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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.

Mesonephric and mesonephric-like adenocarcinomas are uncommon neoplasms of the gynecologic tract that have until recently been poorly understood. Although their morphological, 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 behaviour 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 mesonephric and mesonephric-like adenocarcinomas (30 mesonephric adenocarcinomas (MA) of the uterine cervix, 44 mesonephric-like adenocarcinomas (MLA) of the endometrium, and 25 MLA 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 advanced stage (II-IV) (15/25 [60%] MA of cervix, 25/43 [58%] MLA of endometrium, and 7/18 [39%] MLA of ovary). The majority (46/89 [52%] overall) (12/24 [50%] MA of cervix, 24/41 [59%] MLA of endometrium, and 10/24 [42%] MLA of ovary) developed recurrences, most commonly distant (9/12 [75%] MA of cervix, 22/24 [92%] MLA of the endometrium, and 5/9 [56%] MLA of the ovary). The 5-year Disease Specific Survival (DSS) 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.

BACKGROUND: Vesicoureteral reflux (VUR), backflow of urine into the kidney, is associated with urinary tract infections and chronic kidney disease. Integrity of the vesicoureteral junction (VUJ), where reflux occurs, is determined largely by proper induction of the ureteric bud from the Wolffian duct. Induction is modulated by signals from the surrounding peri-Wolffian duct stroma. We evaluated whether miRNAs in the peri-Wolffian duct stroma are necessary for proper ureteric induction, VUJ formation, and suppression of VUR. METHODS: We generated a mouse with loss of miRNAs in the peri-Wolffian duct stroma. We evaluated embryos for ureteric bud induction defects and expression of genes that regulate induction. We performed cystograms to assess for reflux and assessed VUJs in postnatal mice. RESULTS: Mutant embryos had cranially displaced ureteric bud induction sites versus controls. We observed no changes in expression of genes known to regulate induction. While mutants were early postnatal lethal, they had high rates of VUR versus controls. Mutant VUJs that refluxed had low inserting ureters and shortened intravesicular tunnels versus non-refluxing mice. CONCLUSIONS: We found that miRNAs in the peri-Wolffian duct stroma are required for normal ureteric bud induction, VUJ formation, and prevention of VUR.

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.

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.

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.

Endometrial mesonephric-like carcinomas (MLCa) are uncommon with50 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.

During development of the mouse urogenital complex, the gonads undergo changes in three-dimensional structure, body position and spatial relationship with the mesonephric ducts, kidneys and adrenals. The complexity of genital ridge development obscures potential connections between morphogenesis and gonadal sex determination. To characterize the morphogenic processes implicated in regulating gonad shape and fate, we used whole-embryo tissue clearing and light sheet microscopy to assemble a time course of gonad development in native form and context. Analysis revealed that gonad morphology is determined through anterior-to-posterior patterns as well as increased rates of growth, rotation and separation in the central domain that may contribute to regionalization of the gonad. We report a close alignment of gonad and mesonephric duct movements as well as delayed duct development in a gonad dysgenesis mutant, which together support a mechanical dependency linking gonad and mesonephric duct morphogenesis.

Objective To describe the treatments of a patient using the laparoscopic Davydov’s method for Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome and ureteral reimplantation for hydronephrosis and hydroureter. Design Surgical video article. A consent form from the patient was obtained as appropriate; the nature of the study did not necessitate ethics committee approval. There were no conflicts of interest. Setting University hospital. Patient(s) A 28-year-old woman who presented at our gynecology department with the symptoms of primary amenorrhea and difficult intercourse. She had repaired congenital rectovestibular fistula and imperforate anus at the age of 8. At physical examination, she had a phenotypically normal vulva with a vaginal small pouch (0.5 cm). Magnetic resonance imaging of the pelvis revealed normal ovaries, a primordial uterus, absence of vaginal canal, and a 4.0 × 4.2 × 4.0 cm cystic structure posterior to the bladder. Magnetic resonance urography showed right to left renal crossed-ectopia with inferior fusion, and hydronephrosis and hydroureter from the superior kidney with Grade Ⅳ vesicoureteral reflux. Karyotype was 46, XX. Intervention(s) Saline solution 300 mL was injected into the rectovesical space with an infusion of diluted adrenaline (1:200,000). The goal of this injection was to aid in the identification of tissue planes and reduce blood loss. The space between urethra/bladder and rectum progressively was dissected. Blunt dissection was performed initially with digital separation of tissues. Then, an 8-cm–long neovaginal vault of about 3 cm in diameter was created. The mobilized peritoneum was pulled downward with eight Vicryl sutures and connected to the vaginal epithelium. By cystoscope, we found the left orifice but could not find the right orifice of the hydroureter. Then we ligated the hydroureter by 2-0 absorbable suture near the cyst and cut off the hydroureter, and then incised of all the layers at the top of the bladder to make a bladder flap. We placed the 5 Fr double J stent in the hydroureter and the bladder and anastomozed with the ureteral stump (3-0 Vicryl). Then we removed the cyst laparoscopically. We performed a purse-string stitch to create the apex of the neovagina by taking posterior serosa of the bladder, the pelvic peritoneum between the ovary and rectum, primordial uterus, and anterior rectal serosa. Main Outcome Measure(s) Measurement of the final canal length, sexual function (Female Sexual Function Index), and degree of hydronephrosis. Result(s) Three days later, we started to change the vaginal mold and the patient was advised to wear it day and night for the first postoperative month. The vaginal mold had to be worn each night until normal sexual intercourse was possible. Findings confirmed the cyst was Gartner's duct cyst. One year after the surgery, the final canal length was 9 cm and Female Sexual Function Index score was 28. The ultrasound showed that the degree of hydronephrosis of upper moiety was mild. Conclusion(s) The distal Wolffian ducts in the female are absorbed but may persist as vestigial remnants (Gartner’s duct cysts). A few cases of the combined urogenital-Wolffian anomalies are reported; most of them are associated with the anomalies of mullerian duct fusion, such as Herlyn-Werner-Wunderlich syndrome (uterus didelphys, obstructed hemivagina, and mesonephric duct anomalies). The embryogenesis of the combined anomalies is not completely understood. With comprehensive preoperative assessments, laparoscopic surgery could be a safe and effective treatment to these cases.

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.

