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Nature Jul 2022Gonadal development is a complex process that involves sex determination followed by divergent maturation into either testes or ovaries. Historically, limited tissue...
Gonadal development is a complex process that involves sex determination followed by divergent maturation into either testes or ovaries. Historically, limited tissue accessibility, a lack of reliable in vitro models and critical differences between humans and mice have hampered our knowledge of human gonadogenesis, despite its importance in gonadal conditions and infertility. Here, we generated a comprehensive map of first- and second-trimester human gonads using a combination of single-cell and spatial transcriptomics, chromatin accessibility assays and fluorescent microscopy. We extracted human-specific regulatory programmes that control the development of germline and somatic cell lineages by profiling equivalent developmental stages in mice. In both species, we define the somatic cell states present at the time of sex specification, including the bipotent early supporting population that, in males, upregulates the testis-determining factor SRY and sPAX8s, a gonadal lineage located at the gonadal-mesonephric interface. In females, we resolve the cellular and molecular events that give rise to the first and second waves of granulosa cells that compartmentalize the developing ovary to modulate germ cell differentiation. In males, we identify human SIGLEC15 and TREM2 fetal testicular macrophages, which signal to somatic cells outside and inside the developing testis cords, respectively. This study provides a comprehensive spatiotemporal map of human and mouse gonadal differentiation, which can guide in vitro gonadogenesis.
Topics: Animals; Cell Lineage; Chromatin; Female; Germ Cells; Granulosa Cells; Humans; Immunoglobulins; Macrophages; Male; Membrane Glycoproteins; Membrane Proteins; Mice; Microscopy, Fluorescence; Ovary; PAX8 Transcription Factor; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Receptors, Immunologic; Sex Differentiation; Single-Cell Analysis; Testis; Transcriptome
PubMed: 35794482
DOI: 10.1038/s41586-022-04918-4 -
Virchows Archiv : An International... Nov 2019Endocervical adenocarcinomas (ECAs) are currently classified according to the 2014 World Health Organization (WHO) system, which is predominantly based on descriptive... (Review)
Review
Endocervical adenocarcinomas (ECAs) are currently classified according to the 2014 World Health Organization (WHO) system, which is predominantly based on descriptive morphologic characteristics, considers factors bearing minimal etiological, clinical, or therapeutic relevance, and lacks sufficient reproducibility. The 2017 International Endocervical Adenocarcinoma Criteria and Classification (IECC) system was developed by a group of international collaborators to address these limitations. The IECC system separates ECAs into two major groups-those that are human papillomavirus-associated (HPVA) and those that are non-HPV-associated (NHPVA)-based on morphology (linked to etiology) alone, precluding the need for an expensive panel of immunohistochemical markers for most cases. The major types of HPVA ECA include the usual (with villoglandular and micropapillary architectural variants) and mucinous types (not otherwise specified [NOS], intestinal, signet-ring, and invasive stratified mucin-producing carcinoma). Invasive adenocarcinoma NOS is morphologically uninformative, yet considered part of this group when HPV positive. NHPVA ECAs include gastric, clear cell, endometrioid, and mesonephric types. The IECC system is supported by demographic and clinical features (HPVA ECAs develop in younger patients, are smaller, and are diagnosed at an earlier stage), p16/HPV status (almost all HPVA ECAs are p16 and/or HPV positive), prognostic parameters (NHPVA ECAs more often have lymphovascular invasion, lymph node metastases, and are Silva pattern C), and survival data (NHPVA ECAs are associated with worse survival). A move from the morphology-based WHO system to the IECC system will likely provide clinicians with an improved means to diagnose and classify ECAs, and ultimately, to better personalize treatment for these patients.
Topics: Adenocarcinoma; Cervix Uteri; Female; Humans; Lymphatic Metastasis; Papillomaviridae; Papillomavirus Infections; Prognosis; Reproducibility of Results; Uterine Cervical Neoplasms
PubMed: 31209635
DOI: 10.1007/s00428-019-02601-0 -
The American Journal of Surgical... Apr 2021Mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA) are uncommon neoplasms of the gynecologic tract that have until recently been poorly...
