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.

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 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.

A Comparison of GATA3, TTF1, CD10, and Calretinin in Identifying Mesonephric and Mesonephric-like Carcinomas of the Gynecologic Tract.

Mesonephric carcinomas of the gynecologic tract are neoplasms that are often under-recognized due to their varied morphologic appearances. Recently, GATA3 and TTF1 have been reported to be useful immunohistochemical markers for distinguishing mesonephric carcinomas from its morphologic mimics. Herein, we compared the performance of GATA3 and TTF1 to the traditional markers used for mesonephric carcinomas, CD10 and calretinin. We studied 694 cases: 8 mesonephric carcinomas (7 cervical [includes 3 mesonephric carcinosarcomas], 1 vaginal), 5 mesonephric-like carcinomas (4 uterine corpus, 1 ovarian), 585 endometrial adenocarcinomas, and 96 cervical adenocarcinomas. Mesonephric-like carcinomas were defined as tumors exhibiting the classic morphologic features of mesonephric carcinoma, but occurring outside of the cervix and without convincing mesonephric remnants. GATA3 had the highest sensitivity and specificity (91% and 94%) compared with TTF1 (45% and 99%), CD10 (73% and 83%), and calretinin (36% and 89%). GATA3, however, also stained a substantial number of uterine carcinosarcomas (23/113, 20%). TTF1 was positive in 5/5 (100%) mesonephric-like carcinomas and only 1/8 (13%) mesonephric carcinomas. In 4/6 (67%) TTF1 positive cases, GATA3 exhibited an inverse staining pattern with TTF1. In summary, GATA3 was the best overall marker for mesonephric and mesonephric-like carcinomas, but cannot be used to distinguish mesonephric carcinosarcomas from Müllerian carcinosarcomas. The inverse staining pattern between GATA3 and TTF1, suggests that TTF1 may be useful when GATA3 is negative in small biopsies where mesonephric or mesonephric-like carcinoma is suspected. The greater TTF1 positivity in mesonephric-like carcinomas suggests they may be biologically different from prototypical mesonephric carcinomas.

Mesonephric adenocarcinoma of the uterine corpus.

Mesonephric carcinomas are rare in the female genital tract and usually are found in sites where embryonic remnants of wolffian ducts are usually detected, such as the uterine cervix, broad ligament, mesosalpinx and exceptionally rarely in the uterine corpus. To date, only four cases of mesonephric carcinomas arising in the uterine corpus have been described in literature. Here we report two cases of mesonephric carcinomas arising in a deep intramural location of the uterine corpus in a 55-year-old woman and a 62-year-old woman in Chinese populations. It is believed to be the first report in China. Both cases presented with a little postmenopausal bleeding. Before hospitalized, uterine curettages were programmed for both cases. The pathology reports were mesonephric adenocarcinoma. A total hysterectomy and bilateral salpingo-oophorectomy were performed. On gross examination, the tumors of both cases were confined to the myometrium. Microscopic examination found both tumors of these two cases were adenocarcinomas mixed with spindle cell component. The most primary histologic patterns of the mesonephric adenocarcinomas were tubular glands that varied in size and were lined by one to several layers of columnar cells. Immunohistochemically, the tumor cells expressed positive with CD10, calretinin, vimentin, cytokeratin (AE1/AE3) and epithelial membrane antigen (EMA); but expressions of ER and PR were completely negative. The peculiar location of mesonephric carcinoma of the uterine corpus may be misinterpreted as other histological type neoplasms. Awareness of this rare phenomenon and immunostaining for markers of mesonephric carcinoma can prevent from making a false diagnosis.

Is female adnexal tumour of probable wolffian origin a benign lesion? A systematic review of the English literature.

