Abstract
Tubulo-squamous polyp (TSP) of vagina is a rare, benign, upper vaginal lesion of postmenopausal women. The origin of TSP is unclear, and the lesion is hypothesized to be arising from misplaced prostate-like vaginal skene glands. We describe the clinical, histological and immunohistochemical features of 6 TSPs we encountered in our routine practice. Histologically, TSPs are characterized by mass-forming, submucosal, cystic metaplastic transitional-type epithelium and prostate-like glands. The histological and immunohistochemical findings in TSP are identical to Mullerian (cervical and vaginal) epithelial metaplastic changes described in a setting of exogenous testosterone exposure.
Introduction
Vaginal polyps are rare lesions, with the majority classified as fibroepithelial (stromal) polyps, which typically have a definitive histological diagnosis. 1 A range of other mesenchymal, epithelial or mixed lesions can also manifest as vaginal polypoid masses.2,3 Additionally, there are limited documented reports of the benign Brenner tumor of vagina forming a polypoid mass.4,5 Vaginal tubulo-squamous polyps (TSPs) were characterized by McCluggage and Young in 2007. The authors documented 10 patients with a distinctive uncommon benign vaginal polyp that primarily affects postmenopausal women. 6 Up to date, 7 additional reports of vaginal TSP with variable cell differentiation,7–12 4 vaginal TSP, 13 1 cervical TSP 14 and a TSP arising in the ovary 15 have been reported.
The etiopathogenesis of TSP is unclear. Previous reports have focused on origin from prostate-like glands in vagina (skene glands). 6 TSP-like epithelial changes have been described in cervix and vaginal epithelium of transgender men, treated by testosterone, raising a question whether TSP is a mass-forming metaplastic process. 16 In this report, we describe 6 patients with vaginal TSP (second largest series). Since TSP is a rare lesion, our goal is to increase the awareness about this unusual benign mass-forming vaginal lesion which will also encourage further studies into the etiopathogenesis of TSP.
Materials and Methods
With approval from the Institutional Review Board at Hospital, 6 patients with TSP were identified from the Department of Pathology's archival files. Hematoxylin and eosin-stained slides from formalin-fixed paraffin-embedded tissue were reviewed. Immunohistochemical staining (IHC) for GATA3 and prostate-specific antigen (PSA) was performed with an appropriate control.
Results
Table 1 describes the histological and immunohistochemical features of the 6 TSPs.
Microscopic and Immunohistochemical Findings of 6 TSPs.
Abbreviations: TSP, tubulo-squamous polyp; PSA, prostate-specific antigen.
Patient 1
A 62-year-old female patient presented with a right adnexal mass. An incidental vaginal polyp was removed during total abdominal hysterectomy and bilateral salpingo-oophorectomy. The histopathologic examination resulted in a right adnexal serous adenofibroma, an endometrial polyp and subserosal endometriosis. Grossly, the vaginal polyp consisted of 0.9 × 0.5 × 0.5 cm gray polypoid tissue. Microscopically, the vaginal polyp consisted of well-circumscribed nests of polygonal epithelial cells embedded in a fibrous focally edematous stroma (Figure 1). Epithelial nests showed squamous features. Some nests were dilated and showed central spaces filled with necrotic debris. Some epithelial cells showed elongated nuclei with nuclear grooving consistent with transitional metaplasia. Several mucinous glands, intermixed with transitional metaplasia occasionally resulting in a cribriform arrangement, were present. The surface of the polyp was covered by intact squamous epithelium, which was not connected with the underlying lesion. GATA3 IHC revealed positive staining in the basal cell layer of the surface epithelium and transitional metaplastic epithelium in the TSP. Glands showed moderate to strong cytoplasmic staining for PSA. Glandular epithelium was negative for GATA3.
Patient 1 (A, B), Patient 3 (C, D), and Patient 4 (E, F) H&E and PSA IHC (inset) images. The low power (A, C, E) shows polypoidal tissue covered by squamous mucosa. The stroma shows variably distended cystic spaces lined by squamous and transitional-type epithelium, with scattered mucinous cuboidal to low columnar epithelium-lined glands. PSA IHC shows strong cytoplasmic staining in the glands. IHC, immunohistochemical staining; PSA, prostate-specific antigen.