The urinary bladder collects urine from the kidneys and stores it until the appropriate moment for voiding. The trigone and ureterovesical junctions are key to bladder function, by allowing one-way passage of urine into the bladder without obstruction. Embryological development of these structures has been studied in multiple animal models as well as humans. In this report we review the existing literature on bladder development and cellular signalling with particular focus on bladder development in humans. The bladder and ureterovesical junction form primarily during the fourth to eighth weeks of gestation, and arise from the primitive urogenital sinus following subdivision of the cloaca. The bladder develops through mesenchymal-epithelial interactions between the endoderm of the urogenital sinus and mesodermal mesenchyme. Key signalling factors in bladder development include shh, TGF-β, Bmp4, and Fgfr2. A concentration gradient of shh is particularly important in development of bladder musculature, which is vital to bladder function. The ureterovesical junction forms from the interaction between the Wolffian duct and the bladder. The ureteric bud arises from the Wolffian duct and is incorporated into the developing bladder at the trigone. It was previously thought that the trigonal musculature developed primarily from the Wolffian duct, but it has been shown to develop primarily from bladder mesenchyme. Following emergence of the ureters from the Wolffian ducts, extensive epithelial remodelling brings the ureters to their final trigonal positions via vitamin A-induced apoptosis. Perturbation of this process is implicated in clinical obstruction or urine reflux. Congenital malformations include ureteric duplication and bladder exstrophy.

This study documented, for the first time, the morphological patterns of differentiation of male and female genital organs of Spix cavy (Galea spixii) using histological and ultrastructural analyses, with immuno-localization of steroidogenic enzymes, cytochromes P450 aromatase (P450arom) and 17α-hydroxylase/17, 20-lyase (P450c17), involved in the synthesis of estrogens and androgens respectively throughout fetal sexual development. Undifferentiated gonads of Spix cavy develop into ovaries in females after 25 days of gestation (DG), exhibiting P450arom immunoreactivity. After 25 DG, paramesonephric ducts develop and form oviducts, uterine horns and cranial portion of the vagina. The caudal portion of the vagina originates from the urogenital sinus, and a vaginal closure membrane is present at the end of gestation. Partial channeling of the urethra into the clitoris occurs after 40 DG, but complete channeling never occurs. A preputial meatus emerges near the tip of organ. In males, undifferentiated gonads develop into testes at 25 DG and develop immunoreactivity for P450c17, which is required for androgens synthesis and likely maintenance of mesonephric ducts. Mesonephric ducts develop subsequently, forming the epididymis and ductus deferens. The pelvic urethra develops after 25 DG with channeling into the penis occurring around 30 DG. This is the first morphological study describing the process of sexual differentiation during gestation in a hystricomorph rodent and one of the most comprehensive analyses conducted in any mammal. Male genital organ development follows the general pattern described in other domestic mammals, but does not include formation of the baculum as occurs in mice and rats. In females, clitoral development includes partial canalization by the urethra and development of a preputial meatus. Further studies are required to clarify the mechanisms involved in the differentiative processes described.

The epithelial Wolffian duct (WD) inserts into the cloaca (primitive bladder) before metanephric kidney development, thereby establishing the initial plumbing for eventual joining of the ureters and bladder. Defects in this process cause common anomalies in the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). However, developmental, cellular, and molecular mechanisms of WD-cloaca fusion are poorly understood. Through systematic analysis of early WD tip development in mice, we discovered that a novel process of spatiotemporally regulated apoptosis in WD and cloaca was necessary for WD-cloaca fusion. Aberrant RET tyrosine kinase signaling through tyrosine (Y) 1062, to which PI3K- or ERK-activating proteins dock, or Y1015, to which PLCγ docks, has been shown to cause CAKUT-like defects. Cloacal apoptosis did not occur in RetY1062F mutants, in which WDs did not reach the cloaca, or in RetY1015F mutants, in which WD tips reached the cloaca but did not fuse. Moreover, inhibition of ERK or apoptosis prevented WD-cloaca fusion in cultures, and WD-specific genetic deletion of YAP attenuated cloacal apoptosis and WD-cloacal fusion in vivo. Thus, cloacal apoptosis requires direct contact and signals from the WD tip and is necessary for WD-cloacal fusion. These findings may explain the mechanisms of many CAKUT.

During embryogenesis, different tissues develop coordinately, and this coordination is often in harmony with body growth. Recent studies allow us to understand how this harmonious regulation is achieved at the levels of inter-cellular, inter-tissue, and tissue-body relationships. Here, we present an overview of recently revealed mechanisms by which axial growth (tail growth) drives a variety of morphogenetic events, with a focus on the coordinated progression between Wolffian (nephric) duct elongation and somitogenesis. We also discuss how we can relate this coordination to the events occurring during limb bud outgrowth, since the limb buds and tail bud are appendage anlagen acquired during vertebrate evolution, both of which undergo massive elongation/outgrowth.

Background Fibroblast growth factor receptor 2 (Fgfr2) deletion from murine peri-Wolffian duct stroma (ST) results in aberrant ureteric bud induction, abnormal ureteral insertion into the bladder, and high rates of vesicoureteral reflux (VUR). It is unclear which receptor docking protein(s) is/are responsible for Fgfr2 actions in these tissues. We investigated whether the docking protein, fibroblast receptor substrate 2α (Frs2α), had roles in peri-Wolffian duct stroma similar to Fgfr2. Methods We conditionally deleted Frs2α in per-Wolffian duct stroma with a Tbx18cre mouse line (Frs2αST−/−). We assessed for ureteric induction defects and alterations in downstream targets mediating defects. We performed euthanized cystograms and assessed ureter-bladder junctions via three dimensional (3D) reconstructions. Results Embryonic day (E) 11.5 Frs2αST−/− embryos had many displaced ureteric bud induction sites versus controls. E11.0 Frs2αST−/− embryos had decreased Bmp4 expression and signaling, which can cause abnormal ureteric bud induction. Postnatal day 1 (P1) and P30 Frs2αST−/− mice had higher VUR rates and grades versus controls. Mutant refluxing ureters inserted improperly into the bladder and had shortened intravesicular tunnels versus controls: Conclusions Frs2αST−/− have aberrant ureteric induction sites, improper ureteral insertion, shortened intravesicular lengths and VUR. Induction site defects appear secondary to reduced Bmp4 expression, similar to Fgfr2 mutants.

The reproductive tract in mammals emerges from two ductal systems during embryogenesis: Wolffian ducts (WDs) and Mullerian ducts (MDs). Most of the female reproductive tract (FRT) including the oviducts, uterine horn and cervix, originate from MDs. It is widely accepted that the formation of MDs depends on the preformed WDs within the urogenital primordia. Here, we found that the WD mesenchyme under the regulation of Hedgehog (Hh) signaling is closely related to the developmental processes of the FRT during embryonic and postnatal periods. Deficiency of Sonic hedgehog (Shh), the only Hh ligand expressed exclusively in WDs, prevents the MD mesenchyme from affecting uterine growth along the radial axis. The in vivo cell tracking approach revealed that after WD regression, distinct cells responding to WD-derived Hh signal continue to exist in the developing FRT and gradually contribute to the formation of various tissues such as smooth muscle, endometrial stroma and vascular vessel, in the mouse uterus. Our study thus provides a novel developmental mechanism of FRT relying on WD.