AIMS: To establish the prognosis associated with female adnexal tumour of probable wolffian origin (FATWO) and determine the frequency with which it behaves as a truly benign lesion. METHODS: Medline and Embase electronic databases were interrogated to identify 31 papers describing 63 patients with FATWO with follow up. RESULTS: Fifty (79%, CI 67.4-87.3%) were alive and well but seven patients had recurrent or residual disease (11.1%, CI 5.6-21.5%) and three had died of disease (4.8%, CI 1.6-13.1%). Stage (p = 0.0002) and differentiation (p = 0.0118) showed a significant association with outcome although atypia approached significance at the 5% level (p = 0.0658). One patient with a ruptured tumour had recurrent disease and one other had died of disease (p = 0.2278). There was no association between outcome and age (p = 0.6651), size (p = 0.1912), length of survival (p = 0.2351) tumour site, mitotic rate or necrosis (p = 0.5937, 0.4697 and 0.2016, respectively). CONCLUSION: On the basis of these findings, FATWO cannot be regarded as a benign lesion. These lesions may be confused with well differentiated gynaecological cancers and careful clinicopathological correlation with the extensive use of immunohistochemistry is encouraged to ensure that lesions such as extragonadal endometrioid adenocarcinoma is not confused with FATWO.

Changes in gene expression during Wolffian duct development.

BACKGROUND: Wolffian ducts (WDs) are the embryonic precursors of the male reproductive tract. Their development is induced by testosterone, which interacts with the androgen receptor (AR). The molecular pathways underlying androgen-dependent WD development are largely unknown. We aimed to identify AR target genes important in this process. METHODS: RNA was isolated from rat WDs at E17.5 and E20.5. Affymetrix GeneChip expression arrays were used to identify transcripts up- or downregulated more than 2-fold. Regulation of seven transcripts was confirmed using quantitative PCR. RESULTS: Transcripts from 76 known genes were regulated, including modulators of insulin-like growth factor and transforming growth factor-beta signalling. By controlling these modulators, androgens may indirectly affect growth factor signalling pathways important in epithelial-mesenchymal interactions and organ development. Caveolin-1, also upregulated, may play a role in modifying as well as mediating AR signalling. Differentiation of WD epithelium and smooth muscle, innervation and extracellular matrix synthesis were reflected in regulation of other transcripts. Several genes were previously suggested to be regulated by androgens or contained functional or putative androgen/glucocorticoid response elements, indicating they may be direct targets of androgen signalling. CONCLUSION: Our results suggest novel cohorts of signals that may contribute to androgen-dependent WD development and provide hypotheses that can be tested by future studies.

Extra-pituitary growth hormone in peripheral tissues of early chick embryos.

Early embryonic growth is independent of pituitary growth hormone (GH), since it occurs prior to the differentiation of pituitary somatotrophs. Embryogenesis is therefore thought to be regulated by local growth factors. As GH is now known to be produced in many extrapituitary sites, in which it acts in an autocrine or paracrine manner, the possibility that extra-pituitary GH may participate in embryogenesis and organogenesis was assessed by determining the immunocytochemical presence and location of GH- and GH-receptor (GHR)-like proteins in the peripheral tissues of chick embryos during their 21-day incubation period. Immunoreactive (IR)-GH, detectable by a monoclonal and two polyclonal antibodies for chicken GH, was specifically and ubiquitously present in tissues of 3-day-old embryos. At embryonic day (ED) 5, IR-GH was widespread in ectodermal, mesodermal and endodermal tissues, but it was not present in every cell of each tissue. IR-GH was particularly abundant i! n the neural tube, notochord, limb bud, somites, heart, stomach, liver, kidney, Wolffian duct and the amnion. By ED8, IR-GH was still widespread and was now present in limb bud cartilage, although the heart and liver were no longer GH immunoreactive. GH receptor immunoreactivity was also present in most tissues and cells of ED3-ED8 embryos. These results demonstrate that extrapituitary GH is abundantly present during early embryogenesis, prior to the differentiation of pituitary somatotrophs (at ED12). Since GH- and GHR-like proteins are present in most tissues of the chick embryo, it is proposed that extrapituitary GH may act as a local growth factor during embryonic development.

