Deyin Xing

Identifying mesonephric‐like adenocarcinoma of the endometrium by combining SOX17 and PAX8 immunohistochemistry

AimsMesonephric‐like adenocarcinoma (MLA) of the endometrium or ovary is a rare but distinct endometrial carcinoma which has a combination of characteristic morphological, immunohistochemical (IHC) and molecular features. SOX17 has been recently identified as a highly sensitive and specific marker for endometrial and ovarian carcinomas. In this study, we aimed to investigate SOX17 expression in MLA together with other IHCs to differentiate MLAs from other endometrial carcinomas.MethodsSeventeen previously diagnosed endometrial/ovarian MLAs were collected, and multiple IHCs were performed. Additionally, we performed SOX17, PAX8 and ER on tissue microarrays (TMAs) composed of 652 endometrial carcinomas from 2012 to 2015 when MLA diagnostic criteria were not established.ResultsAll 17 MLAs showed diffuse strong positive PAX8, negative ER and variable TTF1/GATA3 staining. Notably, all MLAs showed negative (n = 10) or focal weak/moderate (n = 7) staining for SOX17, which is more diffuse and stronger than PAX8 in other endometrial carcinoma subtypes. This finding prompted us to screen TMAs with 652 endometrial carcinomas diagnosed before MLA by an approach of combined SOX17 and PAX8 IHCs, and 14 cases with positive PAX8 but negative/focal weak SOX17 were identified. We further studied the 14 cases by examining morphology and performing additional IHCs (TTF1, GATA3, ER and CD10) and would classify seven (50%) of them as MLAs based on morphological features and positive CD10, TTF1 and/or GATA3 staining.ConclusionOur results suggest that a combination of SOX17 and PAX8 IHCs would aid in diagnosing MLA if the results show strong positive PAX8, but negative SOX17.

Uterine MEIS1::NCOA2 Fusion Sarcoma With Lung Metastasis: A Case Report and Review of the Literature

MEIS1::NCOA1/2 fusion sarcomas are a recently described novel entity arising in a variety of locations with a predilection for the genitourinary tract and gynecologic organs. Despite multiple locoregional recurrences, these tumors are thought to behave in a low-grade malignant manner. Here we report a uterine MEIS1::NCOA2 fusion sarcoma with lung metastasis. The patient was a 47-yr-old woman with a history of abnormal uterine bleeding who was found to have a myometrial mass confirmed by pathology to be uterine sarcoma. The tumor was predominantly composed of monotonous spindle cells with scant cytoplasm, crowded nuclei, and brisk mitotic activity, growing in a fascicular and streaming pattern. The morphologic and immunophenotypic features were nonspecific and a diagnosis of high-grade uterine sarcoma with a differential of leiomyosarcoma versus high-grade endometrial stromal sarcoma was rendered. At the 27-mo follow-up, the patient was found to have a lung metastasis consisting of a monotonous round cell sarcoma. A retrospective RNA-based and DNA-based next-generation sequencing of the primary uterine sarcoma revealed a MEIS1::NCOA2 gene fusion, a c.94G>C/p.D32H mutation in exon 3 of CTNNB1 gene, HMGA2, and CDK4 gene amplification, and an intermediate/marginal level of MDM2 gene amplification. Polymerase chain reaction–based molecular analysis further demonstrated that the MEIS1::NCOA2 gene fusion and CTNNB1 somatic mutation were also present in the lung metastasis. This case represents the first case of such gynecologic sarcoma with distant (lung) metastasis, and the second metastatic case among all reported MEIS1::NCOA1/2 fusion sarcomas, highlighting the malignant metastatic potential of this emerging entity. Our case also indicates that HMGA2/CDK4/MDM2 region amplification and CTNNB1 somatic mutation might be recurrent genetic events in this rare sarcoma subtype.