Background The mechanisms by which the rete testis joins the efferent ducts, which joins the Wolffian duct during development, are not known. Mouse and chick models have been helpful in identifying genes that are important for the development of each part, but genes have not been identified as to those that play a role in the joining of each part. Clinical implications of the failure of the male reproductive tract to form a fully functional conduit for spermatozoa are not trivial. Epididymal disjunction, the failure of the efferent ducts to join the testis, is one of several epididymal anomalies that have been observed in some boys who were cryptorchid at birth. Objective A systematic review of studies focusing on the morphogenesis of the mesonephric duct and mesonephric tubules in different species, and identification of clinical issues should there be failure of these tissues to develop. Design PubMed and GUDMAP databases, and review of books on kidney development were searched for studies reporting on the mechanisms of morphogenesis of the kidney and epididymis. Main outcomes measure(s) Gaps in our knowledge were identified, and hypotheses coupled with suggestions for future experiments were presented. Results A total of 64 papers were identified as relevant, of which 53 were original research articles and 11 were book chapters and reviews covering morphogenesis and clinical issues. Investigators utilized multiple species including, human, mouse, chick, Xenopus, bovine, and sheep. Conclusion Fundamental understanding of the morphogenesis of the male reproductive tract is limited, especially the morphogenesis of the rete testis and efferent ducts. Therefore, it is not surprising that we do not understand how each part unites to form a whole. Only one mechanism of joining of one part of the tract to another was identified: the joining of the Wolffian duct to the cloaca via controlled apoptosis.

Programmed cell senescence during embryo development is a recently described process that opens a new perspective to understand the senescence response and that adds a new player whose contribution to development needs to be addressed. Identifying developmental syndromes with a root in deregulated programmed cell senescence will undoubtedly reinforce our view of senescence and could provide a new angle to confront disease. One of the structures that was initially reported to undergo cellular senescence is the mesonephros. During E12.5-E14.5, before regression, mesonephric tubules are positive for the most widely used marker of cell senescence, SAbG, and negative for proliferation marker, Ki67, in a p21Cip1-dependent manner. PKD2 is one of the genes defective in autosomal dominant polycystic kidney disease (ADPKD). Inherited mutations in this gene result in cyst formation in adults after a secondary hit. Polycystin-2 (PC2) protein, the product of PKD2 gene expression, inhibits cell cycle progression by inducing p21Cip1, whereas mutated PKD2 results in increased proliferation and defective differentiation of kidney epithelial cells. Here, we addressed the possibility of defective programmed cell senescence as a consequence of Pkd2 deletion in mice. We analyzed embryos for the expression of the senescence marker SAbG, for the proliferative status of mesonephric tubule cells, and for the expression of p21Cip1, without identifying any noticeable deregulation of cell senescence. Our results exclude defective programmed cell senescence upon Pkd2 ablation as an initial event in ADPKD.

The makings of the reproductive tract Every embryo, regardless of its sex, contains both male and female primitive reproductive tracts before sexual differentiation. To establish a sex-specific reproductive system, female embryos need to remove the components of male tracts. The general consensus contends that removal of the male tracts occurs by default, a passive outcome owing to a lack of testis-derived androgens. Working in mice, Zhao et al. discovered that this process instead was actively promoted by the transcription factor COUP-TFII (see the Perspective by Swain). Without the action of this factor, embryos retained male reproductive tracts, independently of androgen action. These findings unveil unexpected mechanisms underlying the sexually dimorphic establishment of reproductive tracts. Science , this issue p. 717 ; see also p. 648

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 Mullerian 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.

Significance When the bladder’s specialized epithelial lining is damaged by infection or injury, its own basal and intermediate cell progenitors are called upon to restore a functional barrier. Here we show that when these progenitor cells are depleted in conditional Dnmt1 mutant mice, Wolffian duct epithelial cells migrate into the bladder, acquire bladder epithelial cell characteristics, and restore expression of uroplakin, a critical component of barrier function. This is a demonstration of in vivo replacement of damaged bladder epithelium by nonbladder epithelial cells. The capacity of Wolffian duct epithelial cells to replace damaged urothelium can potentially be leveraged for bladder replacement therapies which are often necessitated in patients with carcinoma or neurogenic bladder.

Mesonephric adenocarcinoma (MA) of the vagina is an extremely rare tumour of the female genital tract. There are currently 22 reported cases in the published literature. Consequently, its pathophysiology and disease progression remain poorly understood. A 63-year-old woman presented with a history of a swelling in her vagina. Two-dimensional pelvic floor ultrasound and MRI demonstrated a multiloculated cyst with no malignant features. Initial workup provided a working diagnosis of a suburethral cyst. The diagnosis of MA was made on histology after excision of the cyst. Subsequent postoperative investigation showed no spread of the disease. The patient completed a course of prophylactic brachytherapy to prevent the possibility of any recurrence of disease. Due to its rarity, it remains difficult to diagnose MA of the vagina even on histological analysis. We would therefore recommend a low threshold to excise or perform tissue biopsy of unspecified vaginal masses.

Congenital uterine wall cysts arising from paramesonephric (Mullerian) and mesonephric (Wolffian) ducts are typically incidental findings in most species. We used immunohistochemistry (IHC) to characterize and determine the origin of uterine cysts in Sprague Dawley rats (SD) from multi-generation studies conducted by the National Toxicology Program (NTP). Subserosal uterine cysts were observed in 20 out of 2,400 SD rats evaluated in five studies, and 10 cysts were characterized for this study. Single cysts were unilocular, fluid-filled, and occurred throughout the uterus. Microscopically, all cysts had a well-developed smooth muscle wall, lined by flattened to cuboidal, sometimes ciliated, epithelium that stained intensely positive for cytokeratin 18 (CK-18) and paired box protein 8 (PAX8). Most cyst epithelia displayed weak to moderate positivity for progesterone receptor (PR) and / or estrogen receptor alpha (ER-α), as well as were negative for GATA binding protein 3 (GATA3). Cyst lumens contained basophilic flocculent material. The cysts appeared to be developmental anomalies arising from paramesonephric tissue based on positive PAX8, and ER-α and / or PR staining. Additionally, 70% of the cyts lacked GATA3 expression. Taken together, the subserosal uterine cysts observed in adult rats in these studies most likely arose from the paramesonephric duct.

