From morphology to methylome: epigenetic studies of Müllerian mesonephric-like adenocarcinoma reveal similarities to cervical mesonephric adenocarcinoma†.

Mesonephric adenocarcinomas (MAs) and mesonephric-like adenocarcinomas (MLAs) are rare, aggressive neoplasms that arise in the gynecologic tract and show overlapping morphologic, immunohistochemical, and molecular features. While MAs occur in the cervix and are thought to arise from mesonephric remnants, MLAs occur in the endometrium and ovary and are believed to originate from transdifferentiation of Müllerian lesions. Both MAs and MLAs show a variety of architectural patterns, exhibit frequent expression of GATA3 by immunohistochemistry, and harbor KRAS mutations. In a recent article published in The Journal of Pathology, Kommoss and colleagues used DNA methylation profiling to extend these similarities and showed that MLAs and MAs cluster together based on their epigenetic signatures and are epigenetically distinct from other Müllerian adenocarcinomas. They also showed that MLAs and MAs harbor a high number of global copy number alterations. This study provides evidence that MLAs more closely resemble MAs than Müllerian carcinomas on an epigenetic level. As a result, the authors argue that MLA should be renamed 'mesonephric-type adenocarcinoma.' Further research is needed to establish the relationship between these two entities, their etiology, and pathogenesis. © 2024 The Pathological Society of Great Britain and Ireland.

[A Case of Adenocarcinoma, HPV-independent, Mesonephric Type with Significant Response to Neoadjuvant Chemotherapy].

Adenocarcinoma, HPV-independent, mesonephric type (hereafter referred to as "mesonephric carcinoma") arising from the cervix is rare, its treatment has not been established, and its sensitivity to chemotherapy has not been fully investigated. Here we report on a 30-year-old female patient who presented at our hospital with a chief complaint of abnormal genital bleeding. We suspected cervical cancer. Based on examination, biopsy, and imaging, she was diagnosed with stage IIA2 adenocarcinoma of the cervix and was scheduled for surgery. Because she had a SARS-COV-2 infection, she was given two courses of paclitaxel-carboplatin (TC) therapy, based on the then-current surgical risk assessment after SARS-COV-2 infection, with a waiting period of at least 8 weeks. The patient was deemed to have a partial response and was treated with paclitaxel and carboplatin, after which she was deemed to have a partial response and underwent total hysterectomy. A diagnosis of stage IIA2 mesonephric carcinoma, ypT1b2N0M0, was made after histopathologic examination of an excised specimen. The patient was treated with 4 additional courses of TC therapy after surgery, and has had no recurrence in 13 months. We report a first case of response to neoadjuvant chemotherapy with TC regimen in a patient with mesonephric carcinoma of the cervix.

Mesonephric Adenocarcinoma and Mesonephric-like Adenocarcinoma of the Urinary Tract.

Given the association of mesonephric adenocarcinoma (MA) of the uterine cervix with florid mesonephric hyperplasia, one would expect MAs to rarely arise in other anatomical locations that harbor mesonephric remnants. In contrast, mesonephric-like adenocarcinoma (MLA) is thought to arise from Müllerian origin without an association with mesonephric remnants. The current case series characterizes 4 cases of MA arising in the urinary bladder (1 woman and 3 men), 1 case of MA in the perirenal region (woman), and 1 case of MLA in the ureter (woman). All cases displayed morphologic features similar to MA of the uterine cervix and MLA of the ovary and endometrium, characterized by predominant tubular and focal glandular/ductal architecture. Mesonephric remnants in the bladder wall were closely associated with adjacent MA in cases 1 and 4. MLA in case 6 was associated with mesonephric-like proliferations and endometriosis. All cases (6/6) were diffusely positive for Pax8, and all displayed a luminal pattern of CD10 staining, except case 4 for which CD10 immunostain was not available for review. Gata3 was either focally positive (cases 1, 2, and 6), negative (case 3), or diffusely positive (case 5). TTF-1 was diffusely expressed in cases 1 and 3 and negative in cases 2, 5, and 6. Although a KRAS G12C somatic mutation was detected in case 6, hotspot mutations in KRAS, NRAS, and PIK3CA were not present in other tested cases. Our study demonstrates that MAs and MLAs of the urinary tract share similar histopathogenesis, morphology, and immunophenotype to their counterparts in the female genital tract. We propose that, in the urinary tract, MA might be classified as a distinctive tumor that arises from mesonephric remnants or presumed Wolffian origin if they are not related to Müllerian-type precursors. The tumor displaying similar morphology and immunoprofile to MA but associated with Müllerian-type precursors should be classified as MLA.