Patient 2
A 63-year-old female patient presented with postmenopausal bleeding. During hysteroscopy, a clinically benign polypoid lesion was identified in the vagina and subsequently excised. An endometrial biopsy was also performed and revealed weakly proliferative endometrium with tubal and mucinous metaplasia. The vaginal biopsy was submitted as a soft, irregular tan to white tissue fragment measuring 0.4 × 0.3 × 0.1 cm. Microscopic examination revealed well-circumscribed lesion composed of hypocellular stroma and large nests of squamous epithelium unconnected to the surface epithelium, some of which demonstrated eosinophilic proteinaceous material filled large spaces with a mixture of squamous epithelium, transitional epithelium and small tubular structures lined by polarized low columnar-cuboidal cells with mucinous cytoplasm. Glandular epithelium was positive for PSA and GATA3 positivity confirmed transitional metaplasia.
Patient 3
A 65-year-old female patient without pertinent history presented for an annual gynecologic examination. During the examination, a 0.4 × 0.3 × 0.3 cm upper vaginal polypoid lesion was seen and interpreted as a vaginal cyst by the gynecologist. The cut section revealed a 0.4-cm cyst containing yellow and granular material. On microscopic examination, the polyp-like specimen was lined by unremarkable squamous epithelium, including multiple squamous nests surrounded by fibrous stroma and composed of cells with abundant eosinophilic or clear cytoplasm and focally with intermediate features between squamous and transitional epithelium. Cystic changes and occasional calcifications were present. Laminated keratin was located within one cyst. Small PSA-positive and GATA3-negative glands were present.
Patient 4
A 76-year-old woman, a known patient with endometrial carcinoma, undergoing a total abdominal hysterectomy along with a bilateral salpingo-oophorectomy and pelvic lymph node dissection, was found to have a vaginal polyp. Grossly, the vaginal polyp consisted of a 1.5 × 1.4 × 0.6 cm fragment of pink-tan, fleshy, polypoid tissue. The cut surface revealed a clear mucin-filled cyst. Microscopically, the polyp is composed of cystically dilated spaces embedded in hypocellular stroma. Cysts were lined by squamous, transitional and glandular epithelium. The stromal component of the polyps exhibited low cellularity and comprised bland spindle-shaped fibroblast-like cells with occasionally bizarre nuclei. Glandular epithelium was PSA-positive, and transitional epithelium was GATA3-positive.
Patient 5
A 63-year-old female patient with no known past medical history was referred for gynecologic assessment. During hysteroscopy, a 0.4 cm vaginal mass was found and excised. Grossly, the polyp is comprised 2 pink to yellow friable irregular tissue fragments measuring 0.3 and 0.4 cm in greatest dimension. On microscopic examination, the polyp surface showed squamous epithelium. Directly below the surface epithelium and within the lesion, there was a lobular cystic epithelial proliferation in a hypocellular fibrous stroma. The cystic part was predominantly covered by stratified squamous epithelium, although some cells exhibited cuboidal mucinous-type epithelium. Occasional nuclear grooving was observed. The glandular epithelium was PAS positive, and the transitional epithelium was GATA3-positive.
Patient 6
A 76-year-old woman presented with pelvic organ prolapse. An incidental pink well-defined lesion originating from the vagina was noted and removed during total robotic hysterectomy along with vaginal vault suspension. Grossly, the vaginal lesion consisted of 4-cm, tan, rubbery irregular tissue ranging from 0.7 to 2.0 cm. Microscopically, the vaginal polyp was lined by squamous epithelium, and small glands/tubules were noted within the surface epithelium. The stromal component exhibited low cellularity and was made up of bland spindle-shaped fibroblast-like cells. The glandular epithelium was PSA-positive, and the transitional epithelium was GATA3-positive.
Discussion
This report presents 6 patients with a unique type of vaginal polyp predominantly affecting postmenopausal women. 6 The designation “TSP” was originally based on the presence of an admixture of epithelial and stromal elements including squamous epithelium and minor components of tubules. 6 Additional published reports also included basaloid epithelial elements,8,12 sebaceous glands,9,12 mucinous and goblet cell differentiation 10 and cellular “angiomyofibroblastic-like” stroma. 11 Four vaginal TSP with variable basaloid formations resembling hair follicle structures and sebaceous glands were discussed as well 13 (Table 2). Most of these lesions were reported in the vagina, whereas one cervical polyp resembling a penis with similar features and an ovarian teratoma displaying localized regions reminiscent of TSP has also been documented.14,15 (Table 2)
Clinical and Histological Findings of TSPs From Published Literature and The Current Study.
Abbreviations: TSP, tubulo-squamous polyp; IHC, immunohistochemical staining; PSA, prostate-specific antigen.