Introduction: Zinner syndrome is a rare developmental anomaly of the Wolffian (mesonephric) duct which is characterized by a triad of obstruction of the ejaculatory duct, the ipsilateral seminal vesicle cyst, and the ipsilateral renal agenesis. Usually is totally asymptomatic, however it can also determine symptoms such as lower urinary tract symptoms, perineal pain, ejaculatory disorders such as painful ejaculation or hematospermia, and infertility. Case report: We present a case of a 51 years old men with a 3-year history of lower urinary tract symptoms, perineal pain, obstructed defecation, recurrent urinary tract infections and infertility. CT scan showed a voluminous cystic neoformation of the left seminal vesicle, hypoplasia of the left kidney and ipsilateral ureteronephrosis. The mass was removed using laparoscopic “en block” seminal vesiculectomy with associated ipsilateral nephroureterectomy. No post-operative complications occurred. At 2-month post-operative control the patient reported an improvement of urinary and rectal symptoms.

Summary Introduction Renal agenesis and multicystic dysplastic kidney (MCDK) are usually associated with either an absent or atretic ureter. Occasionally, these renal anomalies may be associated with a dilated tortuous ureter, ureterocele or other cystic malformation of mesonephric duct (MND) remnants. Objectives The objective of this study was to identify and classify anatomical variants of tubulocystic remnants of the MND, with a secondary focus on natural history and management outcomes. Patients and methods A retrospective cohort study of patients seen in the study institution between 2007 and 2014 with a tubulocystic abnormality of MND structures associated with either MCDK or renal agenesis was conducted. Medical imaging and progress notes were reviewed for all patients. Data collected included anatomical information, surgical intervention, histology and outcomes of both conservatively managed and surgically resected MND remnant structures. Results Nineteen patients were identified, 5 girls and 14 boys. Median age at presentation was 4.6 years. Anomalies of the MND occurred on the left in 9 patients and on the right in 10 patients. Mean follow-up was 3.4 years. Patients fell into 3 distinct anatomical groups: Type I, including orthotopic remnants corresponding to ureteric bud structures (ureter and trigone); Type II, including ectopic MND remnants of ureteric bud structures, and Type III, including complex remnants corresponding to MND structures other than those from ureteric bud (vas, epididymis and seminal vesicles). Anomalies of structures arising from urogenital sinus and paramesonephric ducts were also identified. Most patients were asymptomatic and successfully managed conservatively. Transvesical puncture of trigonal cysts provided effective decompression in 5 patients. Partial or complete MCDK regression was seen in 7 patients, whereas MND cystic anomalies did not regress spontaneously. Discussion When MND tubulocystic structures persist along with renal agenesis or MCDK, most arise from ureteric bud structures in an orthotopic position as a ureterocele with or without a blind-ending ureter-like structure. Less commonly, ureteric bud structures insert ectopically into the urogenital tract, or tubulocystic structures arising from the remainder of the MND occur. Embryogenesis of other urogenital structures may also be abnormal, and conditions such as Zinner syndrome and obstructed hemivagina and ipsilateral renal agenesis syndrome should be considered. Conclusions Complications are uncommon, and surgical intervention should be limited to symptomatic patients. Remnants of metanephric blastema may involute, but MND remnants persist.

GATA3 is a transcription factor critical for embryogenesis, development, and cell differentiation. Recent studies have suggested that GATA3 is a sensitive and relatively specific biomarker for urothelial and breast carcinomas, with most Müllerian carcinomas being negative. We investigated GATA3 expression in mesonephric/Wolffian remnants and tumors in the female genital tract. A western blot was performed to assess specificity for the GATA3 antibody. GATA3 immunohistochemistry was performed on 59 formalin-fixed paraffin-embedded mesonephric samples, including 17 mesonephric remnants (MR; 11 cervical and 6 fallopian tube), 15 mesonephric hyperplasias, 21 mesonephric carcinomas, and 6 female adnexal tumors of probable Wolffian origin. Thirty conventional endocervical adenocarcinomas (ENDO-CA), 9 gastric-type cervical adenocarcinomas, and 165 endometrial adenocarcinomas (EM-CA) were also evaluated. GATA3 nuclear intensity and extent of staining was evaluated. The western blot revealed GATA3 expression in seminal vesicle and cell lines derived from breast and urothelial carcinomas, but not in other cell lines including ovarian, cervical, and endometrial cancers. All cervical MRs and mesonephric hyperplasias, 5/6 (83%) fallopian tube MRs, and 20/21 (95%) mesonephric carcinomas were GATA3 positive, although with great variability in both intensity (weak to strong) and extent (1+ to 3+) of staining. Only 1/6 (17%) female adnexal tumors of probable Wolffian origin showed weak multifocal staining. One of 30 (3%) usual-type ENDO-CAs and 3/165 EM-CAs exhibited weak-moderate GATA3 immunoreactivity; all gastric-type cervical adenocarcinomas were negative. GATA3 is a highly sensitive and specific marker for mesonephric lesions in the lower genital tract; however, its utility in the upper genital tract may be more limited. In addition, GATA3 can aid in distinguishing lower genital mesonephric lesions from usual-type and gastric-type ENDO-CAs and uterine EM-CAs.

A variety of mass lesions may affect the vulva. These may be non-neoplastic, or represent benign or malignant neoplasms. A review of benign mass lesions and neoplasms of the vulva is presented.

The mesonephric (Wolffian) duct regresses in females during embryological development. Remnants of this duct may persist typically along the lateral walls of the cervix, vagina, adnexa, and uterine corpus. These mesonephric epithelia may expand into hyperplastic proliferations and rarely form neoplasms. The spectrum of morphology, immunophenotype, clinical presentation, and molecular characteristics of mesonephric lesions is reviewed, with attention to distinction from entities in the differential diagnosis.

Tubal morphogenesis is a fundamental requirement for the development of most mammalian organs, including the male reproductive system. The epididymis, an integral part of the male reproductive tract, is responsible for sperm storage, maturation, and transport. The adult epididymis is a highly coiled tube that develops from a simple and straight embryonic precursor known as Wolffian duct (WD). Proper coiling of the epididymis is essential for male fertility, as sperm in the testis are unable to fertilize an oocyte. However, the mechanism responsible for epididymal development and coiling remains unclear, partially due to the lack of whole organ culture and imaging methods. In this study, we describe an in vitro culture system and whole mount immunofluorescence protocol to better visualize the process of WD coiling and development, which may also be applied to study other tubular organs.

