Clinicopathologic features and outcomes of primary vaginal adenosis as a dermatologic and gynecologic burden: A retrospective study

Investigation: Yan Li. Project administration: Tiantian Han, Lingya Pan. Resources: Yalan Bi. Supervision: Lingya Pan. Writing – original draft: Tiantian Han. Writing – review & editing: Tiantian Han, Ying Jin. Lingya Pan orcid: 0000-0002-2113-0491.

During the 20-year study period, 997 patients were treated for primary vaginal diseases, including malignant and benign disease; of these, 20 patients were treated for histopathologically confirmed primary vaginal adenosis, of whom 16 had been diagnosed by a gynecologist and 4 had been diagnosed by a dermatologist initially for vulvar skin irritation. The age at diagnosis ranged from 9 to 61 years (mean age, 37.9 ± 10.6 years) with parity ranging from 0 to 2. The symptoms and signs of primary vaginal adenosis presented among the study patients were variable and included pain, pruritus, discharge, palpable cysts, patchy or diffuse red stippling, granularity or nodularity, and ulcers (Table 1  ). Four asymptomatic patients were discovered incidentally on routine examination or on the basis of benign gynecologic conditions. Among all patients, 4 had multiple lesions, whereas 14 had a single lesion; the remaining 2 women did not have obvious lesions and were admitted for uterine prolapse and imperforate hymen. The exact locations of the lesions were the lower vagina (9/20), upper part of the vagina (8/20), middle vaginal wall (2/20), and both the lower and upper parts of the vagina (1/20) (Fig. 1 ). Additionally, most lesions invaded the posterior wall of the vagina (10/20). The diameter of the lesions ranged from 0.5 to 4.8 cm (mean diameter, 2 ± 1.6 cm). Clinical features, treatment, and outcome of the 20 study patients. Clinical features, treatment, and outcome of the 20 study patients. A lesion located in the vaginal os (yellow arrow). All 20 patients underwent surgical treatment, and vaginal adenoses were histopathologically confirmed by pathologists who specialized in gynecology. Eighteen patients underwent local vaginal resection with negative margins, of whom, case 10 with vaginal squamous carcinoma had stage I disease and underwent total hysterectomy with local vaginal resection. Additional procedures included hysterectomy, salpingo-oophorectomy, and vaginoplasty for other benign conditions, such as leiomyoma (4/20), adenomyosis (2/20), endometriosis (7/20), Müllerian abnormality (1/20), uterine prolapse (1/20), or chronic vulvar dystrophy (1/20). Regarding those with endometriosis, the lesions involved different parts: 1 involved the ovary, 3 invaded the vagina, 1 involved the Douglas pouch, 1 involved the ovary and Douglas pouch, and 1 involved the ovary and vagina. During the mean follow-up period ranging from 4 to 23 years, 15 patients were alive with no evidence of disease after local vaginal resection. Nevertheless, case 7 with vaginal intraepithelial neoplasia I experienced local recurrence 81 months later from initial treatment, underwent local resection again and then lived free of disease. Case 10 with carcinoma diagnosed initially was included in this study for pathological diagnosis of moderately differentiated squamous cell carcinoma surrounded by adenosis. She experienced local recurrence as the same pathologic diagnosis 2 months later without any intervention and lived with the disease. Three patients (case 4, case 12, and case 19) progressed to vaginal carcinoma at 5 months, 30 months, and 23 years after the initial surgery; their tumor types (the International Federation of Gynecology and Obstetrics [FIGO] stage) were mucinous carcinoma (stage IV), CCC (stage I), CCC (stage I), respectively. Case 4 was treated with adjuvant radiotherapy and tumor debulking after recurrence and then died of advanced disease 13 months after primary surgery. Case 12 underwent local vaginal excision combined with 6 fractions of external radiation at a dose of 45 Gy after recurrence, and then experienced a disease-free status for 7 years; thereafter, she remained alive with disease for 8 years without treatment (per her decision) or regular screening at the date of the investigation. After experiencing alternating symptoms, such as pain, pruritus, ulceration, and bleeding, case 19 underwent regular colposcopic examination every 3 months, by which the diagnosis of vaginal adenosis was histologically confirmed for 18 years. Subsequently, the vaginal lesion progressed to a serous borderline tumor after 5 years, so she underwent regular screening without any treatment. One month from the last follow-up date, she developed CCC in situ.

