Vaginal Adenosis Research Articles

Diagnostic and Therapeutic Approach in a Metastatic Vaginal Adenocarcinoma: A Case Report

BackgroundVaginal adenocarcinomas (VAC) are most often reported after intrauterine exposition to diethylstilbestrol (DES). Rarely, VACs are reported as a malignant transformation of vaginal adenosis or endometriosis, in the context of chromosomal abnormalities or malformations of the uterus or the vagina. VACs without DES exposition have a poor prognosis and a significantly worse outcome compared to vaginal squamous cell carcinomas or DES-associated VACs.ObjectiveHere, we report the case of a primarily metastatic VAC, treated successfully with different lines of chemo-, antiangiogenic, antibody, and immunotherapy.CaseThe 49-year-old patient presented in 5/2018 with a primarily pulmonary metastatic VAC. Significant tumor reduction was seen after six cycles of carboplatin AUC5/paclitaxel 175 mg/m²/bevacizumab 15 mg/kg q3w. Bevacizumab maintenance therapy and later cisplatin mono 50 mg/m² q2w led to local and distant tumor progression. To identify a potential targeted therapy, new tumor biopsies were obtained. Immunohistochemistry revealed ERBB2 expression, and paclitaxel 80 mg/m² weekly plus trastuzumab 4 mg/m² respectively 2 mg/m² q3w was administered. Due to local and pulmonal tumor progression after 6 months and persistent ERBB2 positivity, the therapy was adjusted to trastuzumab emtansine (T-DM1) 3.6 mg/kg q3w; however, the patient remained locally progressive after three cycles of T-DM1 and additionally showed a new bone metastasis. The new tumor biopsies revealed a combined positive score (CPS) of 2 regarding PD-L1, and pembrolizumab 200 mg q3w was initiated. The bone metastasis was radiated and treated with denosumab 120 mg q4w. Extreme tumor regression followed by stable disease was maintained for 9 months. Due to a slow locoregional progress only with new inguinal lymph node and pararectal lymph node metastases, a new tumor biopsy was taken. Molecular profiling showed an ARID1A mutation, a mutational burden of 5.1 mutations per megabase, and no genfusions. Based on these findings, therapy with PD-L1 antibodies, PD-1 antibodies, gemcitabine, or dasatinib was suggested. Therefore, administration of pembrolizumab was continued and local radiation therapy was performed. This led to a decrease in local tumor manifestations and a stable systemic disease.ConclusionOur case demonstrates the diagnostic and therapeutic approach in a patient with primary metastatic vaginal adenocarcinoma. By tumorgenetic profiling, different lines of systemic therapy, namely, antiangiogenic therapy, monoclonal antibody therapy, immunotherapy, and local radiation therapy, were identified and successfully administered.

Vaginal Adenosis in Two Patients with No History of Diethylstilbestrol: A Case Report

Vaginal Adenosis in Two Patients with No History of Diethylstilbestrol: A Case Report

A case of vaginal adenosis with gastric differentiation

Objective: The purpose of this study was to describe the presenting signs and symptoms of a nondiethylstilbestrol (non-DES) exposed patient with vaginal adenosis and illustrate the challenges of making a diagnosis of vaginal adenosis based on histopathological assessment, gross evaluation, and diagnostic imaging.

SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of M\xfcllerian duct epithelium

During female mammal reproductive tract development, epithelial cells of the lower Müllerian duct are committed to become stratified squamous epithelium of the vagina and ectocervix, when the expression of ΔNp63 transcription factor is induced by mesenchymal cells. The absence of ΔNp63 expression leads to adenosis, the putative precursor of vaginal adenocarcinoma. Our previous studies with genetically engineered mouse models have established that fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), bone morphogenetic protein (BMP)/SMAD, and activin A/runt-related transcription factor 1 (RUNX1) signaling pathways are independently required for ΔNp63 expression in Müllerian duct epithelium (MDE). Here, we report that sine oculis homeobox homolog 1 (SIX1) plays a critical role in the activation of ΔNp63 locus in MDE as a downstream transcription factor of mesenchymal signals. In the developing mouse reproductive tract, SIX1 expression was restricted to MDE within the future cervix and vagina. SIX1 expression was totally absent in SMAD4 null MDE and was reduced in RUNX1 null and FGFR2 null MDE, indicating that SIX1 is under the control of vaginal mesenchymal factors: BMP4, activin A and FGF7/10. Furthermore, Six1, Runx1, and Smad4 gene-dose-dependently activated ΔNp63 expression in MDE within the vaginal fornix. Using a mouse model of diethylstilbestrol (DES)-associated vaginal adenosis, we found DES action through epithelial estrogen receptor α (ESR1) inhibits activation of ΔNp63 locus in MDE by transcriptionally repressing SIX1 and RUNX1 in the vaginal fornix.