Mesonephric and mesonephric-like carcinomas of the female genital tract: molecular characterization including cases with mixed histology and matched metastases.

Mesonephric carcinoma of the cervix is a rare tumor derived from Wolffian remnants. Mesonephric-like carcinomas of the ovary and endometrium, while morphologically similar, do not have obvious Wolffian derivation. Here, we sought to characterize the repertoire of genetic alterations in primary mesonephric and mesonephric-like carcinomas, in the distinct histologic components of mixed cases, as well as in matched primary tumors and metastases. DNA from microdissected tumor and normal tissue from mesonephric carcinomas (cervix, n = 8) and mesonephric-like carcinomas (ovarian n = 15, endometrial n = 13) were subjected to sequencing targeting 468 cancer-related genes. The histologically distinct components of four cases with mixed histology and four primary tumors and their matched metastases were microdissected and analyzed separately. Mesonephric-like carcinomas were underpinned by somatic KRAS mutations (25/28, 89%) akin to mesonephric carcinomas (8/8, 100%), but also harbored genetic alterations more frequently reported in Müllerian tumors. Mesonephric-like carcinomas that lacked KRAS mutations harbored NRAS (n = 2, ovary) or BRAF (n = 1, endometrium) hotspot mutations. PIK3CA mutations were identified in both mesonephric-like (8/28, 28%) and mesonephric carcinomas (2/8, 25%). Only mesonephric-like tumors harbored CTNNB1 hotspot (4/28, 14%) and PTEN (3/13, 23%) mutations. Copy number analysis revealed frequent gains of chromosomes 1q and 10 in both mesonephric (87% 1q; 50% chromosome 10) and mesonephric-like tumors (89% 1q; 43% chromosome 10). Chromosome 12 gains were more frequent in ovarian mesonephric-like carcinomas, and losses of chromosome 9 were more frequent in mesonephric than in mesonephric-like carcinomas (both p = 0.01, Fisher's exact test). The histologically distinct components of four mixed cases were molecularly related and shared similar patterns of genetic alterations. The progression from primary to metastatic lesions involved the acquisition of additional mutations, and/or shifts from subclonal to clonal mutations. Our findings suggest that mesonephric-like carcinomas are derived from a Müllerian substrate with differentiation along Wolffian/mesonephric lines.

Cervical Mesonephric Adenocarcinoma With Novel FGFR2 Mutation.

Mesonephric adenocarcinoma is a rare tumor, accounting for <1% of cervical cancers. Well-differentiated mesonephric adenocarcinoma can be difficult to distinguish from diffuse mesonephric hyperplasia. Herein, we report a case of well-differentiated mesonephric adenocarcinoma with an FGFR2 mutation not previously reported in the literature. Nonselective tyrosine kinase inhibitors or FGFR2 inhibitors may represent options for targeted therapy.

An Ovarian Adenocarcinoma With Combined Low-grade Serous and Mesonephric Morphologies Suggests a Müllerian Origin for Some Mesonephric Carcinomas.

Mesonephric carcinomas are rare adenocarcinomas of the female genital tract that occur most commonly in the uterine cervix. They are classically thought to arise from benign mesonephric remnants, and are rarely reported at other sites in the gynecologic tract. Here we present an interesting biphenotypic ovarian adenocarcinoma with intimately associated but distinct components of both low-grade serous carcinoma and mesonephric-like carcinoma. A serous borderline tumor was present adjacent to the invasive carcinoma, and no benign mesonephric precursors were identified. Numerous invasive peritoneal metastases were present, including multiple metastases with both low-grade serous and mesonephric-like elements. Consistent with recent reports, foci of mesonephric-like carcinoma were morphologically and immunohistochemically identical to classic mesonephric carcinoma of the cervix. On molecular analysis, the serous borderline tumor, primary and metastatic low-grade serous carcinoma, and primary and metastatic mesonephric-like carcinoma each harbored a shared NRAS p.Q61R hotspot mutation, shared gains in chromosome 1q and 18p, and shared losses in chromosomes 1p, 18q, and 22. These shared molecular features indicate a clonal relationship between all morphologic elements of this ovarian adenocarcinoma, suggesting that at least some mesonephric carcinomas may arise from Müllerian precursors.

