Acute Pelvic Pain Due to Spontaneous Hemorrhage of a Gartner Duct Cyst.

BACKGROUND: Gartner duct cysts develop from mesonephric duct remnants. They are usually small and asymptomatic, but complications can arise and are uncommonly reported. CASE: A 44-year-old patient presented with acute pelvic pain and pressure, a new vaginal mass, and urinary retention. Examination and magnetic resonance imaging revealed a large, expanding, complex paravaginal mass with extension into the paracervical and ischiorectal spaces, causing cephalad displacement of the uterus. A vaginal approach to cyst incision, hemorrhage control, and marsupialization resulted in complete resolution of symptoms. Pathology demonstrated a Gartner duct cyst without evidence of malignancy. CONCLUSION: Spontaneous hemorrhage of a Gartner duct cyst, although rare, may cause acute symptoms and a new vaginal mass. This diagnosis should be considered in the evaluation of acute-onset pelvic pressure and pain.

The complex and often confusing history, histology and histogenesis of mesonephric, STK11 adnexal tumour and mesonephric-like neoplasms of the upper female genital tract (including broad ligament).

Mesonephric lesions in the female genital tract are uncommon, with those arising from the upper tract being much less frequent than those developing in the lower tract (mesonephric hyperplasia and carcinoma). The most common upper tract lesions include rete cyst/cystadenoma and female adnexal tumour of Wolffian origin (FATWO). The integration of morphological, immunohistochemical and molecular studies on FATWOs has enabled recognition of a novel entity, the STK11 adnexal tumour, which is often associated with Peutz-Jeghers syndrome (~50%) and frequently has a salivary gland morphology but an unknown origin. Similarly, 'mesonephric-like' adenocarcinoma, an entity with striking similarities to mesonephric carcinoma but currently favoured to be of Müllerian derivation based on its association with other Müllerian tumours and molecular findings, has also been recently described, and may histologically mimic both FATWOs and STK11 adnexal tumours. In this review, we provide a historical overview of upper female genital tract mesonephric proliferations and discuss mesonephric lesions, STK11 adnexal tumour, mesonephric-like adenocarcinoma, and mimickers, the most common being endometrioid carcinoma.

Extrauterine Mesonephric-like Neoplasms: Expanding the Morphologic Spectrum.

Mesonephric-like adenocarcinomas (MLA) are rare neoplasms arising in the uterine corpus and ovary which have been added to the recent 2020 World Health Organization Classification of Female Genital Tumors. They have similar morphology and immunophenotype and exhibit molecular aberrations similar to cervical mesonephric adenocarcinomas. It is debated as to whether they are of mesonephric or Mullerian origin. We describe the clinical, pathologic, immunohistochemical, and molecular features of 5 cases of extrauterine mesonephric-like proliferations (4 ovary, 1 extraovarian), all with novel and hitherto unreported features. These include an origin of MLA in extraovarian endometriosis, an association of ovarian MLA with high-grade serous carcinoma, mixed germ cell tumor and mature teratoma, and a borderline ovarian endometrioid tumor exhibiting mesonephric differentiation. Four of the cases exhibited a KRAS variant and 3 also a PIK3CA variant. In reporting these cases, we expand on the published tumor types associated with MLA and report for the first time a borderline tumor exhibiting mesonephric differentiation. We show the value of molecular testing in helping to confirm a mesonephric-like lesion and in determining the relationship between the different neoplastic components. We provide further evidence for a Mullerian origin, rather than a true mesonephric origin, in some of these cases. We also speculate that in the 2 cases associated with germ cell neoplasms, the MLA arose out of the germ cell tumor.

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.

Mesonephric-like Differentiation of Ovarian Endometrioid and High-grade Serous Carcinomas: Clinicopathological and Molecular Characteristics Distinct from Those of Mesonephric-like Adenocarcinoma.