Comparative Analysis Reveals Recurrent Molecular Alterations in Low-Risk Human Papillomavirus 6 and Human Papillomavirus 11-Associated Squamous Cell Carcinoma of the Uterine Cervix and Vulva

Although the association between human papillomavirus (HPV) 6 and HPV11 and squamous cell carcinomas (SCCs) has been well documented, the molecular alterations and mechanisms by which these low-risk HPVs contribute to carcinogenesis remain largely unknown. In this study, we comparatively elucidated the molecular landscape of HPV6/11-associated condylomas (9 cases) and SCCs (8 cases) of the uterine cervix and vulva. Sixteen of 17 cases were successfully analyzed using deep next-generation sequencing. Recurrent molecular alterations in the SCCs included mutations in the TERT promoter (pTERT, 71%), NOTCH1 (57%), NFE2L2 (57%), NOTCH3 (29%), and CDKN2A (29%). Mutations in NOTCH1 and NFE2L2 tended to be mutually exclusive. Less common somatic mutations were each detected in the following genes: AR, ARID1A, ASXL1, BCORL1, DAZAP1, FNDC1, HRAS, KMT2B, NOTCH2, NRAS, PIK3R1, and TP53. Etiologically similar to the SCCs, the vast majority of vulvar and cervical condylomas (7/9, 78%) were infected with HPV6 rather than HPV11. Unlike the SCCs, condylomas rarely harbored recurrent pathogenic somatic mutations. NOTCH1 and NOTCH2 were the only mutant genes detected in both SCCs and condylomas in this series, suggesting a critical role for the NOTCH pathway in the initiation and maintenance of HPV6/11-related early squamous lesions. Although pathogenic mutations in NOTCH1, NOTCH2, ERBB3, ATRX, FGFR2, EPHA5, CARD11, STAG2, and TSC2 were detected in condylomas, none were recurrent, indicating diverse genetic alterations involved in the development of these lesions. Case 8 illustrated a stepwise progression from condyloma to invasive SCC, in which pathogenic mutations in pTERT and NOTCH1 were detected in the SCC (age 58) and the condyloma at age 55, but not in the condyloma at age 44. Our study presents the first report on the molecular landscape of HPV6/11-associated SCCs of the uterine cervix and vulva. We provide evidence that SCCs associated with low-risk HPV are distinct entities, differing from those related to high-risk HPV and more closely resembling HPV-independent neoplasms. Given that low-risk HPV-associated SCCs of the cervix and vulva exhibit unique morphological and molecular features, they should either be described separately within existing classification systems or classified as a distinct new entity.

A Trichoadenoma/Trichoepithelioma/Trichoblastoma-like Lesion in the Uterine Cervix Focally Mimics an Adenoid Basal Tumor

The presence of ectodermal adnexal structures in the uterine cervix, including sebaceous glands, hair follicles, and sweat glands, has been well documented in the literature. In theory, there exists the possibility of developing cutaneous-type lesions from the ectopic ectodermal structures in this location. Here we report the first case of cervical hair follicle-derived proliferations reminiscent of trichoadenoma, trichoepithelioma, and trichoblastoma (TA/TE/TB) in a 52-year-old woman who underwent a prophylactic hysterectomy due to a germline microphthalmia-associated transcription factor (MITF) gene mutation. The lesion was an incidental finding in the cervix, exhibiting a spectrum of morphologic features ranging from germinative TB with basaloid cells, to TE with some degree of infundibulocystic differentiation, to well-differentiated TA. In some areas, hair follicle-like structures were associated with sebaceous glands, forming pilosebaceous units. The proliferations in the TB-like area resembled adenoid basal epithelioma/carcinoma; however, ancillary studies, particularly patchy p16 expression and non-detection of HPV, argued against this diagnosis. Similar to adenoid basal tumors, the TB-like lesion focally expressed NKX3.1, suggesting that it might be related to ectopic prostatic tissue or exhibit prostatic-lineage differentiation. While the theory of misplaced embryonal tissue, or an acquired metaplastic process, has been discussed, the histopathologic origin of these lesions remains largely unknown.

Clinicopathologic Features and Viral Status of Low-risk HPV6 and HPV11-Associated Squamous Cell Carcinoma of the Uterine Cervix and Vulva

