in 3 cases. Mesonephric-like adenocarcinomas, similar to mesonephric adenocarcinomas, are characterized by recurrent KRAS mutations, gain of 1q, lack of PTEN mutations, and gains of chromosomes 10 and 12. PIK3CA mutations, which have not previously been identified in mesonephric adenocarcinoma, were found in 3 of 7 (43%) mesonephric-like adenocarcinomas in our study. Mesonephric-like adenocarcinomas exhibit strikingly similar molecular aberrations to mesonephric adenocarcinomas, but also frequently harbor PIK3CA mutations, demonstrating biological overlap with carcinomas of both mesonephric and Mullerian (endometrioid) differentiation. Given the previously documented association with endometriosis (ovarian neoplasms) and the prominent endometrial involvement (uterine corpus neoplasms), we believe these are best regarded as of Mullerian origin and representing adenocarcinomas which differentiate along mesonephric lines; as such, we propose the term mesonephric-like Mullerian adenocarcinoma.

Aims: Uterine tumour resembling ovarian sex cord tumour (UTROSCT) is an uncommon mesenchymal neoplasm of uncertain histogenesis. While it is considered a neoplasm of uncertain but low malignant potential, there is limited evidence for this as there are no large studies with follow-up. We aimed to determine the clinical behaviour of this uncommon neoplasm and investigate clinicopathological parameters which predict behaviour., Methods and Results: From a series of 34 cases of UTROSCT, mainly from consultation practice, we obtained follow-up information which was obtained by contacting referring pathologists and clinicians. The follow-up periods ranged from 6 to 135 months (mean 39 months). Eight of 34 patients (23.5%) developed extrauterine metastasis to a variety of sites, including pelvic and abdominal peritoneum, ovary, lymph nodes, bone, liver and lung, and three patients (8.8%) died of tumour. Those neoplasms which exhibited malignant behaviour occurred on average in older patients, and were larger and more likely to exhibit necrosis, lymphovascular invasion, cervical involvement, significant nuclear atypia and significant mitotic activity. However, only the presence of necrosis and significant mitotic activity was statistically significant., Conclusions: While our figure of 23.5% of cases exhibiting malignant behaviour may reflect some bias related to consultation practice our results show that, not uncommonly, these neoplasms have an aggressive clinical course with extrauterine metastasis. Given the overlap in pathological parameters between clinically benign and malignant neoplasms, UTROSCTs are all best regarded as potentially malignant., (© 2017 John Wiley & Sons Ltd.)

Inflammatory myofibroblastic tumor (IMT) can occur in a number of anatomic sites, including the uterus. Like its soft tissue counterpart, uterine IMT frequently expresses ALK and harbors ALK genetic rearrangements. The aim of this study is to fully characterize the genetic fusions that occur in uterine IMT. We studied 11 uterine IMTs with typical histology and 8 uterine myxoid smooth muscle tumors (5 leiomyomas, 1 smooth muscle tumor of uncertain malignant potential, and 2 leiomyosarcomas) in which the differential of IMT was considered, using a RNA-sequencing-based fusion assay to detect genetic fusions involving ALK, ROS1, RET, NTRK1/3, and other genes. ALK was expressed in 10 of 11 IMTs and 1 tumor initially categorized as a myxoid leiomyoma (granular cytoplasmic staining with paranuclear accentuation). Fusion transcripts involving ALK were identified in 9 of 10 ALK immunopositive IMTs, with 3 harboring IGFBP5-ALK, 3 harboring THBS1-ALK, 2 harboring FN1-ALK, and 1 harboring TIMP3-ALK. Among the smooth muscle tumors, IGFBP5-ALK fusion transcript was identified in only 1 ALK immunopositive case. Further review revealed that although a diagnosis of IMT was considered for the ALK immunopositive myxoid leiomyoma, this diagnosis was not initially rendered only because fluorescence in situ hybridization analysis was interpreted as negative for ALK genetic rearrangement; this case is best reclassified as an IMT. Notably, all the ALK fusions identified in our study included the transmembrane domain-encoding exon 19 of ALK. Our findings confirm the high frequency of ALK fusions in uterine IMT, with an enrichment of novel 5' ALK fusion partners (IGFBP5, THBS1, and TIMP3) and exon 19-containing ALK fusion. Given that IGFBP5 and FN1 are both situated on the same chromosome as ALK, fluorescence in situ hybridization analysis for ALK rearrangement may not be reliable and a negative result should not exclude a diagnosis of uterine IMT if the histologic features and ALK immunostaining findings are supportive.