BACKGROUND/AIM: Ovarian endometrioid carcinoma (EC) and high-grade serous carcinoma (HGSC) may exhibit various growth patterns and mimic mesonephric-like adenocarcinoma (MLA). We investigated the clinicopathological and molecular features of ovarian carcinomas with mesonephric-like differentiation (MLD). PATIENTS AND METHODS: We analyzed the electronic medical records and pathology slides of two EC-MLD and three HGSC-MLD patients, and conducted immunostaining and targeted sequencing of their samples. RESULTS: All cases showed architectural diversity, compactly aggregated small tubules and ducts, and eosinophilic intraluminal secretions, indicating the possibility of an ovarian MLA. However, the following histological and immunophenotypical features confirmed the diagnoses of EC-MLD and HGSC-MLD: squamous, tubal, and sertoliform differentiation; serous tubal intraepithelial carcinoma; solid, endometrioid, transitional (SET) feature; solid, transitional, endometrioid, mucinous-like (STEM) feature; diffuse expression of hormone receptors and Wilms tumor 1; mutant p53 immunostaining pattern; and wild-type v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog gene. CONCLUSION: A subset of ovarian ECs and HGSCs can display MLD and mimic an MLA. A thorough histological examination combined with ancillary tests is crucial to differentiate between these ovarian neoplastic entities.

Dedifferentiated Mesonephric-like Adenocarcinoma of the Uterine Corpus.

BACKGROUND/AIM: We present a case of uterine dedifferentiated mesonephric-like adenocarcinoma (MLA). CASE REPORT: A 54-year-old woman underwent total hysterectomy for a uterine mass under the impression of a uterine sarcoma. Histologically, MLA exhibited various growth patterns including tubular and glandular architecture. Undifferentiated carcinoma (UC) displayed discohesive tumor cells without any obvious architecture. Immunohistochemically, UC was positive for epithelial markers in very few scattered tumor cells. MLA exhibited the wild-type p53 expression pattern, whereas UC showed a uniform and strong p53 immunoreactivity. Targeted sequencing analysis revealed an identical Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in both components. A pathogenic missense tumor protein 53 (TP53) mutation was detected in UC, but not in MLA. CONCLUSION: The mutant p53 expression pattern exclusively detected in UC was concordant with the presence of missense TP53 mutation. Our observations suggested that TP53 mutation is associated with the possible transformation from MLA to UC.

Incidental mesonephric remnant hyperplasia of the jejunal mesentery: A diagnostic challenge.

Mesonephric remnants are embryonic vestiges of the mesonephric (Wolffian) ducts which regress during normal development. These remnants have been uncommonly reported in the female and male reproductive tract as a spectrum of morphologic lesions that can be misdiagnosed as carcinoma. One case of mesonephric remnant hyperplasia of the jejunal mesentery incidentally found in a 47-year-old man is herein reported. This is the first description of mesonephric hyperplasia arisen in the mesentery. The presence of ducts, tubules, and cysts lined by bland, epithelial, cuboidal cells with scant cytoplasm, and diffuse pseudoinfiltrative growth pattern can raise the possibility of neoplasia. Immunohistochemically, mesonephric epithelia have a characteristic staining. CD10 highlights the apical-luminal aspect of the cells. Besides, intense reactivity is showed for high-molecular-weight cytokeratin (CK), CK7, bcl2, and vimentin. The main differential diagnosis includes mesothelial hyperplasia, epithelial mesothelioma, well-differentiated neuroendocrine tumor, and infiltration due to acinar adenocarcinoma of the prostate. However, a detailed microscopic study with the aid of immunohistochemistry helps separate mesonephric remnants from malignant processes. The mesonephric hyperplasia of the mesentery we have reported adds to the spectrum of mesonephric remnants a new location. Familiarity with this lesion is indispensable to avoid overdiagnosis.

Mesonephric (Wolffian-derived) Adenocarcinoma of the Female Urethra.