Malignant transformation of vaginal adenosis to clear cell carcinoma without prenatal diethylstilbestrol exposure: a case report and literature review

BackgroundWe report an extremely rare case of vaginal clear cell carcinoma, which originated from the malignant transformation of vaginal adenosis without prenatal diethylstilbestrol (DES) exposure.Case presentationIn this case, the patient was a Chinese woman with a history of two decades of intermittent vaginal pain, sexual intercourse pain and vaginal contact bleeding. On September 1, 2011, when the patient was 39 years old, a vaginal biopsy revealed vaginal adenosis. After intermittent drug and laser treatment, her symptoms did not improve. Four years later, on March 4, 2015, another vaginal biopsy for abnormal vaginal cytology revealed atypical vaginal adenosis. After treatment with sirolimus, her symptoms and abnormal vaginal cytology results persisted, and she underwent laparoscopic hysterectomy with bilateral salpingo-oophorectomy and excision of the vaginal lesions. One year after the hysterectomy, on August 15, 2017, the vaginal cytology results suggested atypical glandular cells, and a biopsy revealed vaginal clear cell carcinoma originating from the atypical vaginal adenosis. A wide local resection of the vaginal lesions was performed, followed by concurrent chemoradiotherapy. Regular follow-up over 16 months showed no evidence of the recurrence of vaginal adenosis or cancer.ConclusionsBased on the evolution of a series of pathological evidence, we report the fourth case in the world of vaginal clear cell carcinoma originating from vaginal adenosis without prenatal DES exposure. Wide local excision with radiotherapy provided at least 16 months of disease-free survival.

Clinicopathologic features and outcomes of primary vaginal adenosis as a dermatologic and gynecologic burden

In the recent 20 years, primary vaginal adenosis is extremely rare and the data of clinical presentations, management, and outcome have not been studied systematically.In this retrospective study, women with vaginal adenosis between January 1997 and June 2017 were identified from the hospital's medical records. Data on patient age, history, symptoms, mass location, size, diagnosis, complications, treatment, and recurrence were analyzed by SPSS 20.0.Twenty women were histopathologically diagnosed as having vaginal adenosis (mean age, 37.9 ± 10.6 years). All patients denied utero exposure. The most common symptom was vaginal pain or abnormal bleeding. For all patients, the local vaginal lesions were surgically excised. Seven patients had complications with endometriosis. 15 patients lived without recurrence, and 1 patient underwent postoperative local recurrence after 81 months. Primary vaginal squamous cell carcinoma in another patient was confirmed to arise from adenosis; she survived with disease. The remaining 3 patients developed carcinoma of different types in varied periods of a disease-free state (5 months, 30 months, and 23 years, respectively); 1 patient died of progressive disease, and 2 patients survived with disease.Primary vaginal adenosis is a spontaneous lesion with a propensity for late canceration. Local lesion resection is the primary treatment.

Response of xenografts of developing human female reproductive tracts to the synthetic estrogen, diethylstilbestrol

Human female fetal reproductive tracts 9.5–22 weeks of gestation were grown for 1 month in ovariectomized athymic adult female mouse hosts that were either untreated or treated continuously with diethylstilbestrol (DES) via subcutaneous pellet. Normal morphogenesis and normal patterns of differentiation marker expression (KRT6, KRT7, KRT8, KRT10, KRT14, KRT19, ESR1, PGR, TP63, RUNX1, ISL1, HOXA11 and α-ACT2) were observed in xenografts grown in untreated hosts and mimicked observations of previously reported (Cunha et al., 2017) non-grafted specimens of comparable age. DES elicited several notable morphological affects: (a) induction of endometrial/cervical glands, (b) increased plication (folding) of tubal epithelium, (c) stratified squamous maturation of vaginal epithelium and (d) vaginal adenosis. DES also induced ESR1 in epithelia of the uterine corpus, cervix and globally induced PGR in most cells of the developing human female reproductive tract. Keratin expression (KRT6, KRT7, KRT8, KRT14 and KRT19) was minimally affected by DES. Simple columnar adenotic epithelium was devoid of TP63 and RUNX1, while DES-induced mature vaginal epithelium was positive for both transcription factors. Another striking effect of DES was observed in grafts of human uterine tube, in which DES perturbed smooth muscle patterning. These results define for the first time IHC protein markers of DES action on the developing human reproductive tract, which provide bio-endpoints of estrogen-induced teratogenesis in the developing human female reproductive tract for future testing of estrogenic endocrine disruptors.

