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The American Journal of Surgical... Jan 2019The current World Health Organization (WHO) classification for endocervical adenocarcinoma (EA) is based on descriptive morphologic characteristics; however, it does not...
The current World Health Organization (WHO) classification for endocervical adenocarcinoma (EA) is based on descriptive morphologic characteristics; however, it does not fully reflect our current knowledge of the diverse pathogenesis of cervical glandular neoplasia. A novel classification system, the International Endocervical Adenocarcinoma Criteria and Classification (IECC), which incorporates etiology and biological behavior into the morphologic scheme, has been recently proposed. We aimed to validate the IECC by assessing its interobserver reproducibility in comparison to the WHO system. A cohort of 75 EAs was reviewed independently by 7 gynecologic pathologists and categorized following IECC and WHO criteria based on hematoxylin and eosin material alone and after immunohistochemistry results for p16, PR, p53, Napsin-A, vimentin, CDX2, and GATA3 were provided. Human papillomavirus (HPV) in situ hybridization and polymerase chain reaction results were compared with consensus diagnoses. IECC was superior to WHO in terms of interobserver agreement with κ=0.46 versus 0.3, respectively, on hematoxylin and eosin review and κ=0.51 versus 0.33, respectively, with immunohistochemistry. Under the IECC, 73 (97%) of EAs had majority agreement (≥4 reviewers in agreement) whereas 42 (56%) had perfect agreement (7/7 reviewers in agreement). Conversely, WHO showed majority agreement in 56 (75%) and perfect agreement in only 7 (10%) EAs. Reproducibility was poor in HPV-related WHO types (usual κ=0.36, mucinous not otherwise specified κ=0.13, intestinal κ=0.31, villoglandular κ=0.21) and good in major HPV-unrelated categories (gastric type κ=0.63, clear cell κ=0.81, mesonephric κ=0.5). Classification as per the IECC had excellent correlation with HPV status (by RNA in situ hybridization or polymerase chain reaction). We have shown that the IECC has superior interobserver agreement compared with the WHO classification system, and that distinction between HPV-related and HPV-unrelated EA can be made with good reproducibility and excellent prediction of HPV status. WHO morphologic variants of HPV-related EA are poorly reproducible. Conversely, agreement is high among important high-risk HPV-unrelated subtypes. Thus, our results further support replacing the current WHO classification with the IECC.
Topics: Adenocarcinoma; Female; Humans; Observer Variation; Papillomavirus Infections; Pathology, Clinical; Uterine Cervical Neoplasms; World Health Organization
PubMed: 29877920
DOI: 10.1097/PAS.0000000000001095 -
Biomedicines Aug 2023Data on genetic and immunophenotypical characteristics of uterine mesonephric-like adenocarcinoma (MLA) remain limited. Therefore, we aimed to investigate the...
Mesonephric-like Adenocarcinoma of the Uterine Corpus: Genomic and Immunohistochemical Profiling with Comprehensive Clinicopathological Analysis of 17 Consecutive Cases from a Single Institution.
Data on genetic and immunophenotypical characteristics of uterine mesonephric-like adenocarcinoma (MLA) remain limited. Therefore, we aimed to investigate the clinicopathological, immunohistochemical, and molecular features of uterine MLA. We performed targeted sequencing, array comparative genomic hybridization, and immunostaining in 17, 13, and 17 uterine MLA cases, respectively. Nine patients developed lung metastases. Eleven patients experienced disease recurrences. The most frequently mutated gene was Kirsten rat sarcoma viral oncogene homolog (; 13/17). Both the primary and matched metastatic tumors harbored identical (3/4) and phosphatase and tensin homolog deleted on chromosome 10 (1/4) mutations, and did not harbor any additional mutations. A total of 2 of the 17 cases harbored tumor protein 53 () frameshift insertion and deletion, respectively. Chromosomal gains were detected in 1q (13/13), 10 (13/13), 20 (10/13), 2 (9/13), and 12 (6/13). Programmed cell death-ligand 1 overexpression or mismatch repair deficiency was not observed in any of the cases. Initial serosal extension and lung metastasis independently predicted recurrence-free survival with hazard ratios of 6.30 and 7.31, respectively. Our observations consolidated the clinicopathological and molecular characteristics of uterine MLA. Both clinicians and pathologists should consider these features to make an accurate diagnosis of uterine MLA and to ensure appropriate therapeutic management of this rare entity.