We investigated the frequency, histopathologic, and immunohistochemical characteristics of tubal involvement in uterine serous carcinoma (USC) and aimed to clarify the relationship between "serous tubal intraepithelial carcinoma (STIC)" and USC in these cases. Cases of USC with complete tubal examination were prospectively collected and reviewed for the presence of tubal involvement. Immunohistochemical analysis for p53 and WT1 was performed on the endometrial and tubal tumor in cases with tubal involvement. Of 161 USC cases (pure USC or a component of a mixed carcinoma or a carcinosarcoma), 32 (20%) showed tubal involvement (unilateral: n=19; bilateral: n=13). The uterine tumors in cases with tubal involvement showed a trend toward increased likelihood of deep myometrial and lymphovascular invasion (LVI) compared with those without tubal involvement. The tubal fimbriae were involved in 15/32 cases. Tubal involvement was mucosal in 30/32 cases, mural in 14/32, serosal in 5/32, invasive in 22/32, and there was LVI in the tube in 13/32. STIC-like features were seen in 17/32 cases (7 as the only pattern of involvement, 9 with associated invasive carcinoma, and 5 with LVI). Immunostaining showed complete concordance of p53 and WT1 between the endometrial and tubal tumors in 26/32 cases, the majority being WT1 negative or only focally positive (19/26), and all exhibiting mutation-type p53 staining. On the basis of the histologic and immunohistochemical features, the tubal tumor was considered to represent metastatic USC in 26/32 cases, most likely metastatic USC in 2/32 cases, an independent tubal primary tumor in 3/32 cases, and to be of uncertain origin in the 1 remaining case. STIC-like lesions were considered to represent metastatic USC in 12/17 cases, most likely metastatic USC in 2/17 cases, an independent tubal primary in 2/17 cases, and of uncertain origin in the 1 remaining case. Tubal involvement, including STIC-like lesions, is seen in one fifth of USC when the tubes are examined in their entirety. The tubal involvement is metastatic in the vast majority of cases. Immunohistochemical studies assist, in most cases, in confirming the metastatic nature of the tubal disease. Consideration should be given to completely examining the fallopian tubes in apparent stage I or II USCs, as this will result in upstaging in a significant minority of cases.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare neoplasm which morphologically and immunohistochemically exhibits overlap with an ovarian sex cord tumor. Although many of these neoplasms are positive with markers of ovarian sex cord-stromal tumors, staining is often limited and the pathogenesis of UTROSCT is unknown. To further explore the sex cord lineage of UTROSCT, we studied 19 of these neoplasms and examined the expression of 2 recently described markers of ovarian sex cord-stromal tumors, FOXL2, and steroidogenic factor-1. We also undertook FOXL2 and DICER1 mutation analysis in these cases; a somatic missense mutation in codon C134W (402C→G) of FOXL2 gene has been demonstrated in the vast majority (>95%) of ovarian adult granulosa cell tumors and somatic DICER1 mutations are found in approximately 60% of ovarian Sertoli-Leydig cell tumors. Ten of 19 cases (53%) exhibited nuclear immunoreactivity with FOXL2 and 11 of 19 (58%) exhibited nuclear staining with steroidogenic factor-1. Neither FOXL2 nor DICER1 mutations were identified in any case where there was sufficient tumor tissue for analysis (18 and 9 cases, respectively). Despite exhibiting an immunophenotype characteristic of a sex cord-stromal tumor, mutations in FOXL2 and DICER1, the 2 most common mutations hitherto reported in ovarian sex cord-stromal tumors, are not a feature of UTROSCT.

Aims: To report a series of uterine corpus (n = 7) and ovarian (n = 5) neoplasms which we believe probably represent mesonephric adenocarcinomas based on their characteristic morphology and immunophenotype., Methods and Results: All neoplasms exhibited a relatively constant and characteristic morphological appearance with an admixture of architectural patterns with small glands or tubules, some containing luminal eosinophilic colloid-like material, typically predominating. Solid and papillary architectures were also often present. The nuclear features were characteristic with atypical angulated clear vesicular nuclei which often exhibited overlapping. All the tumours were 'flat' negative with oestrogen receptor and progesterone receptor and all except one exhibited nuclear staining with thyroid transcription factor 1 (TTF1), which was often diffuse. All tumours exhibited wild-type staining with p53. CD10, calretinin and GATA binding protein 3 (GATA3) were positive in a variable proportion of the neoplasms., Conclusions: We believe these neoplasms to represent mesonephric adenocarcinomas which have only rarely been reported to arise in the uterine corpus and never in the ovary. We recommend they be termed mesonephric-like adenocarcinomas until their histogenesis is firmly established., (© 2015 John Wiley & Sons Ltd.)