Metastatic female adnexal tumor of probable Wolffian origin: a case report and review of the literature.

Female adnexal tumor of probable wolffian origin is a rare neoplasm that can present diagnostic difficulties. We report herein a case of a 60-year-old woman with female adnexal tumor of probable wolffian origin arising within the leaves of a broad ligament and, 5 years later, presenting with metastasis to the liver. The morphologic, immunohistochemical, ultrastructural, and DNA ploidy findings of the original and metastatic tumor, differential diagnoses, and the results of the English-language literature review are presented.

Localization of protein gene product 9.5 immunoreactivity in derivatives of the human Wolffian duct and in prostate cancer.

BACKGROUND: Protein gene product 9.5 (PGP 9.5) has been considered to be a neuronal marker, but it is also present in extraneuronal tissues, e.g., the human mammary gland and rat epididymis. Its presence and distribution in the developing and adult male human genital tract have been unknown. METHODS: Immunohistochemical reactions were performed on human embryonic and postnatal specimens of the male genital tract, using commercial monoclonal and polyclonal antibodies. RESULTS: PGP 9.5 immunoreactivity was found in the Wolffian duct of human embryos (55-85 mm crown-rump length). Strong reactivity was observed in mesonephric tubular cells and at the apical rim of Wolffian duct cells. Owing to their PGP 9.5 immunoreactivity, these cells could also be identified on the surface of the embryonic verumontanum, extending from the orifices of the Wolffian duct to a small stretch of the urogenital sinus. There they contrasted sharply against non-Wolffian cells. In the adult human genital tract, PGP 9.5 immunoreactive material was present in the supranuclear portion of some epithelial cells of the epididymal efferent ductules, in isolated cells of the ejaculatory ducts, and in prostate cancer specimens. In the ejaculatory ducts, the PGP 9.5-immunoreactive cells were free of immunoreactivity for semenogelin, the major secretory product of the ejaculatory-vesicular-ampullary complex, and they also lacked chromogranin A-immunoreactivity. In prostate cancer specimens, PGP 9.5 immunoreactivity was never observed in secretory cells (immunoreactive for prostate-specific antigen), but was restricted to neuroendocrine cells, where it occurred either alone or coexpressed with chromogranin A-immunoreactivity. CONCLUSIONS: PGP 9.5-immunoreactivity is prenatally distributed in the Wolffian duct and its derivations; postnatally, it is restricted to a few cells derived from the initial and terminal segment of the Wolffian duct, and to neuroendocrine cells in prostate cancer specimens.

Cellular localization of immunoreactive epidermal growth factor during Wolffian duct differentiation of the fetal mouse.

Previous studies from this laboratory indicated a role for epidermal growth factor (EGF) in androgen-dependent male reproductive tract differentiation of the fetal mouse. Expression of an EGF-like protein during Wolffian duct differentiation was indicated from the determinations by radioimmunoassay (RIA) and radioreceptor assay. To further characterize the protein and to assess its role in male sexual differentiation, expression of the protein has been analyzed by Western blot assay and its tissue-specific cellular expression has been determined by immunocytochemical assay in the present study. Western blot analysis of the 18-day fetal male reproductive tract detected an immunoreactive band of the predicted 6-kDa size. Immunocytochemical analysis also detected EGF-specific immunostaining in the Wolffian duct derivatives. At day 18 of gestation, the staining was localized predominantly in the epithelial nuclei of the Wolffian duct derivatives whereas at days 14 and 16 of gestation, the staining was equally distributed in the mesenchymal and epithelial sites of the Wolffian duct derivative. The intensity of the staining increased with progression of differentiation during the 14th-18th days of gestation. Prenatal exposure to the antiandrogen flutamide significantly reduced the immunostaining of the duct. Thus, a role for EGF in Wolffian duct differentiation is indicated.