Microscopically, vaginal TSP represents a distinctive entity characterized by an admixture of epithelial and stromal components 6 ; the epithelial component consists of well-demarcated nests of squamous and transitional epithelium with associated prostate-type simple glands. In all but 2 patients, there was no connection with the squamous surface epithelium. The epithelial nests can show cystic changes and distension with eosinophilic and proteinaceous debris. The stroma displayed hypocellular, fibrous or edematous patterns with scattered small ectatic vessels and sparse inflammatory cells. Immunohistochemically, GATA3 and PSA stains confirm the diagnosis, highlighting transitional epithelium and prostate glands, respectively.
TSPs are uncommon benign lesions that rarely result in diagnostic problems, although a variety of alterations occasionally complicate histological interpretation. The differential diagnosis encompasses documented reports of vaginal Brenner tumors.4,5 The similarities between these lesions are significant enough to suggest that they may represent the same pathological entity. In all vaginal Brenner tumors that have been reported, the lesions exhibited a polypoid morphology and were characterized by the presence of squamous/urothelial nests, some of which featured small lumina, in addition to tubules and/or cysts.4,5 In most of these reports, the primary epithelium was classified as transitional rather than squamous, which is the reason for the designation of Brenner tumor. Notably, only one vaginal Brenner tumor has been described following the description of TSP; however, TSP was not considered in the differential diagnosis of vaginal Brenner tumor. 5 Additional differential diagnosis is benign mixed tumor of the vagina (spindle cell epithelioma), composed of an admixture of epithelial and stromal elements. The epithelial component consists of nests of benign-appearing squamous cells, and, less frequently, glands. However, the stromal component predominates and consists of numerous spindle cells without atypia, which are usually strongly immunoreactive for cytokeratins. 2
Numerous theories exist concerning the histogenesis of the vaginal TSP. It has been proposed that these polyps may originate from Müllerian and Wolffian structures, the urogenital sinus, or as a result of vaginal adenosis. 6 Alternative theories suggest that the TSP origin may be linked to mesonephric remnants, or eutopic or misplaced Skene glands, equivalent to the prostate in the female. 6 This hypothesis is bolstered by the observation that several documented lesions exhibited positivity for PSA and PSAP (ACP3). 6 Furthermore, vaginal TPS with basaloid elements along with expression of PSA was described as basal cell hyperplasia within prostatic tissue. 8 TSP with mucinous and goblet cell differentiation was also reported as resembling eutopic or misplaced Skene glands with PSA-negative/PSAP-positive glandular epithelium. 10 The additional morphological patterns, such as the presence of sebaceous glands and potential hair structures with variable PSA-positive staining,9,13 and NKX3.1-positive glandular epithelium with focal positivity for PSAP, 12 have been supported the postulated origin of TSP from eutopic or misplaced Skene glands;9,12,13 however, these types of differentiation in these lesions are difficult to explain just from Skene glandular epithelium and the author suggested an abnormal migration of a specific precursor cell or stem-type cell to develop urogenital sinus components as a possible etiology. 12
In this study, we propose that the etiology of TSP may be a metaplastic process similar to the recently described testosterone-induced prostatic-type metaplasia in the female genital tract and breast.16–19 All the patients in our cohort are menopausal without any history of exogenous testosterone exposure. Future studies can investigate blood levels of testosterone and androgen receptor expression in TSP.
Prostatic-type metaplasia has recently been described in the vagina and uterine cervix of patients taking masculinizing hormonal therapy for the purpose of gender transition. 17 Furthermore, similar to TSP reports, prostatic-type metaplasia along with pilar metaplasia were also mentioned in a significant portion of gender-affirming mastectomy specimens. 18 Testosterone-induced virilization-related etiology can explain sebaceous and hair structure differentiation in TPS. Hyperplastic prostatic glands in uterine cervical stroma in a transgender patient on androgen replacement therapy have been recently documented. 19
In conclusion, TSP should be included in the differential diagnosis of vaginal polyps. We anticipate that heightened awareness of this lesion will aid in identifying and distinguishing it from other vaginal glandular lesions. Correct diagnosis will also help in elucidating the etiopathogenesis of TSP.
Footnotes
Ethical Approval
WIH IRB. 1808217
CRediT Author Statement
Conceptualization, data curation and writing original draft done by BA; writing—review and editing by MQ; data curation by SI; conceptualization, data curation and writing—review and editing by KS.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work did not receive any funding from National Institutes of Health (NIH), Wellcome Trust, Howard Hughes Medical Institute or any other organization
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.