Adénose vaginale : à propos d’une observation et revue de la littérature

We report a case of vaginal adenosis in a woman of 42years. This is a rare congenital disorder since cessation of use of diethylstilbestrol (DES), usually of benign course, not to ignore in its tubo-endometrial histological form which may progress to atypical adenosis precursor of vaginal clear cell adenocarcinoma in patients exposed in utero to DES.

The problem of vaginal adenosis

The National Cooperative Diethylstilbestrol Adenosis (DESAD) Project has completed the major portion of its enrollment phase with the examination of more than 300 daughters of women taking synthetic non steroidal estrogens (denotes DES) during pregnancies occurring from the early 1940's to the mid 1960's. The aims of the Project were to fill urgent needs for information on the prevalence and incidence of structural and epithelial abnormalities of neoplastic changes and their complications in these women.

The developmental origin of cervical and vaginal epithelium and their clinical consequences: a systematic review.

Studies on the development of the embryological and fetal development of the cervix and the vagina are rare and mostly go back to the first decades of the last century. The aims of this review were to present the latest knowledge concerning the developmental origin of cervical and vaginal epithelium and to point out new results in the context of different clinical findings. Relevant studies published between 1910 and 2013 were identified via PubMed, MEDLINE, OVID, Web of Science, and EMBASE. The reference lists of retrieved articles were reviewed to locate additional articles. Each abstract was reviewed, and the appropriate publications were obtained and reviewed as well. A total of 33 articles and 8 book chapters were selected for citation in this review. New objective findings clearly show that human prenatal epithelialization of the cervix and vagina results in 3 morphogenetically determined units: (i) the Müllerian columnar epithelium of the endocervix, (ii) the Müllerian squamous epithelium of the ectocervix and the upper vagina, and (iii) the vaginal squamous epithelium of the lower vagina. These results are of high clinical relevance and may provide new insight into the histogenesis of ectopy, vaginal adenosis, and the congenital transformation zone. They should be added to the explanations in gynecological, colposcopical, and gynecopathological textbooks.

Preinvasive Lesions in Gynaecology – Vagina

Preinvasive lesions of the vagina are relatively rare, clearly defined afflictions, originating most of all in association with the highrisk human papillomavirus infection (HR HPV). The most frequent appearance is in coincidence with preinvasive lesions of uterine cervix and in vaginal cuff after hysterectomy. Preinvasive vaginal lesions are divided into squamous lesions (vaginal intraepithelial neoplasia) and nonsquamous lesions. Vaginal adenosis belongs to nonsquamous vaginal preinvasive lesions and is a precursor lesion of vaginal clear cell carcinoma. Surgical and nonsurgical techniques including laser destructive methods and local administration of 5- fluorouracile are used in the treatment of preinvasive lesions of vagina.

Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium

Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal adenosis remains elusive. Here we report that DES induces vaginal adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Müllerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5′ sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate.

Vaginal Adenosis in a 40-year-old Lady: A Case Report and Review of Literature

ABSTRACT Vaginal adenosis, without a history of diethylstilbestrol (DES) exposure, is a rare condition with an unclear etiology. A 40- year-old female presented with complaints of persistent excessive watery vaginal discharge. On examination, there was red, patchy, diffuse lesion all over the vaginal wall and cervix. Histopathological examination of the lesion revealed vaginal adenosis. This case is presented here for its rarity. How to cite this article Hena SNB, Akhter N, Das S, Kutubi A. Vaginal Adenosis in a 40-year-old Lady: A Case Report and Review of Literature. J South Asian Feder Obst Gynae 2013;5(2):80-82.

Development of vesicovaginal fistula caused by vaginal adenosis: A case report

Introduction: Vaginal adenosis is one of the rare diseases of the vagina, and almost all patients are asymptomatic. We report a case of spontaneous vaginal adenosis, which caused vesicovaginal fistula. Case Presentation: Our patient was a 25-year-old Japanese woman. She was admitted to our hospital, and her chief complaint was continuous urine flow from the vagina. We found a tumor with a vesicovaginal fistula in her vagina. Subsequent cytological analysis of vaginal smears showed a normal vaginal mucosa. The patient underwent tumor resection and a fistula patch. Pathological diagnosis was adenosis of the vagina, even though the patient had no known history of intrauterine diethylstilbestrol exposure or Mullerian developmental abnormalities. Conclusion: The clinical course of our case was a malignant tumor, which invasively bored a hole in the vaginal wall forming a vesicovaginal fistula, even though it was a benign lesion. Therefore, overzealous treatment should be avoided in this case.