Mixed Mesonephric Adenocarcinoma and High-grade Neuroendocrine Carcinoma of the Uterine Cervix: Case Description of a Previously Unreported Entity With Insights Into Its Molecular Pathogenesis.

Human papillomavirus (HPV)-negative cervical carcinomas are uncommon and typically encompass unusual histologic subtypes. Mesonephric adenocarcinoma is one such subtype. Mesonephric tumors in the female genital tract are thought to arise from Wolffian remnants, and are extremely rare tumors with widely variable morphology. Sarcomatoid dedifferentiation has been previously described in a few cases, but other forms of dedifferentiation have not been reported. Neuroendocrine carcinoma of the cervix (e.g. small cell carcinoma) is associated with HPV infection, typically HPV 18. These tumors often arise in association with a conventional epithelial component such as squamous cell carcinoma or usual-type endocervical adenocarcinoma. We describe a case of mesonephric adenocarcinoma of the uterine cervix associated with an HPV-negative high-grade neuroendocrine carcinoma at the morphologic and immunophenotypic level, for which we performed targeted massively parallel sequencing analysis of the 2 elements. Both components shared identical mutations in U2AF1 p.R156H (c.467G>A) and GATA3 p.M422fs (c.1263dupG), as well as MYCN amplification. In addition, the neuroendocrine carcinoma harbored TP53 and MST1R mutations not present in the mesonephric carcinoma. Our data suggest a clonal origin of the 2 components of this rare entity, rather than a collision tumor.

Mesonephric adenocarcinoma of the uterine cervix: A case report and review of the literature.

Mesonephric adenocarcinoma is a rare neoplasm of uterine cervix. It originates from the mesonephric ductus remnant or mesonephric hyperplasia area. There have been few such cases reported. Our case was 64 years of age and her tumour held the whole endocervical wall. It was around 5cm in diameter, and had exophytic component as well. Bilateral pelvic and paraaortic lymph nodes were negative for metastasis.

Mesonephric carcinosarcoma involving uterine cervix and vagina: report of 2 cases with immunohistochemical positivity For PAX2, PAX8, and GATA-3.

Mesonephric carcinomas are rare tumors predominantly arising in the uterine cervix from mesonephric remnants. Although the tumor has classic morphologic features, some cases can mimic Müllerian adenocarcinoma and be misdiagnosed, especially those with significant ductal pattern. Moreover, there is an overlap in immunohistochemical results with endometrial and endocervical carcinomas. In this study, we report 2 cases of mesonephric carcinosarcoma, originally diagnosed as Müllerian carcinomas, 1 presenting in the vagina; review immunohistochemical results including positivity for GATA-3, not previously reported and comment on the proposed panel of PAX8, p16, and estrogen receptors as discriminators of Müllerian adenocarcinoma (endocervical or endometrial) versus mesonephric carcinoma.

A rare case of primary ovarian mesonephric adenocarcinoma and a review of the literature.

OBJECTIVE: Are reported in the cervix in the female genital tract, has been reported in very few studies in the literature. In this report, we aimed to present a case with mesonephric carcinoma, which was detected in the ovary and is very rarely seen. CASE REPORT: In a case since the frozen section results of the left adnexal mass were reported as malignant. CONCLUSION: Ovarian mesonephric carcinoma is very rare and exhibits very different morphological patterns. Therefore, immunohistochemical and morphological findings should be evaluated together. If the pathological picture does not fit the common carcinomas of ovarian origin and this entity must be brought to mind, because, if these tumors with different molecular developmental pathways are diagnosed correctly, treatment schemes will change and targeted therapies will be developed too. KEY WORDS: Mesonephric carcinoma, Mesonephric like carcinoma, Ovarian carcinoma.

Mesonephric adenocarcinomas in female genital tract: A case series.