The current World Health Organization (WHO) classification of adenocarcinoma of the urinary tract including the urethra includes uncommon Müllerian-derived carcinomas such as clear cell and endometrioid adenocarcinomas. The concept of primary mesonephric (Wolffian-derived) adenocarcinoma (MA) in the urethra (and urinary tract in general) is currently regarded as controversial as the term "mesonephric" had been also inaccurately applied in the past to label Müllerian-derived carcinomas, particularly clear cell adenocarcinoma. Further, pathologically well-documented or bona fide urethral MAs have not yet to be reported. Herein, we describe 2 examples of MA in elderly females that primarily presented in the urethra and manifested clinically with obstructive lower urinary tract symptoms. Both tumors exhibited histology similar to those in MAs of the female genital tract including the distinctive tubular proliferations with luminal eosinophilic materials. The first case, in addition, showed a variety of patterns including ductal (glandular), solid, fused/sieve-like tubules, dilated tubules, and spindled cells. The second case also showed a transition to the more irregular and poorly formed tubular proliferation of cells with greater nuclear atypia and with a desmoplastic response. Both tumors showed positivity for PAX8, GATA3, and luminal CD10, and 1 tumor analyzed harbored KRAS and ARID1A mutations. One patient received neoadjuvant chemotherapy and underwent resection but had local tumor recurrence and metastasis to the lungs and lumbar spine 12 months after presentation. In conclusion, MA, similar to those occurring in the female genital tract and distinct from the recognized Müllerian-derived carcinomas, may present primarily as urethral tumors. MA in the urethra probably shares a common pathogenesis with vaginal MA as both may originate from the same caudal loci of mesonephric remnants along the closely apposed anterior vaginal and posterior urethral walls. MA should be considered in future classifications for urethral tumors and we recommend that the confusing term "mesonephroid adenocarcinoma" should no longer be used.

Clinicopathologic Characteristics of Mesonephric Adenocarcinomas and Mesonephric-like Adenocarcinomas in the Gynecologic Tract: A Multi-institutional Study.

Mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA) are uncommon neoplasms of the gynecologic tract that have until recently been poorly understood. Although their morphologic, immunohistochemical, and molecular profiles have been recently defined, little is known about their clinical behavior. Small studies have demonstrated inconsistent findings and no large studies have examined the clinical behavior of these adenocarcinomas. In this multi-institutional study, representing the largest and most stringently defined cohort of cases to date, we examined the clinicopathologic features of 99 MAs and MLAs (30 MAs of the uterine cervix, 44 MLAs of the endometrium, and 25 MLAs of the ovary). Only tumors with characteristic mesonephric morphology and either immunohistochemical or molecular support were included. Our results demonstrate that the majority of mesonephric neoplasms presented at an advanced stage (II to IV) (15/25 [60%] MA of the cervix, 25/43 [58%] MLA of the endometrium, and 7/18 [39%] MLA of the ovary). The majority (46/89 [52%] overall, 12/24 [50%] MA of the cervix, 24/41 [59%] MLA of the endometrium, and 10/24 [42%] MLA of the ovary) developed recurrences, most commonly distant (9/12 [75%] MA of the cervix, 22/24 [92%] MLA of the endometrium, and 5/9 [56%] MLA of the ovary). The 5-year disease-specific survival was 74% (n=26) for MA of cervix, 72% (n=43) for MLA of endometrium, and 71% (n=23) for MLA of ovary. Our results confirm that mesonephric neoplasms are a clinically aggressive group of gynecologic carcinomas that typically present at an advanced stage, with a predilection for pulmonary recurrence.

Mesonephric-like adenocarcinoma of the ovary: A case report and a review of the literature.

RATIONALE: Mesonephric-like adenocarcinoma (MLA) from ovary is a very rare tumor which derives from mesonephric duct remnant of the female genital tract. Only six cases have been reported so far in the English literature. PATIENT CONCERNS: A 29-year-old female patient was referred to the local hospital with a 20-day history of abdominal discomfort. DIAGNOSES: Pelvic ultrasound examination revealed a solid and cystic mass measuring 10 cm in diameter in the right adnexal area and a cystic mass measuring 5 cm in the left adnexal area. Postoperative pathology in the local hospital revealed suspected malignancy of the right ovary, and she was then transferred to our institution for definite diagnosis. The tumor mass was finally diagnosed as a primary MLA arising from the right ovary by histological and immunohistochemical examination in our institution. INTERVENTIONS: The patient underwent laparoscopic right adnexectomy and removal of left ovarian cyst in the local institution. Then, she underwent a complete staging surgery including a total hysterectomy, left adnexectomy, pelvic plus para-aortic lymphadenectomy, and omentectomy in our hospital. In addition, she received four cycles of combination chemotherapy with carboplatin plus paclitaxel. OUTCOMES: There is no evidence of recurrence with 13 months of follow-up till now, and we are still following-up this patient. LESSONS: MLA is an extremely uncommon malignancy with difficult diagnosis, unclear treatment and poor prognosis. Familiarizing with the clinical features and optimal management of this rare tumor may increase awareness of the disease among clinicians and pathologists, thus avoiding the misdiagnosis and mistreatment.