Distribution of immunoreactive androgen-binding protein/sex hormone-binding globulin in tissues of the fetal rat.

Androgen-binding protein/sex hormone-binding globulin (ABP/SHBG) is an extracellular carrier protein that binds androgens and estrogens with high affinity. In the adult, ABP/SHBG is thought to function in the male reproductive system and the general circulation in both sexes to modulate the actions of sex steroids. The ABP/SHBG gene is also expressed in the embryonic rat liver, where SHBG is secreted into the fetal blood of male and female rats. The embryo also expresses an alternative SHBG with a unique N-terminal sequence. In this study, the distribution of immunoreactive SHBG in the 17-day-old male fetal rat was determined with six antisera. In general, all of the antisera reacted with the same structures. Specific tissue immunoreactivity was mostly cytoplasmic and/or extracellular. By far the most prominent immunoreactive structures were the mesoderm-derived tissues: connective tissue, striated and cardiac muscle, cartilage, and the liver hematopoietic system. In addition, all regions of the fetal brain contained immunoreactive neurons. In the developing male reproductive system, there was minor reactivity in the testicular cords, whereas the connective tissue in the differentiating Wolffian duct stained with all of the antisera. The Wolffian duct epithelium and epithelia in other developing organs contained small amounts of immunoreactive SHBG, except for the lung, which stained in the epithelial extracellular matrix. An antibody raised against a unique N-terminal peptide specific for the alternative SHBG protein revealed that it was also present in many tissues. These data suggest that SHBG is important for the differentiation of mesodermal tissues. SHBG may modulate the action of androgens in embryonic stroma, thereby regulating development of the epithelium in hormone-dependent tissues.

Female adnexal tumour of probable Wolffian origin: a clinicopathological and immunohistochemical study of three cases.

The clinical and pathological features of three adnexal tumours of probable Wolffian origin are reported. One case was an incidental finding in a patient who died from ovarian carcinoma; in the other two cases the patients presented with lower abdominal pain. The three tumours were well-circumscribed, solid masses arising in the leaves of the broad ligament and histological examination showed bland epithelial cells forming tubular, solid and microcystic patterns. The immunohistochemical profile of the tumours was similar to that of Wolffian duct remnants. They co-expressed cytokeratin and vimentin and lacked epithelial membrane antigen (EMA) reactivity, in contrast to tumours of Müllerian origin which usually express EMA. The differential diagnosis of female adnexal tumours is discussed.

NCAM in developing mouse gonads and ducts.

The expression of the Neural Cell Adhesion Molecule, NCAM, in mouse gonads and ducts was studied from fetal life to maturity. The methods used were immunocytochemical staining and Western blotting. The immunocytochemical studies showed that the only structures that remain NCAM-positive throughout life were the mesonephric-derived rete ovarii and rete testis. Also in the fetal gonads some somatic cell lining the groups of differentiating germ cells were stained. In the immature as well as in the mature ovary the granulosa cells and oocytes of growing and large follicles--but not of small follicles--were stained. A particularly strong staining of the cytoplasm of the oocyte, healthy as well as atretic, was seen. All cells of the testis remained negative except for weakly stained residual bodies and late spermatids. At all ages the male ducts showed only weak staining, whereas in the female Müllerian duct the epithelium became strongly positive at puberty. The stroma of the Müllerian duct was positive during a transitory period around day 16 of fetal life in both sexes. One-dimensional gel immunoblotting of total protein from gonads, rete and ducts from immature and mature mice showed that only the two largest isoforms of NCAM (NCAM-A and NCAM-B) were present. The gonads and the rete of both sexes and the adult uterus expressed only NCAM-B, whereas NCAM-A was also detected in the adult epididymis. The present findings suggest that NCAM may be involved in the normal development and formation of both the gonads and ducts.(ABSTRACT TRUNCATED AT 250 WORDS)