ABSTRACT: Mesonephric adenocarcinoma (MNAC) is a very rare tumor that originates from mesonephric duct remnants of the female genital tract. Only a few cases were reported in the literature, and most of them occurred in the cervix, extremely rare in the uterine body and ovary. MNAC was rarely reported to arise in the uterine corpus, but never was reported in the ovary. Mesonephric-like adenocarcinomas are recently suggested to describe these neoplasms arising from the uterine corpus and ovary. Due to the rareness of the disease, little is known regarding clinical characteristics, pathological diagnosis, prognosis, and optimal management strategy of MNAC in the female reproductive system. We report a series of MNACs arising from the vagina, cervix, uterine corpus, ovary, and fallopian tube, to summarize the clinical characteristics, pathological diagnosis, treatment, and prognosis.We retrospectively analyzed all MNACs in the female genital tract derived from our institute from January 2010 till January 2020. Patients' clinical details and follow-up were obtained from hospital records and scans were obtained from picture archiving and communication system.A total of 11 patients were included. The median age of onset of symptoms was 52 years. All patients underwent total hysterectomy and bilateral salpingo-oophorectomy, and lymph node dissections were performed in 7/11 (63.6%) patients. Two/eleven (18.2%) received neoadjuvant chemotherapy before surgery and 7/11 (63.6%) received adjuvant chemotherapy after primary surgery. Of the 11 patients, only 1 patient received adjuvant radiation therapy. One patient died at the end point of this study, 9 patients (81.8%) survived and 1 patient was lost to follow-up. The mean follow-up duration was 33.5 months.Although there is no consensus for the optimal treatment of this rare disease, radical surgery is considered to be the initial choice for localized lesion. Given the high malignancy, the majority of MNAC or mesonephric-like adenocarcinoma patients who underwent adjuvant chemotherapy received 4 to 8 cycles of carboplatin/paclitaxel as a first-line treatment after primary surgery with a median progression-free survival of 12 months. Treatment for recurrent disease in these patients included gemcitabine, carboplatin, and paclitaxel. Radiation was very limited in the treatment of the disease.

Cervical Mesonephric Adenocarcinoma: A Case Report of a Rare Gynecological Tumor from Embryological Remains of the Female Genital Tract.

INTRODUCTION: Malignant mesonephric tumors are uncommon in the female genital tract, and they are usually located where embryonic remnants of Wolffian ducts are detected, such as the uterine cervix. The information about these tumors, their treatment protocol, and prognosis are scarce. CASE REPORT: A 60-year-old woman with postmenopausal vaginal bleeding was initially diagnosed with endometrial carcinoma. After suspicion co-testing, the patient underwent a loop electrosurgical excision of the cervix and was eventually diagnosed with mesonephric adenocarcinoma. She was subjected to a radical hysterectomy, which revealed International Federation of Gynecology and Obstetrics (FIGO) IB1 stage, and adjuvant radiotherapy. The follow-up showed no evidence of recurrence after 60 months. CONCLUSION: We present the case of a woman with cervical mesonephric adenocarcinoma. When compared with the literature, this case had the longest clinical follow-up without evidence of recurrence, which reinforces the concept that these tumors are associated with a favorable prognosis if managed according to the guidelines defined for the treatment of patients with cervical adenocarcinomas. Though a rare entity, it should be kept in mind as a differential diagnosis for other cervical cancers.

Mesonephric adenocarcinoma in the uterine corpus: A case report and review of the literature.

Mesonephric adenocarcinoma (MNA) is a rare malignancy arising from the mesonephric remnant of the female reproductive tract, typically found in the cervix. MNA is uncommon in the uterine corpus, only 33 cases have been described in the literature. A 55-year-old postmenopausal woman presented with pink vaginal discharge and bilateral hip pain for 2 months, with the help of histopathologic observation and immunohistochemical staining, a diagnosis of "MNA" was made. The tumor invaded the whole layer of myometrium without endometrium involvement, mesonephric remnants and hyperplasia of the mesonephric duct were also found at the periphery of the neoplasm. After the operation, the patient was treated with 3 cycles of chemotherapy. The patient was followed for 6 months with disease. Further experience to diagnose and cure this rare tumor is warranted.