The current 2014 World Health Organization (WHO) Classification of mixed epithelial and mesenchymal tumours of the uterus includes categories of carcinosarcoma, adenosarcoma, adenofibroma, adenomyoma and atypical polypoid adenomyoma, the last two lesions being composed of an admixture of benign epithelial and mesenchymal elements with a prominent smooth muscle component. In this review, each of these categories of uterine neoplasm is covered with an emphasis on practical tips for the surgical pathologist and new developments. In particular, helpful clues in the distinction between carcinosarcoma and dedifferentiated endometrial carcinoma will be discussed. In addition, salient features to help distinguish between adenofibroma, adenosarcoma, embryonal rhabdomyosarcoma and other mesenchymal neoplasms in the differential diagnosis will be outlined. Finally, a discussion of adenomyoma and its main differential diagnostic considerations will be covered.

Mesonephric carcinoma is a rare form of gynecologic cancer derived from mesonephric remnants usually located in the lateral wall of the uterine cervix. An analogous tumor occurs in the adnexa, female adnexal tumor of probable Wolffian origin. The pathogenesis and molecular events in mesonephric carcinoma are not known. The aim of this study was to examine the molecular alterations in mesonephric carcinoma to identify driver mutations and therapeutically targetable mutations. This study consisted of 19 tumors from 17 patients: 18 mesonephric carcinomas (15 primary tumors and three metastatic tumors) and 1 female adnexal tumor of probable Wolffian origin. In two patients, both primary and metastatic tumors were available. Genomic DNA was isolated and targeted next-generation sequencing was performed to detect mutations, copy number variations, and structural variants by surveying full exonic regions of 300 cancer genes and 113 selected intronic regions across 35 genes. Fluorescence in situ hybridization (FISH) for 1p and 1q was performed in two cases. Eighty-one percent (13/16) of mesonephric carcinomas had either a KRAS (n=12) or NRAS (n=1) mutation. Mutations in chromatin remodeling genes (ARID1A, ARID1B, or SMARCA4) were present in 62% of mesonephric carcinomas. All mesonephric carcinomas lacked mutations in PIK3CA and PTEN. The most common copy number alteration was 1q gain, found in 12 (75%) mesonephric carcinomas; this was confirmed by FISH in two cases. Mesonephric carcinoma is characterized by molecular alterations that differ from those of more common variants of cervical and endometrial adenocarcinoma, which harbor KRAS/NRAS mutations in 7% and 25% of cases, respectively. KRAS/NRAS mutations are common in mesonephric carcinoma and are often accompanied by gain of 1q and mutations in chromatin remodeling genes. Targeting inhibitors of the RAS/MAPK pathway may be useful in the treatment of mesonephric carcinoma.

Atypical polypoid adenomyoma (APA) is an uncommon uterine lesion that commonly recurs after local excision and is occasionally associated with or precedes the development of atypical hyperplasia or endometrioid adenocarcinoma. Despite the fact that about 230 cases have been reported in the literature, only 2 studies of 6 and of 7 cases have investigated the molecular aspects; as such, molecular alterations that occur in APA remain largely unknown. We undertook a comprehensive immunohistochemical and molecular analysis of 21 cases of APA in 17 patients (including 4 recurrent/persistent lesions). The analyzed genes were PTEN and TP53 (by fluorescence in situ hybridization) and KRAS, BRAF, EGFR, and NRAS (all by polymerase chain reaction). Immunohistochemical staining was performed for PTEN, p53, mTOR, β-catenin, HNF-1β, and GLUT1 and for the mismatch-repair proteins MLH-1, MSH-2, MSH-6, and PMS-2. In most cases, there was nuclear expression of β-catenin in squamous morules and expression of HNF-1β, mTOR, and GLUT1 in the glandular component. All cases exhibited "wild-type" expression of p53. A common finding was loss of PTEN expression (6/19 cases). In 1 of these cases, loss of PTEN expression was accompanied by PTEN deletion. Mutation of the KRAS gene was found in 5/19 cases. Intact mismatch-repair protein expression was present in all cases, and TP53 abnormalities or mutations of EGFR, NRAS, or BRAF genes were not found. Given the association with atypical hyperplasia and endometrioid adenocarcinoma and the shared immunohistochemical and molecular features, we feel that, conceptually, APA is best regarded as analogous to a localized form of atypical hyperplasia.