We investigate a patient with right kidney agenesis. Imaging showed the presence of a cystic mass dislocating the bladder. The specimen showed three formations: a kidney remnant, a ureter with blind-ending branch, and a cyst, from which departed another tubular structure, considered the deferential duct. The specimen was sampled. The supposed kidney was formed by cystic structures. Examination of the tubular structures disclosed smooth muscle fibers with no lumen, whereas the cyst was surrounded by fibrous and hemorrhagic walls. Collaboration among specialists allowed the diagnosis of Zinner syndrome, a congenital malformation due to an abnormal development of the Wolffian duct.

Background: Cervical polyps (CP) are quite common in adults, they are extremely rare in children and adolescents. CP containing mesonephric duct remnants (MDR) are few millimeters in size and seldom grossly visible. Case: A 14-year-old female admitted with massive vaginal bleeding with an intact wide hymeneal opening. Pelvic MRI revealed 47 mm × 25 mm × 35 mm polypoid mass originating from the endometrial cavity. During vaginoscopy, a polypoid mass was detected at 9 o'clock position of right lip of ectocervix and was totally excised. Light microscopy showed CP including small round or branched glands containing inspissated eosinophilic secretions and patchy chronic inflammatory infiltrate. The patient was diagnosed as gaint CP containing MDR. Conclusion: Giant CP is an uncommon variant of classical polyps and exhibit distinct clinical and pathologic features. However, MDR are benign lesions of cervix, detailed histopathological evaluation should be performed to all CP to differentiate malignant lesions.

The Wolffian duct (WD) undergoes morphological changes induced by androgens to form the epididymis, which is an organ essential for sperm maturation. Androgen action in WD epithelium involves paracrine factors of mesenchymal origin that function by still poorly understood mechanisms. Here we studied the antimicrobial β-defensin SPAG11C as a new player in duct morphogenesis, localized prenatally in the WD mesenchyme. Organotypic culture of rat WDs and tissues from Androgen Receptor (AR) knockout mice (ARKO) were used. Our results show that androgen/AR signaling differentially regulated SPAG11C expression at mRNA and protein levels in the developing WD. WDs incubated with recombinant human SPAG11C were shorter and less coiled as a result of reduced epithelial cell proliferation, but not increased apoptosis. Our results suggested β-defensin SPAG11C as an androgen-target required for WD morphogenesis. This highlights the multifunctional repertoire of the β-defensin protein family and their potential contribution to the in utero environment that determines male reproductive success.

Reproductive tract abnormalities and male infertility have higher incidence in autosomal dominant polycystic kidney disease (ADPKD) patients than in general population. In this work, we revealed that Pkd1, whose mutations account for 85% of ADPKD cases, is essential for male reproductive tract development. Disruption of Pkd1 caused a spectrum of defects in the murine male reproductive tract. The earliest visible defect in Pkd1-/- reproductive tract was cystic dilation of the efferent ducts, which are derivatives of the mesonephric tubules. Epididymis development was delayed or arrested in the Pkd1-/- mice. No sign of epididymal coiling was seen in the Pkd1 null mice. Disruption of Pkd1 in epithelia alone using the Pax2-cre mice was sufficient to cause efferent duct dilation and coiling defect in the epididymis, suggesting that Pkd1 is critical for epithelial development and maintenance in male reproductive tract. In-depth analysis showed that Pkd1 is required to maintain tubulin cytoskeleton and important for Tgf-β/Bmp signal transduction in the epithelia of male reproductive tract. Altogether, our results provide the first direct evidence for developmental roles of Pkd1 in male reproductive tract and provide new insights in reproductive tract abnormalities and infertility in ADPKD patients.

We report the presence of epididymis-like tubules in unilateral renal hypodysplasia in 3 adult men. Microscopy showed dilated tubules lined by ciliated columnar epithelium and smaller basal cells, morphologically resembling epididymal tubules. Small tubules lined by cuboidal epithelium were also present in all cases, with glomeruli in 2 cases. The epididymis-like tubules expressed CD10, CK7, PAX8, and AR in the luminal epithelium, while the basal cells were positive for p63, CK7, and focally for CD10. The smooth muscle bundles around the epididymis-like tubules were focally AR and WT1 (cytoplasmic) positive. The epididymis-like tubules were negative for ER, PR, and WT1. CK7 and PAX8 stained all the collecting ducts, with AR staining some. Bowman's capsule, parietal and visceral epithelial cells expressed CD10; WT1 stained the visceral and parietal epithelial cells. Glomerular parietal cells expressed PAX8 and focally, CK7. Proximal tubules were positive for CD10 (luminal membranous and weak cytoplasmic). Distal tubules expressed CK7, PAX8 and AR. An occasional small tubule was ER positive. Scattered stromal cells expressed ER, PR, and AR. The urothelium of the renal pelvis/upper ureter expressed CK7 in all layers, CD10 in the superficial layers, PAX8 in the basal layers and p63 in all layers except the umbrella layer. The epididymis-like tubules replicate the pattern of the mesonephros-derived normal epididymis in expressing CK7, PAX8, CD10, and AR. This supports a mesonephric rather than metanephric origin for these tubules. The aberrant expression of some markers may be a manifestation of the dysplastic nature of the kidneys.

Zebrafish provide an excellent model in which to assess the role of the renin-angiotensin system in renal development, injury, and repair. In contrast to mammals, zebrafish kidney organogenesis terminates with the mesonephros. Despite this, the basic functional structure of the nephron is conserved across vertebrates. The relevance of teleosts for studies relating to the regulation of the renin-angiotensin system was established by assessing the phenotype and functional regulation of renin-expressing cells in zebrafish. Transgenic fluorescent reporters for renin ( ren), smooth muscle actin ( acta2), and platelet-derived growth factor receptor-beta ( pdgfrb) were studied to determine the phenotype and secretory ultrastructure of perivascular renin-expressing cells. Whole kidney ren transcription responded to altered salinity, pharmacological renin-angiotensin system inhibition, and renal injury. Mesonephric ren-expressing cells occupied niches at the preglomerular arteries and afferent arterioles, forming intermittent epithelioid-like multicellular clusters exhibiting a granular secretory ultrastructure. In contrast, renin cells of the efferent arterioles were thin bodied and lacked secretory granules. Renin cells expressed the perivascular cell markers acta2 and pdgfrb. Transcriptional responses of ren to physiological challenge support the presence of a functional renin-angiotensin system and are consistent with the production of active renin. The reparative capability of the zebrafish kidney was harnessed to demonstrate that ren transcription is a marker for renal injury and repair. Our studies demonstrate substantive conservation of renin regulation across vertebrates, and ultrastructural studies of renin cells reveal at least two distinct morphologies of mesonephric perivascular ren-expressing cells.