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.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Databases, Factual; Endometrial Neoplasms; Female; Humans; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; North America; Northern Ireland; Ovarian Neoplasms; Progression-Free Survival; Registries; Time Factors; Uterine Cervical Neoplasms; Wolffian Ducts
PubMed: 33165093
DOI: 10.1097/PAS.0000000000001612 -
Journal of Clinical Medicine Feb 2021Mesonephric-like adenocarcinoma is a recently described rare neoplasm occurring in the uterine corpus and ovary. This under-recognized subtype of carcinoma can be very... (Review)
Review
Mesonephric-like adenocarcinoma is a recently described rare neoplasm occurring in the uterine corpus and ovary. This under-recognized subtype of carcinoma can be very challenging to diagnose. In mesonephric adenocarcinoma a variety of growth patterns can be present within the same tumor, as a result of which they can be misinterpreted and diagnosed as low-grade endometrioid adenocarcinoma, clear cell carcinoma, or even serous carcinoma and carcinosarcoma. We report a case of mesonephric-like adenocarcinoma misdiagnosed as a low-grade endometrioid endometrial adenocarcinoma that had an early local recurrence and metastasized to the liver and the lungs. Histopathological, immunohistochemical and molecular analysis were performed and compared to published literature, providing a comprehensive overview of the current knowledge. Databases (Pubmed, Web of Science, Google Scholar) were searched with a combination of the following search terms: mesonephric-like, mesonephric, adenocarcinoma, carcinoma, uterine body, uterine corpus, endometrium. Mesonephric-like adenocarcinoma is a difficult-to-diagnose entity. Advanced diagnostics, including improved morphologic, immunohistochemical and molecular knowledge can help develop new therapeutic strategies against this specific subtype of endometrial cancer with an aggressive clinical behavior.
PubMed: 33670088
DOI: 10.3390/jcm10040698 -
European Journal of Case Reports in... 2021Zinner syndrome is a developmental anomaly of the urogenital tract. This condition is defined by the triad of unilateral renal agenesis, ipsilateral seminal vesicle cyst...
UNLABELLED
Zinner syndrome is a developmental anomaly of the urogenital tract. This condition is defined by the triad of unilateral renal agenesis, ipsilateral seminal vesicle cyst and ipsilateral ejaculatory duct obstruction. The syndrome is due to malformation of the mesonephric duct during embryogenesis. The condition used to be rare but is now frequently encountered due to the advent of MRI and CT. MRI confirms the diagnosis by revealing the seminal vesicle cyst and its contents, and the ejaculatory duct obstruction, while CT confirms renal agenesis. We report the case of a young patient with Zinner syndrome.
LEARNING POINTS
Zinner syndrome consists of the triad of renal agenesis, seminal vesicle cyst and ejaculatory duct obstruction.Any insult during embryogenesis of the mesonephric duct in men can result in Zinner syndrome.Pelvic MRI is the gold standard to confirm the diagnosis of Zinner syndrome.
PubMed: 34268266
DOI: 10.12890/2021_002628 -
Modern Pathology : An Official Journal... Apr 2023Endometrial carcinoma (EC) can be divided into 4 prognostic molecular subtypes, and no specific molecular profile (NSMP) type is the most commonly occurring type...
Endometrial carcinoma (EC) can be divided into 4 prognostic molecular subtypes, and no specific molecular profile (NSMP) type is the most commonly occurring type (∼50%). Although described as having an intermediate to favorable prognosis, this subtype encompasses pathologically and molecularly diverse tumors. We aimed to identify factors associated with outcomes within the NSMP ECs that might be used to stratify prognosis and direct treatment. Clinicopathologic, immunohistochemical, and genetic features of a large series of NSMP EC were used to identify parameters that could identify the subset associated with a very favorable outcome (disease-specific death rate <5% at 5 years, termed low-risk NSMP). A total of 1110 NSMP ECs were profiled. In a univariate analysis, stage, grade, lymphovascular invasion, estrogen receptor (ER) and progesterone receptor (PR) expression, L1CAM overexpression, and mutations in PIK3CA were associated with disease-specific survival. Two critical features, grade and ER expression, identified a low-risk NSMP subset (grade 1-2, ER-positive [>1%], 84% of cases), which showed a 5-year disease-specific death rate of 1.6% across all stages and 1.4% within stage I. The remaining cases (high-risk NSMPs, grade 3, and/or ER-negative status) were responsible for most of the disease-specific deaths (disease-specific death rate at 5 years, 22.9%; hazard ratio compared with that of low-risk NSMPs: 16.3; 95% CI, 8.4-31.7). Within NSMP EC, the low-risk and high-risk categories were of prognostic significance independent of the stage on a multivariate analysis. Low-grade and ER-positive NSMP ECs are a homogeneous low-risk group associated with an exceptionally favorable prognosis in which de-escalation and/or endocrine therapy strategies can be applied. Grade 3 and/or ER-negative status identifies a high-risk NSMP subset, including rare high-grade histotypes (eg, clear cell, dedifferentiated, and mesonephric-like), responsible for most NSMP-related deaths. Subclassification of NSMPs allows for the category of low-risk EC molecular subtypes to be dramatically expanded because it now includes both POLEmut and the much more common low-risk NSMP EC.