PubMed: 37626765
DOI: 10.3390/biomedicines11082269 -
Cureus Feb 2021The epididymal appendage, or the appendix epididymis, is a developmental remnant of the mesonephric duct that sprouts from the head of the epididymis. Due to its...
The epididymal appendage, or the appendix epididymis, is a developmental remnant of the mesonephric duct that sprouts from the head of the epididymis. Due to its pedunculated anatomical configuration, the epididymal appendage is prone to torsion and can become a rare cause of an acute scrotum. Given its often challenging and atypical presentation, high clinical suspicion and Doppler ultrasonography are needed to guide diagnosis. We report a challenging case of epididymal appendage torsion that required prompt surgical exploration to accurately diagnose. Awareness of this condition and its radiological findings can play an important role in reaching an accurate diagnosis and avoiding surgical intervention.
PubMed: 33758707
DOI: 10.7759/cureus.13412 -
Radiologia Brasileira 2020Although secondary involvement of the broad ligament by malignant tumors arising elsewhere in the abdomen and pelvis is common, primary tumors in this location are rare....
Although secondary involvement of the broad ligament by malignant tumors arising elsewhere in the abdomen and pelvis is common, primary tumors in this location are rare. Tumors of the broad ligament can be of mesenchymal and mixed nature, such as leiomyoma, the most common neoplasm; epithelial tumors of Müllerian type, imposing a challenge to differentiate them from other adnexal masses; unique tumors from mesonephric origin; and tumor-like lesions. Most neoplasms in this region, whether benign or malignant, usually present clinically with vague symptoms and are often discovered during a routine gynecological examination. Suspicion of such location and knowledge of the potential range of lesions of this region may allow for planning minimally invasive surgical interventions. To be considered tumor from the broad ligament, it should not be connected with either the uterus or the ovary. Thus, the imaging approach to establish the differential diagnosis includes excluding an ovarian, uterine, or tubal origin by recognizing these separately and by rebutting imaging clues pointing to these origins. This pictorial essay reviews some of the imaging findings that may suggest such location and presents some of the possible differential diagnoses by means of illustrative confirmed cases.
PubMed: 33071380
DOI: 10.1590/0100-3984.2019.0073 -
Hypertension (Dallas, Tex. : 1979) Mar 2022The renin-angiotensin system is highly conserved across vertebrates, including zebrafish, which possess orthologous genes coding for renin-angiotensin system proteins,...
BACKGROUND
The renin-angiotensin system is highly conserved across vertebrates, including zebrafish, which possess orthologous genes coding for renin-angiotensin system proteins, and specialized mural cells of the kidney arterioles, capable of synthesising and secreting renin.
METHODS
We generated zebrafish with CRISPR-Cas9-targeted knockout of renin () to investigate renin function in a low blood pressure environment. We used single-cell (10×) RNA sequencing analysis to compare the transcriptome profiles of renin lineage cells from mesonephric kidneys of with zebrafish and with the metanephric kidneys of and mice.
RESULTS
The larvae exhibited delays in larval growth, glomerular fusion and appearance of a swim bladder, but were viable and withstood low salinity during early larval stages. Optogenetic ablation of renin-expressing cells, located at the anterior mesenteric artery of 3-day-old larvae, caused a loss of tone, due to diminished contractility. The mesonephric kidney exhibited vacuolated cells in the proximal tubule, which were also observed in mouse kidney. Fluorescent reporters for renin and smooth muscle actin ()), revealed a dramatic recruitment of renin lineage cells along the renal vasculature of adult fish, suggesting a continued requirement for renin, in the absence of detectable angiotensin metabolites, as seen in the YFP mouse. Both phenotypes were rescued by alleles lacking the potential for glycosylation at exon 2, suggesting that glycosylation is not essential for normal physiological function.