We report 2 ovarian neoplasms in women aged 58 and 69 years composed of an admixture of adenosarcoma and a predominant stromal component morphologically and immunohistochemically in keeping with juvenile granulosa cell tumor. As far as we are aware, this association has not been reported previously. We speculate that, in both cases, the juvenile granulosa cell tumor component arose from the adenosarcoma as an unusual form of sarcomatous overgrowth of sex cord elements., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The contemporary oncologic pathology report conveys diagnostic, prognostic, predictive, and hereditary predisposition information. Each component may be premised on a morphologic feature or a biomarker. Clinical validity and reproducibility are paramount as is standardization of reporting and clinical response to ensure individualization of patient care. Regarding hereditary predisposition, morphology-based genetic referral systems in some instances have eclipsed genealogy-based systems, for example, cell type in ovarian cancer and BRCA screening. In other instances such as Lynch syndrome, morphology-based schemas supplement clinical schemas and there is an emerging standard of care for reflex biomarker testing. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome predisposes patients to uterine and cutaneous leiomyomas (LMs) and renal cell carcinomas (RCCs). Several authors have emphasized the role pathologists may play in identifying this syndrome by recognizing the morphologic characteristics of syndromic uterine LMs and RCCs. Recently immunohistochemical overexpression of S-(2-succinyl) cysteine (2SC) has been demonstrated as a robust biomarker of mutation status in tumors from HLRCC patients. In this blinded control-cohort study we demonstrate that the proposed morphologic criteria used to identify uterine LMs in HLRCC syndrome are largely irreproducible among pathologists and lack sufficient robustness to serve as a trigger to triage cases for 2SC immunohistochemistry or patients for further family/personal history inquiry. Although refinement of morphologic criteria can be considered, in view of the availability of a clinically robust biomarker, consideration should be given to reflex testing of uterine LMs with an appropriate age cut off or in the setting of a suspicious family history.

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.

In its classical form, embryonal rhabdomyosarcoma (ERMS, botryoid type) is a vaginal neoplasm occurring in infants and young girls and is often not considered in the differential diagnosis of uterine corpus and cervical spindle cell tumors in adult women. Clinicopathologic and immunohistochemical features of 25 cases of ERMS in women 20 years of age or older were analyzed. Patient age ranged from 20 to 89 years (mean, 44.4 y; median, 46 y), with 8 patients aged 20 to 39 years, 14 patients aged 40 to 59 years, and 3 patients older than 60 years of age. Tumors originated in the cervix in 20 cases and in the uterine corpus in 5. They were characterized by an edematous hypocellular spindle cell proliferation, typically with cellular condensation beneath epithelial surfaces (cambium layer), in which tightly packed hypercellular foci were scattered. Neoplastic cells had hyperchromatic nuclei and minimal cytoplasm, usually with delicate cytoplasmic processes. Occasionally, elongated or globular cells with eosinophilic cytoplasm (rhabdomyoblasts) were evident, but cytoplasmic cross-striations were only rarely identified. Apoptotic bodies and mitotic figures were usually identified in the hypercellular foci. Hemorrhage was common, often making recognition of the hypercellular foci difficult. Desmin and myogenin were coexpressed in 22 of 23 (95.6%) tumors evaluated. Proliferative activity, as assessed by Ki-67 expression, was notably elevated in all tumors evaluated, typically concentrated in the hypercellular foci. Estrogen and progesterone receptors were expressed focally in only 3 of 12 (25%) and 1 of 8 (12.5%) tumors evaluated, respectively. Follow-up was available in 7 cases. Five patients were alive without evidence of disease with follow-up of 3 to 8 years, and 1 patient was alive with disease at 5 months. One patient died at 5 months with pulmonary nodules, but it was not determined whether this was due to metastatic ERMS or the patient's known ductal breast carcinoma. ERMS has a broader clinical profile than classically expected and should be considered in the differential diagnosis of a uterine corpus or cervical spindle cell tumor, regardless of patient age. Recognition can be rendered difficult by the hypocellular background, which can suggest a benign polyp or low-grade tumor, and hemorrhage, which can obscure the characteristic hypercellular foci. Identification of hypercellular foci in which mitotic activity and apoptotic bodies are found, desmin and myogenin are coexpressed, proliferative activity is notably elevated, and hormone receptor expression is usually absent is very useful for establishing the diagnosis.