Mesonephric Adenocarcinoma of the Uterine Corpus: A Report on 2 Cases With Comparison to Its Cervical Counterpart.

Mesonephric adenocarcinoma (MA) is a rare tumor of the female genital tract that develops in the uterine cervix. Recently, a few cases of MA arising from the uterine body have been reported, whereas the differences between these 2 entities remain unknown. Two uterine MAs and 1 cervical MA were included in this study. In uterine MA, there was an admixture of various growth patterns with tubular, glandular, slit-like, papillary, and solid architectures. Both tumors extensively involved the endometrium, while no mesonephric remnants were noted. Immunostaining was diffusely positive for TTF-1, while there was only focal staining for GATA3. KRAS somatic mutation was present in both uterine cases. In cervical MA, the tumor also had different growth patterns but no endocervical mucosa involvement. A residual mesonephric duct was present. GATA3 showed diffuse staining, but TTF-1 was totally negative. Therefore, uterine MA was not entirely consistent with its cervical counterpart in both morphologic characteristics and immunostaining.

Ovarian Combined Low-grade Serous and Mesonephric-like Adenocarcinoma: Further Evidence for A Mullerian Origin of Mesonephric-like Adenocarcinoma.

Mesonephric-like adenocarcinomas are rare neoplasms occurring in the uterine corpus and ovary which bear a close morphologic resemblance to cervical mesonephric adenocarcinomas. They also have a similar immunophenotype and harbor similar molecular abnormalities to mesonephric adenocarcinomas and it is debated whether they are truly of mesonephric origin or represent Mullerian neoplasms closely mimicking mesonephric adenocarcinomas. We report an unusual case with bilateral ovarian serous borderline tumors and extraovarian low-grade serous carcinoma (invasive implants). In one ovary, there was a component of mesonephric-like adenocarcinoma. The immunophenotypes of the serous and the mesonephric-like components were distinct and as expected for the individual tumor types (serous component diffusely positive with WT1 and estrogen receptor and negative with GATA3, TTF1 and CD10; mesonephric-like component WT1 and estrogen receptor negative and GATA3, TTF1, and CD10 positive; both components diffusely positive with PAX8 and exhibiting "wild-type" p53 immunoreactivity). In all components (bilateral serous borderline tumors, low-grade serous carcinoma and mesonephric-like adenocarcinoma), an identical KRAS mutation was detected (NM_004985.4): c.35G>A, p.(G12D) proving a clonal association between the serous and mesonephric-like components and excluding a collision neoplasm. This represents the second reported case of a combined ovarian low-grade serous tumor and mesonephric-like adenocarcinoma; in the previously reported case, an identical NRAS mutation was present in both components. These 2 cases provide evidence that ovarian mesonephric-like adenocarcinomas have, at least in some cases, a Mullerian origin and differentiate along mesonephric lines. We present additional evidence for this by reviewing associated findings in published and unpublished ovarian mesonephric-like adenocarcinomas; 8 of 11 of these neoplasms contained other Mullerian lesions in the same ovary, mainly endometriosis and adenomas/adenofibromas.

Pkd1-targeted mutation reveals a role for the Wolffian duct in autosomal dominant polycystic kidney disease.

Several life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.

Mesonephric-like Carcinoma of the Endometrium: A Subset of Endometrial Carcinoma With an Aggressive Behavior.