CONCLUSIONS
Phenotypic similarities and transcriptional variations between mouse and zebrafish renin knockouts suggests evolution of renin cell function with terrestrial survival.
Topics: Animals; Animals, Genetically Modified; Blood Pressure; Clustered Regularly Interspaced Short Palindromic Repeats; Kidney; Mice; Mice, Knockout; Renin; Renin-Angiotensin System; Transcriptome; Zebrafish
PubMed: 35000430
DOI: 10.1161/HYPERTENSIONAHA.121.18600 -
The American Journal of Surgical... Aug 2018The International Endocervical Adenocarcinoma Criteria and Classification was developed to separate endocervical adenocarcinomas (ECAs) into 2 main categories on the...
The International Endocervical Adenocarcinoma Criteria and Classification was developed to separate endocervical adenocarcinomas (ECAs) into 2 main categories on the basis of morphology such as human papilloma virus-associated (HPVA) and non-human papilloma virus-associated adenocarcinomas. We aimed to improve the diagnostic accuracy of International Endocervical Adenocarcinoma Criteria and Classification by performing a comprehensive immunohistochemical evaluation and constructing objective immunohistochemical-based algorithms for the classification of these tumors. Tissue microarrays were constructed from 297 of 409 cases used to develop the original classification. Immunostains included p16, p53, estrogen receptor (ER), progesterone receptor, androgen receptor, Vimentin, CK7, CK20, HER2, HIK1083, MUC6, CA-IX, SATB2, HNF-1beta, napsin A, PAX8, CDX2, GATA3, p63, p40, and TTF-1. High-risk human papilloma virus (HR-HPV) was detected by in situ hybridization (ISH) using probes against E6 and E7 mRNA expressed in 18 different virus types. Vimentin, ER, and progesterone receptor were expressed in a significant minority of ECAs, mostly HPVAs, limiting their use in differential diagnosis of endometrioid carcinoma when unaccompanied by HPV-ISH or p16. HR-HPV ISH had superior sensitivity, specificity, and negative and positive predictive values compared with p16, as published previously. HNF-1beta did not have the anticipated discriminatory power for clear cell carcinoma, nor did MUC6 or CA-IX for gastric-type carcinoma. HNF-1beta and napsin A were variably expressed in clear cell carcinoma, with HNF-1beta demonstrating less specificity, as it was ubiquitously expressed in gastric-type carcinoma and in the majority of HPV-associated mucinous (predominantly intestinal-type and invasive ECA resembling stratified mucin-producing intraepithelial lesion [iSMILE]) and usual-type carcinomas. HIK1083 was expressed in nearly half of gastric-type carcinomas, but not in the vast majority of other subtypes. GATA3 was positive in 10% of usual-type adenocarcinomas and in single examples of other subtypes. Rare gastric-type and HPVA mucinous carcinomas displayed HER2 overexpression. Androgen receptor was positive in 6% of usual-type adenocarcinomas. Aberrant p53 expression was found in only 3.6% of usual-type HPVA carcinomas, but it was more prevalent in mucinous (intestinal type and iSMILE) HPVAs and non-human papilloma virus-associates (particularly in gastric-type carcinoma, >50% of cases). The following diagnostic classification algorithms were developed with the above data. Carcinomas without overt cytoplasmic mucin (endometrioid, usual-type endocervical, clear cell, and mesonephric carcinomas) can be subclassified using HR-HPV ISH, ER, and GATA3, whereas carcinomas with easily appreciated cytoplasmic mucin (endometrioid carcinoma with mucinous features, HPVA mucinous, and gastric-type carcinomas) can be subclassified with HR-HPV ISH and ER.
Topics: Adenocarcinoma; Algorithms; Biomarkers, Tumor; Cyclin-Dependent Kinase Inhibitor p16; Europe; Female; GATA3 Transcription Factor; Humans; Immunohistochemistry; In Situ Hybridization; Mucins; Neoplasm Invasiveness; North America; Papillomaviridae; Predictive Value of Tests; RNA, Viral; Receptors, Estrogen; Reproducibility of Results; Tissue Array Analysis; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms
PubMed: 29851704
DOI: 10.1097/PAS.0000000000001090 -
Biomedicines Apr 2022Pannexins are transmembrane glycoproteins that constitute channels involved in purinergic signaling through ATP release from cells in various physiological and...