Objectives: The objective of this study was to investigate the relationship between BRCA1 protein expression, as determined by immunohistochemistry, and clinical outcome in uterine serous carcinoma (USC)., Methods: A tissue microarray containing duplicate cores of 73 cases of USC was immunohistochemically stained with mouse anti-BRCA1 (Ab-1) mouse monoclonal (MS110) antibody. The cores were scored in a semiquantitative manner evaluating both the distribution and intensity of nuclear staining. BRCA1 protein expression was correlated with progression-free survival., Results: Seventy-two of 73 cases were assessable, and there was a statistically significant decreased progression-free survival for those cases exhibiting tumor cell nuclei staining of 76% or greater (P = 0.0023)., Conclusions: Our study illustrates that a low level of BRCA1 protein expression is a favorable prognostic indicator in USC, similar to what is observed in high-grade serous ovarian carcinoma. Further studies should focus on the BRCA1 status of USCs at a molecular level and also investigate whether BRCA1 protein expression is associated with response to chemotherapy in USC.

Aims: DOG1 is a recently described marker of gastrointestinal stromal tumour (GIST) which is considered to be extremely sensitive and, among mesenchymal neoplasms, quite specific for this tumour type. Following the identification of DOG1 immunoreactivity in a uterine leiomyosarcoma, we wished to ascertain how prevalent DOG1 immunoreactivity was in this tumour type., Methods: We stained a series of uterine leiomyosarcomas (n=26) with DOG1 and with CD117 (c-kit), another marker of GIST. Staining with both markers was classified as negative, focal (<50% tumour cells positive) or diffuse (≥50% tumour cells positive)., Results: DOG1 immunoreactivity was present in seven of 26 (27%) leiomyosarcomas. Staining was focal in five cases and diffuse in two. CD117 was positive in three of 26 (11.5%) cases, two focal and one diffuse. Two cases were positive with DOG1 and CD117. One of five uterine leiomyomas was focally positive with DOG1, and one extrauterine pelvic leiomyoma was diffusely positive with this marker., Conclusions: Since GISTs have rarely been described as primary uterine neoplasms, the presence of DOG1 immunoreactivity in a uterine leiomyosarcoma may result in diagnostic confusion, and a panel of markers is necessary for diagnosis. Uterine leiomyosarcomas should be added to the list of mesenchymal neoplasms which may be DOG1 positive.

Stromal myxoid change is a rare feature of non-neoplastic disease of the uterus. "Myometrial myxoidosis" with secondary myometrial hypertrophy was reported in 2 patients with systemic lupus erythematosus. Uterine myxoid stromal change was also described as an unusual pseudoneoplastic condition of uncertain etiology in 3 patients, one of whom had neurofibromatosis type 1 (NF1; von Recklinghausen disease). We have now identified multifocal uterine myxoid change in the hysterectomy specimen of another patient with NF1; we describe the findings in both patients and review the relevant literature. The myometrium and cervical stroma in both NF1 patients contained tracts and nodules of hypocellular myxoid stromal material composed of bland spindle-shaped cells and interspersed small blood vessels. The myxoid stromal material was strongly and diffusely immunopositive for CD34 and CD10 but did not label for desmin, smooth muscle actin, h-caldesmon, neurofilament protein, S100, or epithelial membrane antigen. The myxoid material in the NF1 patients was better demarcated than in the 2 reported cases of myometrial myxoidosis in systemic lupus erythematosus, and more widely distributed, extensively involving the cervix and the myometrium. The occurrence of this rare, distinctive pattern of multifocal uterine myxoid change in 2 patients with NF1 seems unlikely to represent simply a chance association. The identification of multifocal uterine myxoid change in non-neoplastic myometrium or cervical stroma should raise the possibility of underlying NF1.