Ovarian mesonephric-like adenocarcinoma arising in serous borderline tumor: a case report with complex morphological and molecular analysis.

BACKGROUND: Mesonephric-like adenocarcinoma (M-LAC) is a rare, recently described tumor occurring in the uterine corpus and ovary, which shares the same morphological and immunohistochemical features with the more common mesonephric adenocarcinoma (MAC), which mostly arises the uterine cervix. Despite the similarities between these tumors, the histogenesis of M-LAC is still disputable. CASE PRESENTATION: Sixty-one-year-old woman presented with an advanced tumor of the left ovary with intraabdominal spread and liver metastases. After receiving 5 cycles of neoadjuvant chemotherapy, she underwent a hysterectomy with bilateral salpingo-oophorectomy, and resection of the liver metastasis, omentum, and appendix. Histologically, the ovarian tumor consisted of two components, whose morphology and immunohistochemical results were typical of either a serous borderline tumor (immunohistochemical positivity for PAX8, WT1, ER and PR) or a mesonephric-like carcinoma (immunohistochemical positivity for PAX8, TTF1 and GATA3). Only the component of the mesonephric-like adenocarcinoma metastasized to the omentum and liver. A molecular analysis with a panel of 271 genes (size 1020 kbp) was performed separately on samples from the borderline tumor, primary ovarian mesonephric-like adenocarcinoma, and liver metastasis. The results showed the clonal origin of all samples, which shared the same KRAS (NM_004985.3:c.34G > T, p.(G12C)) and PIK3CA (NM_006218.2:c.1633G > A, p.(E545K)) somatic mutations. Moreover, in the sample from the primary mesonephric-like carcinoma and its liver metastasis a likely pathogenic somatic MYCN mutation (NM_005378.4:c.131C > T, p.(P44L) was found. In all samples, the deletion of exons 9-10 in the CHEK2 gene was present, which is in concordance with the previously performed genetic testing of the blood specimen which revealed the hereditary CHEK2 mutation in this patient. CONCLUSIONS: Our result support the theory that at least some mesonephric-like ovarian adenocarcinomas are of Müllerian origin. The serous borderline tumor seems to be a precursor of mesonephric-like adenocarcinoma, which has been proven in our case by both tumors sharing the same mutations, and the presence of cumulative molecular aberrations in the mesonephric-like adenocarcinoma.

Atypical Mesonephric Hyperplasia of the Uterus Harbors Pathogenic Mutation of Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) and Gain of Chromosome 1q.

BACKGROUND/AIM: Mesonephric carcinoma (MNC) is a rare but notable entity of the female genital tract. While many researchers have acknowledged and studied MNC, much remains unknown on the characteristics of mesonephric remnant (MNR) or hyperplasia (MNH). There has not been any study examining the molecular features of MNR and MNH so far. The aim of this study was to investigate the clinicopathological and molecular characteristics of ten uterine mesonephric lesions, including two MNRs without atypia, four MNHs without atypia, and three MNHs with atypia. MATERIALS AND METHODS: We reviewed the electronic medical records and all available slides of ten cases from multiple institutions. Targeted sequencing and array comparative genomic hybridization were performed. RESULTS: Three atypical MNHs displayed nuclear enlargement, mild-to-moderate nuclear pleomorphism, and nuclear membrane irregularity, and harbored pathogenic Kirsten rat sarcoma 2 viral oncogene homolograt sarcoma 2 viral oncogene homolog (KRAS) mutation. Two of those that co-existed with MNC harbored the same sequence alterations as each of their adjacent MNC. One of the three atypical MNHs harbored chromosome 1q gain. CONCLUSION: Atypical MNH is a potential premalignant lesion in which KRAS mutation and chromosome 1q gain play an important role in the early stage of mesonephric carcinogenesis.

Clinicopathologic and Molecular Characteristics of Mesonephric Adenocarcinoma Arising From the Uterine Body.