Pannexins are transmembrane glycoproteins that constitute channels involved in purinergic signaling through ATP release from cells in various physiological and pathological processes. In this study, the distribution of Panx1 expression in different cell populations of healthy postnatal human kidneys and during human embryonic and early fetal development was investigated by double immunohistochemistry. In addition, the glomerular and tubular expression of Panx1 was examined in patients with type 2 diabetes mellitus (DM2) and the control group, and renal Panx1 expression was correlated with serum creatinine. In the 6th week of embryonic development (DW), Panx1 expression was found in mesonephric glomeruli and mesonephric tubules. At the transition from 6th to 7th DW, Panx1 immunoreactivity was found in the mesonephric tubules and mesonephric duct, as well as in the metanephric ureteric bud and ampullae. In the 7th DW, strong Panx1 immunoreactivity was observed in the developing ureteric bud in the metanephros, whereas no Panx1 immunoreactivity was found in the metanephric cup. In the 8th DW, Panx1 expression was also found in the ureteric bud of the metanephros, the renal vesicle and comma-shaped nephron, and the epithelial cells of Bowman's capsule. Expression of Panx1 was found at an early stage in both the paramesonephric duct and the mesonephric duct and diminished toward the 8th DW. During the 6th-10th DW, colocalization of Panx1 with alpha smooth actin (aSMA) was found in developing blood vessels. In the postnatal kidney, strong Panx1 immunoreactivity was present in medullary and cortical collecting duct cells, renin-producing cells, and proximal tubules. Very weak Panx1 immunoreactivity was found in certain distal tubule cells and the thin descending limbs of the loop of Henle. Panx1 immunoreactivity was also found in nephrin-immunoreactive podocytes. Panx1 was not colocalized with aSMA immunoreactivity in the vessels of the postnatal human kidney, but it was present in the endothelium. A significant positive correlation was found between Panx1 expression in glomeruli and serum creatinine only in diabetic patients and was not found in the nondiabetic group. The spatiotemporal expression of Panx1 during the early stages of human kidney development supports its possible role in cellular differentiation, migration, and positioning in the developing human kidney. In addition, our data suggest that glomerular Panx1 expression is a potential indicator of worsening renal function in patients with type 2 diabetes.
PubMed: 35625681
DOI: 10.3390/biomedicines10050944 -
PloS One 2019Primed nephron progenitor cells (NPCs) appear in metanephric mesenchyme by E11.5 and differentiate in response to the inductive WNT9b signal from the ureteric bud....
Primed nephron progenitor cells (NPCs) appear in metanephric mesenchyme by E11.5 and differentiate in response to the inductive WNT9b signal from the ureteric bud. However, the NPC WNT-receptor complex is unknown. We obtained M15 cells from E10.5 mesonephric mesenchyme and systematically analyzed components required for canonical WNT9b-responsiveness. When M15 cells were transfected with a β-catenin luciferase reporter plasmid, exposure to recombinant WNT9b resulted in minimal luciferase activity. We then analyzed mRNA-expression of WNT-pathway components and identified Fzd1-6 and Lrp6 transcripts but not Rspo1. When M15 cells were treated with recombinant RSPO1 the response to transfected WNT9b was augmented 4.8-fold. Co-transfection of M15 cells with Fzd5 (but no other Fzd family member) further increased the WNT9b signal to 16.8-fold and siRNA knockdown of Fzd5 reduced the signal by 52%. Knockdown of Lrp6 resulted in 60% WNT9b signal reduction. We confirmed Fzd5, Lrp6 and Rspo1 mRNA expression in CITED1(+) NPCs from E15.5 embryonic mouse kidney. Thus, while many WNT signaling-pathway components are present by E10.5, optimum responsiveness of E11.5 cap mesenchyme requires that NPCs acquire RSPO1, FZD5 and LRP6.