Uterine serous carcinoma (USC) is an aggressive variant of Type 2 endometrial carcinoma, which in most cases exhibits, at least focally, a papillary architecture. Occasionally, especially in small biopsy specimens, it may be difficult to distinguish between USC and a variety of metaplastic or reactive processes. In particular, papillary syncytial metaplasia (PSM), as a result of endometrial breakdown, may be confused with USC or its precursor serous endometrial intraepithelial carcinoma. In such cases, immunohistochemistry is often undertaken, the panel of markers usually including estrogen receptor (ER), p53, p16, and MIB1. The expected immunoprofile of USC is ER negative, p53 and p16 positive, and a high MIB1 proliferation index, although studies have shown that significant numbers of cases deviate from this immunophenotype. With regard to the aforementioned markers, PSM has not been studied extensively, but intuitively, the expected immunophenotype would be ER positive, p53 and p16 negative, and a low MIB1 proliferation index. After 2 index cases in which breaking down menstrual endometrium with florid PSM was misdiagnosed on an endometrial biopsy as USC or suspected USC, in part due to the observed immunophenotype, we studied the expression of ER, p53, p16, MIB1, and HMGA2 (a recently described useful marker of USC) in 10 further cases of PSM associated with endometrial breakdown. We illustrate that compared with a nonbreaking down endometrium, PSM is characterized by a decreased expression of ER and an increased expression of p53 (although still wild-type staining) and p16, the latter marker typically being diffusely positive. HMGA2 is negative, and there is a low MIB1 proliferation index. In cases of PSM, which are morphologically problematic, the immunophenotype may further heighten the suspicion of serous malignancy and potentially result in a misdiagnosis.

Aims: Serous carcinoma is the prototype of type 2 uterine carcinoma. In many cases, establishing a diagnosis is straightforward, but problems can arise in that papillary variants of endometrioid carcinoma may be mistaken for serous carcinoma, and glandular variants of serous carcinoma may be misdiagnosed as endometrioid carcinoma. Markers such as p53, oestrogen receptor and p16 may be of use in problematic cases, but there is overlap and these may not therefore be of value in an individual case. It has been shown recently that high-mobility group AT-hook 2 (HMGA2) is expressed by most ovarian serous carcinomas, and our aim was to ascertain whether it is also expressed in uterine serous carcinoma and of value in its distinction from endometrioid carcinoma., Methods and Results: Whole tissue sections of uterine serous (n = 33) and endometrioid (n = 38) carcinoma were immunostained using HMGA2 antibody. As many of the diagnostic problems relate to the distinction between serous carcinoma and grade 3 endometrioid carcinoma, tissue microarrays (TMAs) containing uterine serous (n = 71) and uterine grade 3 endometrioid (n = 68) carcinomas were also stained. Staining was classified as negative (totally negative or occasional nuclei positive), 1+ (<10% of nuclei positive), 2+ (10-49% of nuclei positive), 3+ (50-74% of nuclei positive), or 4+ (≥75% of nuclei positive). On the whole tissue sections, positive staining was also classified as weak, moderate, or strong, and an immunohistochemical composite score, taking into account both extent and intensity of staining, was calculated. On whole tissue sections, there was a statistically significant difference between HMGA2 staining in serous and endometrioid carcinomas with regard to both extent and composite score, with higher expression in serous carcinomas (P < 0.0001). Thirty of 33 (91%) serous carcinomas were positive, usually with diffuse (3+ or 4+) staining. All five cases of serous endometrial intraepithelial carcinoma (EIC) (the postulated precursor of uterine serous carcinoma) were positive, as were 14 of 38 (37%) endometrioid carcinomas, usually with 1+ or 2+ staining. There was a statistically significant difference in HMGA2 staining in the TMAs between the serous and grade 3 endometrioid carcinomas, with higher expression in the former (P < 0.0001)., Conclusions: Immunoreactivity for HMGA2 is diffusely positive in whole tissue sections in most uterine serous carcinomas and negative in most endometrioid carcinomas, although, as with other markers, there is overlap in individual cases. In conjunction with other markers, HMGA2 may be of value in problematic uterine carcinomas where the differential diagnosis includes serous and endometrioid carcinoma. As HMGA2 is expressed in serous EIC, this suggests that it may be implicated in the early development of uterine serous carcinoma., (© 2012 Blackwell Publishing Ltd.)

Malignant transformation of a uterine leiomyoma is an exceedingly rare phenomenon. Previous reported examples of malignant neoplasms to arise so include leiomyosarcoma, angiosarcoma, and malignant mesenchymoma. We report an intramural carcinosarcoma arising in a uterine leiomyoma in a 38-year-old woman. This case is unique in being the first recorded carcinosarcoma arising within a uterine leiomyoma and the first example of an epithelial neoplasm to do so. We discuss the differential diagnosis and possible pathogenesis of the tumor that has likely arisen secondary to epitheliogenesis in a mesenchymal neoplasm.