Endometrial mesonephric-like carcinomas (MLCa) are uncommon with <50 reported cases thus far. Previous studies have characterized the histologic, immunohistochemical, and molecular features of MLCa; however, there is limited information with respect to outcome. This single-institution study of 23 uterine MLCas characterizes the behavior of such a neoplasm. Uterine MLCas (2004-present) had review of histologic features, immunohistochemical results, molecular profile, and clinical information (stage, treatment, follow-up). The behavior of MLCa was compared with low-grade endometrioid carcinomas (ECas) and uterine serous carcinomas (USCs) treated at our institution from 2004 to present. All MLCas had a mixture of previously described architectural and cytologic features most notably ductal and/or tubular architecture (21/23), nuclei resembling those of papillary thyroid carcinoma (18/23), and at least focal intraluminal eosinophilic secretions (20/23). Immunoperoxidase studies facilitated diagnosis in 22 cases: CD10, 10/10; calretinin, 5/15; estrogen receptor (≥10% nuclei), 6/21; progesterone receptor, 1/15; GATA-3, 15/16; TTF-1, 11/16. Fourteen of 17 tested cases had a KRAS mutation (7 as the only alteration; 7 with additional mutations including PIK [n=5]; PTEN [n=2], CTNNB1 [n=1]).One case had mutations in PTEN, PIK, and CTNNB1 without KRAS; 2 cases had no detectable somatic mutation. Overall, 48% of patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage 3 or 4 disease with the following uterine risk factors: >50% myometrial invasion, 20/23; lymphovascular space invasion, 16/23; cervical stromal invasion, 7/23. Twenty patients had adjuvant therapy (7 radiation only; 13 chemotherapy±radiation), whereas 3 patients had either unknown or declined therapy. Follow-up was known for 21 patients: 17 patients had recurrences or never achieved remission with the lung being the most common recurrence site (n=9); 7 patients died of disease. The median progression-free survival was 18.2 months for MLCa compared with 183 months for ECa and 67.1 months for USC. The median overall survival for MLCa was 70.6 months compared with 139.1 months for USC (median survival for ECa not reached). Uterine MLCa is uncommon with most tumors recognized by architectural heterogeneity, vesicular, overlapping nuclei with grooves, and eosinophilic luminal secretions. The typical immunoprofile includes low to absent expression of hormone receptors but at least focal expression of GATA-3 and/or TTF-1. Most tested cases had a KRAS mutation although genetic mutations typically associated with ECa are not uncommon. Compared with more commonly encountered types of ECa, MLCa is more aggressive with a tendency towards earlier and distant recurrence.

c-KIT Analysis and Targeted Molecular Sequencing of Mesonephric Carcinomas of the Female Genital Tract.

Mesonephric carcinoma is a rare malignancy, thought to derive from Wolffian remnants. To date, no targeted molecular therapeutic options have been identified. On the basis of limited case reports, c-KIT immunohistochemical expression has been reported in female adnexal tumors of Wolffian origin, and targeted therapy with Imatinib has been attempted with mixed success. Currently, it is unclear whether c-KIT immunohistochemical expression is seen in mesonephric carcinoma, a tumor that is thought to be related to female adnexal tumors of Wolffian origin, and how this correlates with KIT mutational status. In this study, we assessed the immunohistochemical expression of c-KIT and KIT mutational status, in a series of 13 mesonephric neoplasms (5 cervical [including 2 cervical carcinosarcomas], 3 uterine corpora, 4 ovarian, and 1 vaginal/pelvic). The intensity of staining and proportion of cells showing cytoplasmic/membranous staining for c-KIT were recorded. KIT was sequenced using a next-generation sequencing panel that targeted 120 hotspots and 17 exons in 33 known actionable cancer genes. This panel included KIT exons 9, 11, and 13, and 6 hotspots (T670, D816, D820, N822, Y823, A829). Although c-KIT immunohistochemical expression was observed in the majority of mesonephric carcinomas (10/12 cases; 83%), no KIT mutations were detected. This cautions pathologists against the use of c-KIT immunohistochemistry as a surrogate marker for KIT-activating mutations in this setting. Consistent with previous studies, the majority of mesonephric neoplasms (10/13; 77%) harbored KRAS mutations. Additional mutations were found in CTNNB1 (2/13, 15%), TP53 (2/13, 15%), and PIK3CA (1/13, 8%).