Topics: Female; Humans; Receptors, Estrogen; Endometrial Neoplasms; Prognosis; Risk Factors; Biomarkers, Tumor; Carcinoma, Endometrioid
PubMed: 36788084
DOI: 10.1016/j.modpat.2022.100085 -
Archives of Pathology & Laboratory... Apr 2015Renal dysplasia is an aberrant developmental disease usually diagnosed during the perinatal and childhood years. Prevalence is estimated at 0.1% of infants (via... (Review)
Review
Renal dysplasia is an aberrant developmental disease usually diagnosed during the perinatal and childhood years. Prevalence is estimated at 0.1% of infants (via ultrasound screening) and 4% of fetuses and infants (via autopsy study). Occurrences may be combined with abnormalities in the collecting system or associated with complex syndromes. Histopathology shows primitive tubules surrounded by a fibromuscular collar. The differential diagnosis includes renal dysplasia, hypoplasia, and renal atrophy. Immunohistochemical expression of the paired box genes 2 and 8 (PAX2/8) and Wilms tumor 1 (WT1) is increased in the primitive ducts and fibromuscular collar, respectively. Renal dysplasia pathogenesis is not well understood, but may be caused by a nephron-inductive deficit due to ampullary inactivity or abnormal budding of the ureteric bud from the mesonephric duct. Either the PAX2 mutation only or cross-talk with the p53 pathway is involved in this deficit. Nephrectomy is the treatment of choice for symptomatic renal dysplasia.
Topics: Diagnosis, Differential; Humans; Immunohistochemistry; Kidney; Kidney Diseases; Nephrectomy; PAX2 Transcription Factor; PAX8 Transcription Factor; Paired Box Transcription Factors; WT1 Proteins
PubMed: 25822765
DOI: 10.5858/arpa.2013-0660-RS -
Modern Pathology : An Official Journal... Jan 2023Given the association of mesonephric adenocarcinoma (MA) of the uterine cervix with florid mesonephric hyperplasia, one would expect MAs to rarely arise in other...
Given the association of mesonephric adenocarcinoma (MA) of the uterine cervix with florid mesonephric hyperplasia, one would expect MAs to rarely arise in other anatomical locations that harbor mesonephric remnants. In contrast, mesonephric-like adenocarcinoma (MLA) is thought to arise from Müllerian origin without an association with mesonephric remnants. The current case series characterizes 4 cases of MA arising in the urinary bladder (1 woman and 3 men), 1 case of MA in the perirenal region (woman), and 1 case of MLA in the ureter (woman). All cases displayed morphologic features similar to MA of the uterine cervix and MLA of the ovary and endometrium, characterized by predominant tubular and focal glandular/ductal architecture. Mesonephric remnants in the bladder wall were closely associated with adjacent MA in cases 1 and 4. MLA in case 6 was associated with mesonephric-like proliferations and endometriosis. All cases (6/6) were diffusely positive for Pax8, and all displayed a luminal pattern of CD10 staining, except case 4 for which CD10 immunostain was not available for review. Gata3 was either focally positive (cases 1, 2, and 6), negative (case 3), or diffusely positive (case 5). TTF-1 was diffusely expressed in cases 1 and 3 and negative in cases 2, 5, and 6. Although a KRAS G12C somatic mutation was detected in case 6, hotspot mutations in KRAS, NRAS, and PIK3CA were not present in other tested cases. Our study demonstrates that MAs and MLAs of the urinary tract share similar histopathogenesis, morphology, and immunophenotype to their counterparts in the female genital tract. We propose that, in the urinary tract, MA might be classified as a distinctive tumor that arises from mesonephric remnants or presumed Wolffian origin if they are not related to Müllerian-type precursors. The tumor displaying similar morphology and immunoprofile to MA but associated with Müllerian-type precursors should be classified as MLA.
Topics: Male; Female; Humans; Uterine Cervical Neoplasms; Proto-Oncogene Proteins p21(ras); Adenocarcinoma; Mesonephroma; Urinary Tract
PubMed: 36788068
DOI: 10.1016/j.modpat.2022.100031