Topics: Animals; Cells, Cultured; Mesoderm; Mice; Nephrons; Signal Transduction; Stem Cells; Wnt Proteins; beta Catenin
PubMed: 30978219
DOI: 10.1371/journal.pone.0215139 -
Diagnostic Pathology Nov 2019Sex cord-like elements are rarely observed in uterine lesions, but these morphological patterns could appear in a variety of uterine tumors and non-tumorous lesions. In...
BACKGROUND
Sex cord-like elements are rarely observed in uterine lesions, but these morphological patterns could appear in a variety of uterine tumors and non-tumorous lesions. In this review, we collected the literatures regarding the uterine tumorous and non-tumorous lesions containing sex cord-like elements and summarized these lesions in terms of clinicopathological, immunohistochemical, and molecular features in order to further understand these lesions and provide some new ideas for differential diagnosis.
MAIN BODY
This section provides a comprehensive overview of the clinicopathological, immunohistochemical, and molecular features of uterine lesions with sex cord-like architectures including uterine tumors resembling ovarian sex cord tumors, endometrial stromal tumors, adenomyosis, endometrial polyps, leiomyoma, epithelioid leiomyosarcoma, adenosarcoma, sertoliform endometrioid carcinoma, corded and hyalinized endometrioid carcinoma, mesonephric adenocarcinoma, and mesonephric-like adenocarcinoma. The differential diagnosis based on morphology, immunohistochemistry, and molecular alterations has also been discussed.
CONCLUSION
The sex cord-like areas in these lesions show heterogeneous but similar morphological features. Additionally, immunohistochemical staining plays a limited role in differential diagnosis. Furthermore, it is of significance for pathologists to better understand these lesions in order to avoid confusion and mistakes during pathological diagnosis, especially in a biopsy/curettage specimen.
Topics: Adenocarcinoma; Carcinoma, Endometrioid; Female; Humans; Ovarian Neoplasms; Sex Cord-Gonadal Stromal Tumors; Uterine Cervical Neoplasms; Uterine Neoplasms
PubMed: 31739799
DOI: 10.1186/s13000-019-0909-y -
The American Journal of Surgical... Jan 2019Mesonephric adenocarcinoma (MNAC) is a rare tumor of the female genital tract mainly occurring in the uterine cervix. To date, only a few cases of MNAC arising from of...
Mesonephric adenocarcinoma (MNAC) is a rare tumor of the female genital tract mainly occurring in the uterine cervix. To date, only a few cases of MNAC arising from of the uterine body (UB-MNAC) have been reported. The clinicopathologic and molecular characteristics of UB-MNAC remain unknown. In this study, we investigated the clinical, histopathologic, immunohistochemical, and genetic features of UB-MNAC. In total, 11 cases were included. Six patients developed metastatic disease, most commonly in lungs (5/6). Histopathologically, UB-MNAC was characterized by an admixture of tubular, glandular, papillary, retiform, glomeruloid, sex cord-like, and comedonecrosis-like architectural patterns. Three adverse pathologic characteristics, including advanced International Federation of Gynecology and Obstetrics stage, high mitotic activity, and presence of lymphovascular the invasion, were independent factors predicting the development of metastasis. All cases were positive for GATA-binding protein 3 and paired box 2 expression and showed wild-type p53, patchy p16, and preserved PTEN expression, as indicated by immunohistochemistry. Next-generation sequencing using 12 samples (11 primary tumors and 1 metastatic tumor) revealed 42 single nucleotide variations in 16 genes, mostly in KRAS (10/12) and ARID1A (9/12). Copy number variation was found in 16 genomic regions, and consisted of 57 gains and 10 losses, with 1q gain (11/12) being the most prevalent. In conclusion, UB-MNAC displays an aggressive biological behavior, with a tendency to metastasize to the lungs. Adverse pathologic characteristics reflect the aggressive nature of UB-MNAC. Distinct molecular features of UB-MNAC include frequent somatic mutations of KRAS and ARID1A and gain of 1q.
Topics: Adenocarcinoma; Aged; Female; Humans; Mesonephroma; Middle Aged; Uterine Neoplasms
PubMed: 29189288
DOI: 10.1097/PAS.0000000000000991