In sturgeon, the acquisition of the potential for motility activation called spermatozoon maturation takes place outside testes. This process can be accomplished in vitro by pre-incubation of immature testicular spermatozoa in seminal fluid collected from fully mature Wolffian duct sperm. Addition of trypsin inhibitor to the pre-incubation medium disrupts spermatozoon maturation. There are no available data for the role of proteolysis regulators in fish spermatozoon maturation, while their role is recognized in mammalian sperm maturation. The present study evaluated the involvement of seminal fluid proteases and anti-proteolytic activity in the sterlet spermatozoon maturation process. Casein and gelatin zymography and quantification of amidase and anti-proteolytic activity were conducted in sturgeon seminal fluid from Wolffian duct sperm and seminal fluid from testicular sperm, along with spermatozoon extracts from Wolffian duct spermatozoa, testicular spermatozoa, and testicular spermatozoa after in vitro maturation. We did not find significant differences in proteolytic profiles of seminal fluids from Wolffian duct sperm and ones from testicular sperm. Zymography revealed differences in spermatozoon extracts: Wolffian duct spermatozoon extracts were characterized by the presence of a broad proteolytic band ranging from 48 to 41 kDa, while testicular spermatozoon extracts did not show such activity until after in vitro maturation. The differences in amidase activity coincided with these results. It may not be the levels of proteolytic and anti-proteolytic activity per se, but the alterations in their interactions triggering a cascade of signaling events, that is crucial to the maturation process.

The Müllerian duct (MD) and Wolffian duct (WD) are embryonic tubular tissues giving rise to female- and male reproductive tracts, respectively. In amniote embryos, both MD and WD emerge bisexually, but subsequently degenerate in the males and females, respectively. Here, by using MD-specific gene manipulations in chicken embryos, we identify the molecular and cellular mechanisms that link the early MD specification to tubular invagination. Early (pre-) specification of MD precursors in the coelomic epithelium requires BMP signaling and its downstream target Pax2 in a WD-independent process. Subsequently, the BMP/Pax2 axis induces Lim1 expression, a hallmark of MD specification, for which FGF/ERK- and WD-derived signals are also required. Finally, the sequential actions of the BMP/Pax2- and FGF/Lim1 axes culminate in the epithelial invagination to form a tubular structure driven by an apical constriction, where apical accumulation of phospho-myosin light chain is positively regulated by FGF/ERK signaling. Our study delineates mechanisms governing the early formation of MD, and also serves as a paradiagmatic example of how an epithelial cell sheet is transformed to a tubular structure, a process seen in a variety of developmental contexts.

Summary Background The classical theory of Müllerian origin of upper vagina fails to explain complex urogenital malformations like OHVIRA syndrome; the Acien’s hypothesis, however, unravels the hidden embryopathogenesis. As per Acien, Wolffian (mesonephric) ducts instead of Müllerian ducts and sinovaginal bulbs, give rise to the vagina. The new hypothesis, however, retains the concept of origin of the ureters (with ureters inducing renal development) by the former and the uterus by Müllerian ducts. Thus, a failure of development of mesonephros/mesonephric duct gives rise to absent ureters and hence absent homolateral kidney; blind ending (obstructed) ipsilateral hemivagina and cessation of support to paramesonephric ducts which leads to unfused uterus (uterus didelphys). Hence, the new hypothesis explains all components of OHVIRA syndrome. On a parallel track, unilateral anomalous development of the mesonephros in males causes atresia of the homolateral ejaculatory duct that results in obstruction of the proximally placed seminal vesicle. Besides, there is absence of the ipsilateral kidney (Zinner syndrome). Case Report In this manuscript, we describe four cases of OHVIRA syndrome. Case 1 was a 34-year-old nulligravida, married since fourteen years, who presented with a 5-month history of pelvic inflammatory disease and dyspareunia. Regular menses in the patient and azoospermia in her husband delayed the diagnosis. Case 2 was a 14-year-old girl who presented with dysmenorrhea and lower abdominal pain since a few months. Case 3 was a 27-year-old female who presented with infertility and dysmenorrhea. Case 4 was a 15-year-old female who presented with a one-year history of dysmenorrhea and cyclic pelvic pain. In all cases, one of the uterine horns revealed collection due to a hemivaginal septum and an absent ipsilateral kidney; thus, establishing the diagnosis of OHVIRA syndrome. The case 4 additionally revealed homolateral vaginal agenesis. Conclusions On the basis of our 4 cases, we support the Acien’s hypothesis of Wolffian origin of vagina which explains the development of OHVIRA syndrome. Besides, we emphasize the need to suspect this syndrome in a female with a pelvic mass and absence of homolateral kidney. Finally, we believe that OHVIRA due to its Wolffian origin is a female equivalent of Zinner syndrome in males. Therefore, we propose OSVIRA (Obstructed Seminal Vesicle and Ipsilateral Renal Agenesis) as an acronym for Zinner syndrome analogous to OHVIRA.

The ducts associated with sperm transport from the testicular lobules to the Wolffian ducts in Ambystoma maculatum were examined with transmis- sion electron microscopy. Based on the ultrastructure and historical precedence, new terminology for this net- work of ducts is proposed that better represents primary hypotheses of homology. Furthermore, the terminology proposed better characterizes the distinct regions of the sperm transport ducts in salamanders based on anatomy and should, therefore, lead to more accurate comparisons in the future. While developing the above ontology, we also tested the hypothesis that nephrons from the genital kidney are modified from those of the pelvic kidney due to the fact that the former nephrons function in sperm trans- port. Our ultrastructural analysis of the genital kidney supports this hypothesis, as the basal plasma membrane of distinct functional regions of the nephron (proximal convoluted tubule, distal convoluted tubule, and collecting tubule) appear less folded (indicating decreased surface area and reduced reabsorption efficiency) and the proxi- mal convoluted tubule possesses ciliated epithelial cells along its entire length. Furthermore, visible luminal fil- trate is absent from the nephrons of the genital kidney throughout their entire length. Thus, it appears that the nephrons of the genital kidney have reduced reabsorptive capacity and ciliated cells of the proximal convoluted tubule may increase the movement of immature sperm through the sperm transport ducts or aid in the mixing of seminal fluids within the ducts. J. Morphol. 274:344-360

Background In women, during embryologic development, the paired Müllerian (paramesonephric) ducts fuse distally and develop into the uterus, cervix, and upper vagina. If the Wolffian ducts persist in vestigial form, they can lead to Gartner’s cysts, mainly located in the right wall of the vagina. This is one of the few studies of Gartner’s cysts with a series of consecutive cases over a long period of time who were exclusively subject to clinical observation. Although Gartner’s cysts are found in approximately 0.1 to 0.2 % of women, controversy exists regarding the course of action to be taken. Case presentation We describe the cases of four women who were 38-years old, 53-years old, 37-years old, and 49-years old at their first appointment and who were of mixed ethnicity, mixed ethnicity, black, and mixed ethnicity respectively. The follow-up of these patients ranged from 2 to 17 years. In these four cases the location of the cysts was the right wall of the vagina. Transvaginal ultrasound was the test of choice for diagnostic confirmation. In the cases presented in this study, the women were asymptomatic and chose to be observed clinically. Conclusions This is the first study reporting long-term clinical observation of these lesions. This study shows that conservative treatment can be a safe option for asymptomatic patients with vaginal Gartner’s duct cysts.