Uterine adenosarcomas are uncommon mixed Müllerian neoplasms, most commonly arising in the uterine corpus. A new Federation of International Gynecologic Organization staging system for these tumors has recently been implemented. This staging system is an improvement on the earlier generic application of the 1988 Federation of International Gynecologic Organization staging system for endometrial cancer to adenosarcoma. Herein, we report 3 uterine adenosarcomas with unusual features. For 2 of these, no specific staging guidelines are provided by either the earlier or, more importantly, the new staging system. The first case is of an adenosarcoma arising in the eutopic endometrium with involvement of underlying adenomyosis without myometrial invasion; the second originated in a mural adenomyoma in the absence of eutopic endometrial involvement; and the third case encompassed synchronous endometrial and extrauterine (peritoneal) neoplasms. Such cases are rare, and there is insufficient evidence to be definitive about staging. Thus, we suggest a descriptive reporting strategy for adenosarcomas with these unusual features. We also propose a reporting nomenclature for such cases to ensure standardization such that they can be adequately recorded in synoptic reporting protocols. This will facilitate reliable data collection such that an evidence-based staging system for these scenarios may be derived.

Background: Uterine leiomyomas are extremely common in surgical pathology practice and in the vast majority there are no issues in diagnosis. Progestogens are widely prescribed drugs for a variety of indications, including abnormal uterine bleeding, and are often given to women with leiomyomas but the pathological features of leiomyomas treated with progestogens are poorly described., Methods: We report the pathological features in eight cases of uterine leiomyomas in women who had been treated with oral progestogens or a progestogen-containing intrauterine device; all cases were received in consultation because the features raised concern for leiomyosarcoma, smooth muscle tumour of uncertain malignant potential or a benign leiomyoma with unusual features. Additionally, we reviewed a series of cases of uterine leiomyomas (n=99) in women who exhibited progestogenic effects in the endometrium., Results: The morphological features in the consult cases, which were widespread and marked and which varied somewhat from case to case, included small and/or large areas of infarct-type necrosis (sometimes mimicking coagulative tumour cell necrosis) with surrounding increased cellularity, mitotic activity, nuclear pyknosis, cytoplasmic eosinophilia, epithelioid morphology, stromal oedema, haemorrhage, and myxoid change and infiltration by CD56 positive granulated lymphocytes. Sometimes the features resulted in an almost deciduoid appearance. Similar features were present to a minor degree in significant numbers of the additional series of cases., Conclusions: Pathologists should be aware of these progestogen-associated features when reporting uterine leiomyomas whether or not the clinician has indicated that the woman is taking progestogens since otherwise a diagnosis of leiomyosarcoma or smooth muscle tumour of uncertain malignant potential may be rendered. Useful features in suggesting a benign leiomyoma, in addition to recognition of the morphological features described which, in combination, are characteristic of progestogens, are the lack of true nuclear atypia and the low mitotic activity away from the abnormal areas.

We report 3 cases of a hitherto undescribed phenomenon in women aged 46 to 49 in which there was replacement of the myometrium or cervical stroma by an accumulation of hypocellular myxoid stromal material containing bland spindle-shaped cells and small blood vessels. In all cases, this change was conspicuous, and in 2 it was multifocal and widespread, resulting in consideration of an infiltrative myxoid mesenchymal neoplasm. Immunohistochemistry revealed a characteristic immunophenotype with diffuse strong positivity with CD34 and CD10 but no immunoreactivity with the smooth muscle markers desmin, alpha-smooth muscle actin, and h-caldesmon. In comparison, 3 cases of uterine myxoid leiomyoma were positive with smooth muscle markers and negative with CD34 and CD10. We believe the lesion we describe to be an unusual pseudoneoplastic, possibly degenerative, phenomenon. The patients past medical histories were unremarkable, with no history of connective tissue disease (myometrial myxoidosis has rarely been described in association with lupus erytematosus) or Carney's syndrome. Two patients had been prescribed local or systemic progestogens, raising the possibility of an association with these compounds. Pathologists should be aware of this unusual pseudoneoplastic phenomenon to avoid a misdiagnosis of a neoplastic lesion.