In this retrospective study, data of patients with vaginal adenosis from the departments of dermatology and gynecology were combined. From 1997 to 2017, 20 cases were retrieved from the electronic databases at Peking Union Medical College Hospital in China. As a case series, this study does not need approval of the Peking Union Medical College Hospital Ethics Committee, but all patients were informed of the study and provided consent. Clinical information, including age at diagnosis, location of the lesions, symptoms, pathology, and therapeutic procedures, were extracted from the hospital medical records. Follow-up data, including postoperative complications and survival, were collected by telephone and from outpatient records. And there is no loss. The overall survival or time to recurrence was calculated from the date of operation to the date of relapse, death, or final follow-up (July 13, 2017). Analyses of the data were performed with SPSS, version 20.0 (IBM Corp., Armonk, NY).

Since vaginal adenosis is benign and almost asymptomatic, the presence of this disease is often overlooked by a dermatologist or gynecologist. [ 3 ] Vaginal adenosis is mostly a coincidental finding, as the diagnostic criteria and clinical treatment guidelines of this lesion are difficult to find. [ 4 ] Although primary vaginal adenosis has been described for more than 100 years, the condition has been rarely reported in the last 20 years due to withdrawal of DES (Table 2 ). DES was found to have a strong association with the development of CCC or adenocarcinoma from adenosis. [ 1 , 4 ] Other sporadic case reports suggested alternative causes of vaginal adenosis, such as sulfonamide-induced Stevens-Johnson syndrome, [ 5 ] carbon dioxide laser treatment, 5-fluorouracil therapy, [ 6 ] and tamoxifen uterine-exposure. [ 7 ] However, the low incidence rate hindered the study of the etiology of vaginal adenosis. Even if the pathogenesis of vaginal adenosis is still not completely understood, in the cases of adenosis after vaginal inflammation, it is suggested that adenosis develops as a metaplastic process similar to other well-known types of metaplasia that occur as a result of noxious stimuli in other parts of the body. [ 6 ] The present study's data might contribute to a better understanding of this rare condition. Review of reported cases in the past 20 years. All patients denied utero exposure of DES, thus confirming that other aetiological factors may contribute to the development of adenosis. [ 1 ] The pathogenesis of vaginal adenosis is unknown, yet some researchers showed that if the biological process of the developing vagina remained incomplete, squamous epithelium during organogenesis of the lower female reproductive tract might switch to a columnar 1. [ 2 ] Our cases may shed new light on a possible correlation between vaginal adenosis and endometriosis. Unlike the reported cases, about half the patients had endometriosis in our study; the vaginal glandular epithelium may be derived from heterotopic endometrium without stroma, which is important for differentiation (Fig. 2 ). Another possibility is that menstruation blocked by the vaginal malformation led to vaginal adenosis. Although it is possible that the coexistence of vaginal adenosis and endometriosis in these cases occurred simply by chance, we believe that it is likely that the endometriosis was a precursor to vaginal epithelial changes. Although never mentioned in several previous reports on this subject, the relationship between endometriosis and adenosis has gained little attention in the literature (Table 2 ). Vaginal adenosis consistent with benign-looking glands (A: H&E 100x). The same sample of endometriosis shows endometrial stroma (B: H&E 100x). According to data of the epidemic period, vaginal adenosis affects less than 4% of DES-unexposed women but 8% to 10% of the general population. [ 8 , 9 ] The mean age of all patients with lesions reported recently is 40.9 years, which is older than that of our patients (37.9 years; Tables 1 and 2 ). The main populations with DES exposure were born from 1950 to 1959, accounting for 70%, according to Hoover et al. [ 1 ] Different from the worldwide distribution, the study at our center showed that most patients (70%) were born from 1960 to 1979 (Table 1  ). Besides, the effect of vaginal adenosis on infertility had been ruled out in this study, which is in contrast to the findings of another study. [ 1 ] In accordance with reported studies, [ 3 , 4 , 6 – 8 , 10 – 13 ] the common clinical presentations of vaginal adenosis are vaginal pain (7/20) and bleeding (8/20) (Table 1  ). However, some patients are asymptomatic