Despite being designated as “noncarcinogenic” human papillomavirus (HPV) types, mono-infection with HPV6 or HPV11 has been found in squamous cell carcinomas (SCCs) at specific sites, including the larynx, penis, anus, and rarely, the lower female genital tract. The association between clinicopathologic features, viral status, and the carcinogenic mechanisms related to these low-risk HPVs remains unclear. The current study characterizes a series of low-risk HPV6 and HPV11-associated SCCs of the uterine cervix (6 cases) and vulva (2 cases). The diagnosis of SCC was made through the identification of stromal invasion in 6 cases. In case 2, the diagnosis of cancer was made after metastases to the sigmoid colon and liver. The patient in case 6 was diagnosed with intramucosal papillary SCC given multiple recurrences. While all tumors displayed a similar verruco-papillary architecture, the cytologic features, and immunostaining patterns suggest 2 groups of lesions: one with high-grade cytology and a high Ki-67 proliferation index (>60% of lesional cells), and the other with low-grade cytology and a low Ki-67 (20% to 30% of lesional cells). The detection of HPV6 in 7 of 8 cases underscores its critical role in carcinogenesis at these anatomic sites. Case 8 represented the only patient who was infected with HPV11 and who had a well-controlled human immunodeficiency virus infection. Correlating with viral status, all cases, except case 7, demonstrated a negative or focal p16 staining pattern. In case 7, despite a block pattern of p16 staining often seen in predicting high-risk HPV, we employed several methods to confirm HPV6 as the sole HPV infection. Although this descriptive study does not establish an etiological mechanism for how HPV6/11 leads to malignant transformation, our results exclude the possibility of viral integration through a quantitative polymerase chain reaction-based analysis of the E2/E6 ratio. Our study highlights and expands upon the clinicopathologic features of a distinct group of low-risk HPV6/11-associated SCCs in the cervix and vulva. Although rare, recognizing this group of lesions is important for pathologists and oncologists, as it provides a basis for guiding appropriate prevention strategies and treatment modalities based on the viral type.

Ovarian Sertoli–Leydig cell tumors with heterologous rhabdomyosarcoma: Clinicopathologic features and molecular analysis highlighting recurrent genetic alterations

Aims Ovarian Sertoli–Leydig cell tumor (SLCT) with heterologous rhabdomyosarcoma (RMS) is exceptionally rare. While the presence of heterologous elements in SLCT is highly predictive of an underlying DICER1 mutation, the molecular alterations in these tumors, including in SLCTs with heterologous RMS, remain largely unknown. In this study, we aimed to characterize the clinicopathologic features of these rare tumors, and in a subset of cases, we analyzed in detail their molecular changes to investigate potential recurrent and component‐specific genetic alterations. Methods and results We report clinicopathologic features of 11 ovarian SLCTs with heterologous RMS (positivity for desmin and myogenin); 10 were in keeping with embryonal and 1 with pleomorphic RMS. The patients showed a bimodal age distribution: seven patients (64%) were aged 33 years or younger (mean 20) and four patients (36%) were aged 52 years or older (mean 60). All tumors were unilateral. In addition to the RMS components, 8 of 11 cases (73%) contained other heterologous elements, including gastrointestinal‐type mucinous epithelium (5 cases) and immature cartilage (3 cases). Seven of 11 cases (64%) underwent next‐generation sequencing analysis. All tumors tested molecularly (7/7, 100%) harbored hotspot DICER1 mutations. Of these, six cases (86%) also carried a second nonsense or frameshift loss‐of‐function DICER1 mutation. One case had only a p.D1810Y hotspot mutation and consisted of high‐grade sarcoma with focal rhabdomyoblastic differentiation (focal expression of desmin and myogenin) in keeping with pleomorphic RMS; the pleomorphic sarcoma component also exhibited mutation‐type p53 expression. In addition to DICER1 mutations, TERT c.‐124C>T promoter (4 cases) or TP53 mutations (3 cases) were present in all cases and were mutually exclusive. Component‐specific analysis in two cases revealed shared common DICER1 hotspot mutations in both the SLCT and RMS components, supporting a clonal origin. In 1 case, a TERT promoter c.‐124C>T somatic mutation was present only in the RMS component. In the other case, the TERT promoter mutation was found in both components, while a BRAF p.V600E mutation was exclusive to the RMS component. Conclusion Our study demonstrates that the majority (86%) of SLCTs with heterologous RMS harbor double DICER1 mutations (a hotspot mutation and a nonsense or frameshift loss‐of‐function mutation), supporting the existing knowledge on DICER1 mutations associated with RMS heterologous elements, the presence of which should trigger genetic counselling. Our findings also suggest that molecular alterations other than DICER1 , namely, TERT promoter and TP53 mutations, may contribute to component‐specific oncogenic transformation.