Mullerian adenosarcoma is an uncommon, but not rare, mixed tumor containing a neoplastic but benign or mildly atypical epithelial element and a sarcomatous, usually low-grade, stromal component. The most common site is the uterine corpus but adenosarcoma also occurs in the cervix and ovary and more rarely in the vagina, fallopian tube, arising from peritoneal surfaces, or outside the female genital tract, for example in the intestine. Most uterine cases have a polypoid gross appearance, sometimes resulting in the formation of multiple polyps. Characteristic histologic features include a low power "phyllodes-like" architecture with leaf-like projections lined by a variety of benign Mullerian type epithelia, sometimes with squamous metaplasia. Intraglandular stromal protrusions are a characteristic feature. The stroma may be uniformly cellular but there is typically increased cellularity around the epithelial elements, resulting in the formation of a cambium layer. Using the World Health Organization definition, stromal mitotic activity of 2 or more per 10 high-power fields is required for a diagnosis of adenosarcoma but in practice the diagnosis is made with stromal mitotic activity less than this if the characteristic architecture and cambium layer is present. The stromal component is usually morphologically "low-grade" and of endometrial stromal or fibroblastic type (hormone receptor and CD10 positive). Sometimes it is high grade, resembling undifferentiated sarcoma. Additional features sometimes present include heterologous stromal elements or sex cord-like differentiation. Uterine adenosarcomas are, in general, low-grade neoplasms capable of local recurrence after polypectomy or hysterectomy and much less commonly distant metastasis. The 2 most important adverse prognostic factors, which sometimes coexist, are deep myometrial invasion and sarcomatous overgrowth; the latter is usually associated with morphologically "high-grade" stromal elements with loss of expression of hormone receptors and CD10. Adenosarcoma may be confused with a variety of lesions and one of the main differential diagnoses is adenofibroma in which the stromal component is, by definition, morphologically benign. However, occasional adenofibromas recur or even metastasize. As such, it has been suggested that all adenofibromas should be classified as adenosarcomas, albeit with low-malignant potential. Ovarian adenosarcomas are much more likely to exhibit malignant behavior than their uterine counterparts, probably due to the lack of an anatomic barrier to peritoneal dissemination.

We describe a highly unusual lesion characterized grossly by the formation of a cavity within the lower uterine segment and upper endocervix that communicated with bilateral fistulae to both parametria. Histologically, the cavity and fistulous tracts were entirely coated by fibrinous material with underlying intermediate trophoblastic cells with atypical degenerate nuclei, absent mitotic activity, and a low MIB1 proliferation index. The overall cellular morphology of the lesion was similar to that of the well-circumscribed placental site nodule or plaque. Apart from the lining of the fistulae, there was no invasion of the myometrium by the trophoblastic cells. The patient had undergone previous cesarean deliveries; the lesion was related to the surgical site and was probably secondary to the previous surgery. In a review of the literature, we identified only a single previous report of a somewhat similar case. We propose the term uterine diffuse intermediate trophoblastic lesion resembling placental site plaque for this rare condition.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare uterine neoplasm composed predominantly or exclusively of cells which resemble those seen in sex cord tumors of the ovary. Since its initial morphologic description, it has been unclear whether UTROSCT represents a variant within the spectrum of endometrial stromal tumors (ESTs), which may rarely exhibit areas of sex cord-like differentiation, or whether it is a distinct uterine neoplasm unrelated to ESTs. Recently, several studies have revealed a recurrent t(7;17) translocation resulting in a JAZF1-JJAZ1 gene fusion in over 60% of EST and its variants, including 2 out of 4 endometrial stromal tumors with sex cord-like elements (ESTSCLE). We examined UTROSCTs for evidence of the JAZF1-JJAZ1 gene fusion by fluorescence in situ hybridization and by reverse transcriptase polymerase chain reaction in 24 and 20 cases, respectively. The JAZF1-JJAZ1 gene fusion was not identified in any tumor by either method. Although we cannot entirely exclude that UTROSCT represents a variant of ESTSCLE which lacks this translocation, our findings suggest that UTROSCT does not share the genetic mechanism common to the majority of ESTs with or without sex cord-like differentiation, and therefore most likely represents a distinct neoplasm unrelated to ESTSCLE.

Summary: We report a rare composite uterine mesenchymal neoplasm in a 66-year-old woman composed of approximately equal amounts of leiomyosarcoma and embryonal rhabdomyosarcoma, the latter containing foci of immature cartilage. Immunohistochemically, both components were positive with desmin. The leiomyosarcomatous element was positive with alpha smooth muscle actin and h-caldesmon and the rhabdomyosarcomatous component with myogenin and myo-D1. In a review of the literature, we have identified only a single example of a similar case. This is likely to represent rhabdomyosarcomatous differentiation in a leiomyomatous neoplasm or alternatively bidirectional differentiation from an uncommitted mesenchymal stem cell.