Mesonephric adenocarcinoma (MNAC) is a rare tumor of the female genital tract mainly occurring in the uterine cervix. To date, only a few cases of MNAC arising from of the uterine body (UB-MNAC) have been reported. The clinicopathologic and molecular characteristics of UB-MNAC remain unknown. In this study, we investigated the clinical, histopathologic, immunohistochemical, and genetic features of UB-MNAC. In total, 11 cases were included. Six patients developed metastatic disease, most commonly in lungs (5/6). Histopathologically, UB-MNAC was characterized by an admixture of tubular, glandular, papillary, retiform, glomeruloid, sex cord-like, and comedonecrosis-like architectural patterns. Three adverse pathologic characteristics, including advanced International Federation of Gynecology and Obstetrics stage, high mitotic activity, and presence of lymphovascular the invasion, were independent factors predicting the development of metastasis. All cases were positive for GATA-binding protein 3 and paired box 2 expression and showed wild-type p53, patchy p16, and preserved PTEN expression, as indicated by immunohistochemistry. Next-generation sequencing using 12 samples (11 primary tumors and 1 metastatic tumor) revealed 42 single nucleotide variations in 16 genes, mostly in KRAS (10/12) and ARID1A (9/12). Copy number variation was found in 16 genomic regions, and consisted of 57 gains and 10 losses, with 1q gain (11/12) being the most prevalent. In conclusion, UB-MNAC displays an aggressive biological behavior, with a tendency to metastasize to the lungs. Adverse pathologic characteristics reflect the aggressive nature of UB-MNAC. Distinct molecular features of UB-MNAC include frequent somatic mutations of KRAS and ARID1A and gain of 1q.

Cytologic features of upper gynecologic tract adenocarcinomas exhibiting mesonephric-like differentiation.

BACKGROUND: Mesonephric adenocarcinomas are rare neoplasms which most commonly arise in the lateral cervix and vagina. Tumors with similar morphologic, immunophenotypic, and molecular characteristics recently have been described in the uterine corpus and ovary. Herein, the authors sought to characterize the cytomorphologic features of adenocarcinomas exhibiting mesonephric-like differentiation arising in the upper gynecologic tract. METHODS: Institutional databases were queried retrospectively for tumors of the upper gynecologic tract described as a "tumor of Wolffian origin" or "with mesonephric features" between 2007 and 2017. All available cytologic material was reviewed. Cytomorphologic characteristics were evaluated by 3 pathologists. RESULTS: The current study cohort consisted of 8 cases taken from 7 patients. Primary sites included the ovary (3 cases); endometrium (4 cases); and pelvis, not otherwise specified (1 case). All cases demonstrated tight 3-dimensional clusters of overlapping cells. Additional architectural features included tubular (5 of 8 cases; 63%) and papillary (3 of 8 cases; 38%) formations. Cells were small with scant (7 of 8 cases; 88%) to moderate (1 of 8 cases; 12%) cytoplasm. Three of the 8 cases (38%) demonstrated extracellular hyaline globules. Nuclei were uniform in size (6 of 8 cases; 75%) or showed mild anisonucleosis (2 of 8 cases; 25%). Nuclear grooves and indentations were observed in all cases. Mitoses (5 of 8 cases; 63%) and apoptotic bodies (4 of 8 cases; 50%), when present, were rare. No necrosis was noted. CONCLUSIONS: Adenocarcinomas exhibiting mesonephric-like differentiation show a monotonous population of small cells with scant to moderate cytoplasm and abundant nuclear grooves arranged in tight, overlapping, 3-dimensional clusters. Occasionally, papillary or tubular architecture, as well as extracellular hyaline globules, may be seen. These features should prompt further testing (eg, immunohistochemistry) to confirm the diagnosis and to exclude potential mimics.

Carcinosarcoma of the uterine cervix: a rare pathological finding originating from mesonephric remnants.

Carcinosarcoma of the uterine cervix is a very rare tumour that has been described in less than 70 cases in the literature. It is less common compared with carcinosarcoma of the uterine corpus and it can have two origins: the Müllerian ducts and the mesonephric duct remnants. The association of mesonephric carcinoma with a sarcomatous component was reported in only 11 cases, including the following. We describe a case of a 64-year-old woman, presenting with vaginal bleeding and a cervical lesion reported as a sarcoma of endometrial stroma in the first biopsy. After exclusion of distant disease, she was submitted to radical surgery and the final histopathological examination showed a carcinosarcoma of the cervix with mesonephric origin.