Epididymo-orchitis is a devastating complication of imperforate anus. Without proper treatment the condition may result in infertility. Nevertheless, the exact etiology and optimal management of epididymo-orchitis in anorectal malformation are unknown.Retrospective review of our hospital records between 1997 and 2010 identified 6 cases of epididymo-orchitis in 82 boys with anorectal malformation. Extensive search of the literature revealed 35 additional cases. Clinical details of these 41 patients were analyzed using chi-square testing.Epididymo-orchitis occurred predominantly (86%) in high or intermediate anorectal malformation with rectourinary fistula. Median age at onset of epididymo-orchitis was 6 months and there was no side predilection. Urinary tract infection was noted in 54% of patients. Persistent mesonephric duct syndrome (27%), urethroejaculatory duct reflux (22%), vasovesical ectopia (10%), neurovesical dysfunction (34%) and urethral stricture/stenosis (17%) were frequently associated risk factors for epididymo-orchitis. In 73% of patients epididymo-orchitis recurred with exclusive antibiotic treatment. Diverting colostomy was ineffective in preventing epididymo-orchitis. Division of rectourinary fistula was curative in 36% of patients, while in 34% epididymo-orchitis recurred even after division of rectourinary fistula. Division of rectourinary fistula is likely to resolve epididymo-orchitis in the absence of additional risk factors. Vasectomy was required in 22% of patients to prevent recurrence.In addition to rectourinary fistula, urinary reflux into the vas deferens and neurovesical dysfunction are major risk factors for epididymo-orchitis in anorectal malformation. Division of rectourinary fistula is curative in only a third of cases. In the remaining cases some form of surgical disruption of the vas deferens is needed to resolve recurrent epididymo-orchitis.

Embryonic kidney development begins with the outgrowth of the ureteric bud (UB) from the Wolffian duct (WD) into the adjacent metanephric mesenchyme (MM). Both a GDNF-dependent and GDNF-independent (Maeshima et al., 2007) pathway have been identified. In vivo and in vitro, the GDNF-dependent pathway is inhibited by BMPs, one of the factors invoked to explain the limitation of UB formation in the unbudded regions of the WD surrounding the UB. However, the exact mechanism remains unknown. Here a previously described in vitro system that models UB budding from the WD was utilized to study this process. Because Protein kinase A (PKA) activation has been shown to prevent migration, morphogenesis and tubulogenesis of epithelial cells (Santos et al., 1993), its activity in budded and non-budded portions of the GDNF-induced WD was analyzed. The level of PKA activity was 15-fold higher in the unbudded portions of the WD compared to budded portions, suggesting that PKA activity plays a key role in controlling the site of UB emergence. Using well-characterized PKA agonists and antagonists, we demonstrated that at various levels of the PKA-signaling hierarchy, PKA regulates UB outgrowth from the WD by suppressing budding events. This process appeared to be PKA-2 isoform specific, and mediated by changes in the duct rather than the surrounding mesenchyme. In addition, it was not due to changes in either the sorting of junctional proteins, cell death, or cell proliferation. Furthermore, the suppressive effect of cAMP on budding did not appear to be mediated by spread to adjacent cells via gap junctions. Conversely, antagonism of PKA activity stimulated UB outgrowth from the WD and resulted in both an increase in the number of buds per unit length of WD as well as a larger surface area per bud. Using microarrays, analysis of gene expression in GDNF-treated WDs in which the PKA pathway had been activated revealed a nearly 14-fold decrease in Ret, a receptor for GDNF. A smaller decrease in GFRα1. a co-receptor for GDNF, was also observed. Using Ret-null WDs, we were able to demonstrate that PKA regulated GDNF-dependent budding but not GDNF-independent pathway for WD budding. We also found that BMP2 was higher in unbudded regions of the GDNF-stimulated WD. Treatment of isolated WDs with BMP2 suppressed budding and resulted in a 3-fold increase in PKA activity. The data suggests that the suppression of budding by BMPs and possibly other factors in non-budded zones of the WD may be regulated in part by increased PKA activity, probably partially through downregulation of Ret/GFRα1 coreceptor expression.

The male to female (M/F) fetal death ratio in Japan from the mid 1970s to 2005s has consistently increased while total fetal deaths have declined. Public health records and other evidence were reviewed to assess the recent trends in infant renal failure, the congenital anomalies of the kidney and urinary tract (CAKUT), and the sex ratio of these disorders. The M/F infant death ratio caused by renal failure has increased from 0.75 to 3.0 over the past 3 decades. There has been an increase in CAKUT as a cause for fetal and infant deaths, and renal hypoplasia and dysplasia were male predominant. The increase in the M/F deaths ratio caused by infant renal failure, as well as increased male predominant CAKUT suggests that the Wolffian duct regression might have affected the initial development of the kidney and male genital tract thus contributing to male fetal deaths.

p53 is best known as a tumor suppressor that regulates cell-cycle, differentiation, and apoptosis pathways, but its potential role in embryonic development and organogenesis remains controversial. Here, p53(-/-) embryos bred on C57Bl6 background exhibited a spectrum of congenital abnormalities of the kidney and urinary tract, including ureteric bud (UB) ectopia, double ureters/collecting systems, delayed primary branching of the UB, and hypoplastic metanephroi. We observed ectopic UB outgrowth from the Wolffian duct (WD) in one third of p53(-/-) embryos. The prevalence of duplex was higher in embryos than in neonates, and ex vivo organ culture suggested that ectopic ureters can regress over time, leaving behind a dysplastic pole ("segmental dysgenesis"). Transgenic expression of dominant negative p53 or conditional inactivation of p53 in the UB but not in the metanephric mesenchyme lineage recapitulated the duplex phenotype. Mechanistically, p53 inactivation in the WD associated with enhanced sensitivity to glial cell line-derived neurotrophic factor (GDNF)-induced ectopic budding and potentiated phosphatidylinositol-3 kinase activation by GDNF in UB cells. Unlike several other models of UB ectopia, hypersensitivity of p53(-/-) WD to GDNF is not accompanied by reduced Sprouty-1 or anterior expansion of the GDNF domain. In summary, our data lend support for a restrictive role for p53 activity in UB outgrowth from the WD.