Coexistence of endometrial mesonephric-like adenocarcinoma and endometrioid carcinoma suggests a Müllerian duct lineage: a case report.

BACKGROUND: Endometrial mesonephric-like adenocarcinomas exhibit classical histologic features of mesonephric carcinoma; however, it remains unclear whether these tumors represent mesonephric (Wolffian) carcinoma or endometrioid (Müllerian) carcinomas that closely mimic mesonephric carcinoma. CASE PRESENTATION: A 32-year-old Japanese primigravida presented with atypical vaginal bleeding. An endometrial biopsy suggested low-grade endometrioid carcinoma, and she was administered medroxyprogesterone acetate. Her tumor recurred 6 years later, and she underwent hysterectomy, salpingo-oophorectomy, and omentectomy, at which point she was diagnosed with mesonephric-like adenocarcinoma of the uterine endometrium. Retrospective pathological review of the initial biopsy confirmed coexisting low-grade endometrioid carcinoma and mesonephric-like adenocarcinoma of the uterine endometrium. On immunohistochemistry, the endometrioid carcinoma component was diffuse positive for estrogen and progesterone receptors but negative for thyroid transcription factor 1. However, the mesonephric-like adenocarcinoma component exhibited a mixture of estrogen receptor- and thyroid transcription factor 1-positive cells within the same glands. CONCLUSIONS: We encountered a patient with coexisting endometrial mesonephric-like adenocarcinoma and low-grade endometrioid carcinoma, which was treated using medroxyprogesterone acetate therapy, resulting in recurrence of mesonephric-like adenocarcinoma alone. These clinicopathological findings support the prevailing notions that mesonephric-like adenocarcinoma is a Müllerian adenocarcinoma exhibiting mesonephric differentiation.

Targeted Genomic Profiling of Female Adnexal Tumors of Probable Wolffian Origin (FATWO).

Female adnexal tumor of probable Wolffian origin (FATWO) is a rare gynecologic neoplasm of low-malignant potential presumed to be derived from mesonephric remnants in the upper female genital tract. Similarly, mesonephric remnants in the lower female genital tract are thought to be the origin for mesonephric carcinoma. Although the molecular alterations in mesonephric carcinoma have been recently reported, the pathogenesis of and molecular alterations in FATWO are not well understood. The aims of this study were to examine the molecular alterations in FATWO and to establish whether these neoplasms are molecularly similar to mesonephric carcinoma. Eight FATWOs underwent massively parallel sequencing to detect single nucleotide variations, copy number variations, and structural variants by surveying exonic DNA sequences of 300 cancer genes and 113 introns across 35 genes. Good quality DNA was isolated from 7 of 8 cases. Novel KMT2D variants (1 frameshift, 3 missense) were identified in 4 of 7 cases (57%), but were variants of uncertain biologic significance. STK11 mutations (both frameshift) were identified in 2 of 7 cases (29%); one of these was in a patient with a known history of Peutz-Jeghers syndrome. A mutation in the chromatin remodeling gene ARID1B was identified in 1 of 7 cases (14%). No cases harbored KRAS, NRAS, TP53, PIK3CA, PTEN, or DICER1 mutations. There were relatively low numbers of copy number variations, and no recurrent copy number variations were identified. One case demonstrated moderate copy gain of CCND1. No structural variants were identified. In summary, FATWO is characterized molecularly by the absence of KRAS/NRAS mutations (characteristic of mesonephric carcinoma), absence of DICER1 mutations (characteristic of Sertoli-Leydig cell tumor) and frequent KMT2D mutations of unknown biologic significance. FATWOs exhibit a limited number of molecular aberrations that are significantly different from those reported in tumors in the differential diagnosis, and our results question the relationship of mesonephric carcinoma with FATWO. Disease-defining molecular alterations for FATWO have yet to be discovered.