and are diagnosed incidentally during a general physical examination or treatment for other ailments. The location of vaginal lesions may be related with the pathogen: vaginal adenosis caused by Stevens–Johnson syndrome and toxic epidermal necrolysis often occur in the lower one-third of the vagina; nevertheless, DES-induced lesions are usually found in the upper two-thirds of the vagina. [ 5 ] In this study, the distribution of lesions was random. There is a paucity of literature reporting the clinical management and outcome of vaginal adenosis. The carcinogenesis of vaginal adenosis in DES-exposed patients is extremely rare (reported in 0.1% of the cases), and the pathological classification is mostly CCC. [ 1 ] Adenosis induced by DES was reported as the precursor of vaginal carcinomas previously; in vaginal CCC, glandular epithelium was identified in 80% of patients. [ 9 , 14 ] However, the incidence of CCC is significantly different from the incidence of adenosis caused by DES exposure. Thus, there may be no direct evidence of a relationship between adenosis with carcinomas, or the risk of malignant transformation from adenosis to carcinoma may be lower with a slow progression. Yet, this study cannot support this hypothesis, as the course of carcinogenesis was discrepant: 5 months, 30 months, or 23 years. Tumor types described in relevant literature include CCC and adenocarcinoma. [ 4 , 6 , 13 ] In this study, there were 3 types, including mucinous carcinoma, squamous cell carcinoma, and CCC. According to the literature, CCC is associated with vaginal adenosis in DES-exposed women, while mucinous carcinoma and squamous cell carcinoma may arise in a context of chronic inflammation. [ 15 , 16 ] For the clinical treatment of vaginal adenosis, local resection is preferred. Immune response modifiers, such as imiquimod, can achieve ideal goals in the treatment of vaginal lesions, for example, complete response of vaginal intra-epithelial neoplasia in 57% to 86% of patients. [ 17 ] Another intervention, including lesion resection or cauterization, to control symptoms may be more feasible. [ 12 ] Additionally, Vigliani et al [ 18 ] suggested that blocking aromatase activity via bilateral oophorectomy or owing to natural menopause would be an effective alternative. Given the potential malignant transformation, follow-up of these patients is mandatory to identify carcinomatous lesions. Most of our patients (16/20) had complete remission after local vaginal excision and are receiving cervical and vaginal cancer screening at recommended intervals, but symptomatic women with or without pathological recurrent lesions undergo a Papanicolaou smear or colposcopy more frequently. Primary vaginal adenosis is an extremely rare pre-carcinomatous lesion. Currently, there is a lack of clinical strategies for patients with this abnormality. Analysis of the clinical features and outcomes of patients with DES exposure over the past 20 years in this study indicated differences in the pathogen, year of birth, age of onset, fertility, complications, and clinical outcomes. Although a causal association remains to be proven, clinicians should be mindful of the possibility of vaginal glandular alteration when managing patients with endometriosis. This study is the first to document clinical examinations, follow-up data, and ascertainment of outcomes in China. Further large-scale studies on the rarity of spontaneous vaginal adenosis are needed to better inform and establish the optimal treatment.

Vaginal adenosis, defined as the development of columnar epithelium in the vagina, is the most common anomaly in young girls and female adults exposed to diethylstilbestrol (DES) in utero. [ 1 ] DES was administered to prevent abortion during pregnancy in the United States and European countries from the 1940s to the 1970s. [ 1 , 2 ] Although lacking direct proof, adenosis is widely accepted to be the precursor of clear cell adenocarcinomas, as the presence of adenosis has been found in all daughters exposed to DES with vaginal clear cell carcinoma (CCC). [ 2 ] The National Cooperative Diethylstilbestrol Adenosis project registered 4653 patients with utero exposure to DES and analyzed pregnancy complications and the risk of cervical neoplasia or breast cancer, and treated them. [ 1 ] However, in China, there is no report on cases of DES exposure, and vaginal adenosis is an uncommon disease. Therefore, this study describes 20 cases of vaginal adenosis and summarizes the data of diagnosis, management, and outcomes. Additionally, pertinent literature was reviewed, and the potential origin and effective management of this disease are discussed.