We report a rare case of a left ejaculatory duct that allotropically protrudes towards or invades the left vesicle triangular area with its dead end. The patient simultaneously exhibited multiple congenital malformations of the homolateral urogenital system, such as absence of the left kidney, dysplasia and allotopia of the left seminal vesicle, absence of the left ureterostoma, separation between the left testis and the epididymis tail, and maldevelopment of the left testis. According to all clinical and laboratory evidence, the case represented a new syndrome, which we named Wuyang's syndrome. It involved a rare phenomenon in embryonic development; the dysplastic proximal vas precursor, having intruded into a common mesonephric duct and accidentally encroaching on the ureteric bud position, resulted in the absence or dysplasia of the homolateral urinary tract and ectopic invasion of the bladder by the homolateral seminal tract.

The kidney collecting duct system and the ureter derive from the ureteric bud, an outgrowth of the Wolffian duct. It is generally believed that glial cell–derived neurotrophic factor (GDNF) plays a critical role in this earliest stage of kidney development, but 30 to 50% of knockout mice that lack

In this study the development of the bovine Fallopian tube was investigated using light microscopic methods. Formation and differentiation of the Müllerian duct were studied in mesonephroi of 16 embryos and fetuses with a crown-rump lengths (CRL) of 0.9-8.4 cm. The funnel field, the rostral beginning of the Müllerian duct was first observed at a CRL of 0.9 cm. It appears as a thickening of the mesothelium on the craniolateral side of the mesonephros. During later development the Müllerian duct emerges by caudal outgrowth from the funnel field. Formation of a common basal lamina surrounding the caudal tips of Müllerian and Wolffian ducts could be observed at all stages up to CRL of 2.7 cm. The mesothelium and the epithelium of the Wolffian duct adjacent to the Müllerian duct showed a modification of epithelium height in all examined stages. Probably the Wolffian duct influences the growth of Müllerian duct by epithelio-mesenchymal interactions. Fetuses from a CRL of 12.0 to 94.0 cm were used for investigation of the prenatal differentiation of the oviductal mucosa. Folding of the oviductal mucosa started at a CRL of 29.0 cm and continued until birth. Individual primary, secondary and tertiary folds are formed in special proliferation zones and epithelium-folding buds. The cellular differentiation of the oviductal epithelium involves the formation of ciliated and secretory cells during different times of prenatal development. Ciliogenesis was first detected at a CRL of 33.0 cm. Active secretory cells could be observed in the oviductal epithelium from a CRL of 64.0 cm onwards.

Androgens are thought to separately regulate stabilization and differentiation of the Wolffian duct (WD), but the time windows for these effects are unclear. To address this, fetal rats were exposed to flutamide within either an early window (EW) [embryonic day 15.5 (E15.5) to E17.5], when the WD degenerates in the female, or a later window (LW) (E19.5–E21.5), when the WD morphologically differentiates in the male, or during the full window of WD development (FW) (E15.5–21.5). WDs were examined for abnormalities during fetal (E21.5) or postnatal life, and anogenital distance and prostate presence/absence were recorded. Exposure to FW- or EW-flutamide, but not to LW-flutamide, induced comparable abnormalities in the fetal WD at E21.5, namely reduced WD coiling, reduced cell proliferation, reduced epithelial cell height, altered epithelial vimentin expression, and reduced expression of smooth muscle actin in the WD inner stroma. Exposure to EW- or FW-flutamide, but not to LW-flutamide, resulted in incomplete/absent WDs in more than 50% of males by adulthood, although such abnormalities were infrequent in fetal life. These findings suggest that androgen action during the EW is sufficient to promote WD morphological differentiation several days later. Because the androgen receptor is expressed in the WD stroma but not in the epithelium during this EW, WD differentiation is likely to be dependent on androgen-mediated signaling from the stroma to the epithelium. In conclusion, the critical window for androgen action in regulating WD development in the rat is between E15.5 and E17.5. This window is also important for prostate formation and anogenital distance masculinization.

Mesonephric adenocarcinoma is a rare tumor type that is usually found in areas where the Wolffian duct was present during the fetal period. We report a case of mesonephric adenocarcinoma of the uterine corpus in a 66-year-old woman who presented with vaginal bleeding. Pelvic magnetic resonance imaging revealed a 2.7-cm-sized irregular thickening and enhancement of the uterine body. The diagnosis following endometrial curettage biopsy was endometrioid adenocarcinoma, and the patient underwent a total hysterectomy with bilateral salpingo-oophorectomy. The tumor was composed of small tubular and ductal components, and a retiform appearance was also observed in the deeper areas. The tumor cells were immunopositive for cytokeratin, vimentin, CD10 with a luminal staining pattern, PAX2, and PAX8, and immunonegative for estrogen receptor and progesterone receptor, which was consistent with tumor of mesonephric origin. Mesonephric neoplasms reveal relatively low-grade nuclear feature, characteristic immunoprofiles (immunonegative for ER and PR, and immunopositive for CD10, PAX2, PAX8, and GATA3), and unique tumor location (myometrium), whereas Müllerian neoplasms such as endometrial adenocarcinoma show various morphology, immunopositivity for ER and PR, and primarily endometrial location. As described above, an integration of the clinical features, morphologic characteristics, and immunohistochemical profiles is needed to make a diagnosis.

Organ shape and size are important determinants of their physiological functions. Epithelial tubes are anlagen of many complex organs. How these tubes acquire their complex shape and size is a fundamental question in biology. In male mice, the Wolffian duct (WD; postnatally known as epididymis) undergoes an astonishing transformation, where a straight tube only a few millimetres long elongates to over 1000 times its original length and fits into a very small space, due to extensive coiling of epithelium, to perform the highly specialized function of sperm maturation. Defective coiling disrupts sperm maturation and leads to male infertility. Recent work has shown that epithelial cell proliferation is a major driver of WD coiling. Still, very little is known about the molecular signals involved in this process. Testicular androgens are known regulators of WD development. However, epithelial androgen receptor signalling is dispensable for WD coiling. In this study, we have shown that Wnt signalling is highly active in the entire WD epithelium during its coiling, and is limited to only a few segments of the epididymis in later life. Pharmacological and genetic suppression of Wnt signalling inhibited WD coiling by decreasing cell proliferation and promoting apoptosis. Comparative gene expression analysis identified Fibroblast growth factor 7 (Fgf7) as a prime Wnt target gene involved in WD coiling and in vitro treatment with Fgf7 protein increased coiling of WDs. In summary, our work has established that epithelial canonical Wnt signalling is a critical regulator of WD coiling and its precise regulation is essential for WD/epididymal differentiation.