Primary neuroendocrine carcinoma of the vagina with coexistent atypical vaginal adenosis: A rare entity

Primary neuroendocrine carcinoma of the female genital tract is a rare entity with aggressive clinical behavior and a poor prognosis. This kind of malignancy arising in the vagina is extremely rare. We report a case of primary neuroendocrine carcinoma of vagina arising in a setting of atypical vaginal adenosis.

The development of cervical and vaginal adenosis as a result of diethylstilbestrol exposure in utero

Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow-up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Müllerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces adenosis lesions in the cervix and vagina. This review describes mouse models that can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses their molecular pathogenesis.

Primary Vaginal Mucinous Adenocarcinoma of Gastric Type Arising in Adenosis

We report 2 cases of primary vaginal mucinous adenocarcinoma arising in adenosis in nondiethylstilbestrol-exposed women, 1 with uterus didelphys. Both tumors exhibited morphologic and immunohistochemical features (MUC6 and/or HIK 1083 positivity) identical to the recently described cervical gastric-type adenocarcinoma, a subtype of mucinous adenocarcinoma that is non-human papillomavirus related and possibly related to adenoma malignum. Both neoplasms were intensely p53 positive, suggesting that TP53 mutation may be implicated in their development. We believe that the vaginal tumors arose from adenosis through atypical adenosis, as benign and atypical glands were present at the periphery of the neoplasms. In reporting these cases, we discuss atypical adenosis and other types of non-diethylstilbestrol-associated vaginal adenocarcinomas. At least 9 other examples of primary vaginal, or more uncommonly cervical, adenocarcinomas arising in non-diethylstilbestrol-exposed women with congenital genitourinary malformations have been reported, suggesting a probable causal association between congenital malformation, vaginal adenosis, and vaginal adenocarcinoma.

Multimodal therapy in the treatment of vaginal adenocarcinoma arising from endocervicosis

Primary vaginal adenocarcinoma is a rare gynecologicmalignancy. It is thought to arise from vaginal adenosis, endometriosis, embryonic remnants, in-utero DES exposure, or endocervicosis. A computer generated literature search using PubMed and the English search terms “‘primary vaginal adenocarcinoma’ and ‘vaginal endocervicosis’” yielded two cases of vaginal endocervicosis, one associated with a primary non-clear cell vaginal adenocarcinoma [1,2].We report the first case of a metastatic primary vaginal adenocarcinoma thought to arise from malignant transformation of vaginal endocervicosis.

Primary Vaginal Adenocarcinoma Arising in Vaginal Adenosis After CO2 Laser Vaporization and 5-Fluorouracil Therapy

We present a case of a 45-year-old woman with a long-standing history of persistent cervical dysplasia that resulted in a hysterectomy. Subsequent vaginal smears revealed high-grade vaginal intraepithelial neoplasia (VAIN III) on Pap smear with positive human papilloma virus (HPV) testing. Over the course of 2 years, the patient underwent 2 CO(2) laser vaporization procedures of the upper vagina and intermittent 5-fluorouracil therapy. A biopsy performed at the time of the second laser procedure revealed endocervical-type well-differentiated adenocarcinoma, associated with VAIN III. HPV in situ hybridization for HPV types 16 and 18 was positive in both the glandular and squamous mucosa. The patient has no known history of intrauterine diethylstilbestrol exposure or mullerian developmental abnormalities. Subsequently, the patient underwent a radical upper vaginetcomy with bilateral pelvic lymph nodes dissection and bilateral salpingo-oophorectomy. The vaginectomy specimen showed residual adenocarcinoma associated with VAIN-III and extensive vaginal adenosis with free resection margins. This is the second reported case in the literature of adenocarcinoma arising in vaginal adenosis after 5-fluorouracil. Herein, we highlight these important findings and shed some light on the pathogenesis of vaginal adenosis and the subsequent development of vaginal adenocarcinoma.

Relevance and consequences of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in gynecology

Erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can be distinguished by location, morphology and extent of cutaneous and mucosal lesions. EM has minimal effects on pregnancy and the genital tract. SJS and TEN on the other hand are related with premature labor and vaginal scarring that can lead to long-term painful lesions, stenosis, vaginal adenosis and telangiectasia. A 33-year-old G3P2 with a medical history of SJS has multiple recurrences during pregnancy of what seems to be EM instead of SJS with a favorable outcome. Differentiation between EM, SJS and TEN is important in gynecology to predict the effects of the diseases on the genital tract and on pregnancy.