Keywords: Clear Cell Carcinoma of the Vagina; Immunotherapy

Introduction

Approximately 1 in 100,000 women will be diagnosed with invasive or in situ vaginal cancer (typically squamous cell histology) [1], with an average age at diagnosis being approximately 60 years. Squamous cell carcinoma is more common with the increasing age of the patient [1], and most cases of vaginal cancer are related to human papillomavirus (HPV), as is the case with cervical cancer [2]. Adenocarcinomas account for 10% of vaginal cancer cases, representing almost all primary vaginal cancers in women under 20 years of age [3], and may arise in areas of vaginal adenosis, Wolffian resting elements, periurethral glands, and foci of endometriosis. Clear cell variants are the best-known type of adenocarcinoma, mainly because of their occurrence in young women exposed in utero to diethylstilbestrol (DES) [4]. Roughly clear cell carcinomas of the vagina present as polypoid masses on the anterior wall of the vagina, and about 70% of patients present in stage I at diagnosis. No randomized clinical trials define the treatment of vaginal cancer, given its rarity. Instead, the treatment approach is extrapolated from cervical and anal cancers [5]. We report a case of a patient with primary metastatic clear cell carcinoma of the vagina unrelated to exposure to diethylstilbestrol, who underwent treatment with immunotherapy with excellent response, along with a review of the pathology and advances of medicine with immunotherapy in this setting.

Case Report

In October/2019, a 55 y female started with massive vaginal bleeding. There were no noticeable elements in her previous medical history, with two previous pregnancies, one miscarriage, and one vaginal birth. A magnetic resonance imaging (MRI) of the pelvis was performed on 10/31/2019, which showed the presence of a rounded lesion involving the urethra, measuring 4.2 x 4.1 x 3.0 cm in the largest craniocaudal, anteroposterior and transverse axes, respectively, with lobulated and well-defined limits, close to the anterior wall of the distal half of the vaginal canal, with loss of the cleavage plane, promoting an impression on the vaginal canal (Figure 1). She underwent a biopsy of the lesion in December 2019, and diagnosis was adenocarcinoma with papillary growth affecting soft tissues of the vagina. Histological and immunohistochemical findings showed a high-grade invasive adenocarcinoma, with the possibility of the lesion being primary of the vagina. Since image exams showed urethral involvement, a primary urothelial tumor was questioned, and a pathological and immunohistochemical review study was requested and carried out on 03/19/2020. Its result was compatible with grade 3 clear cell carcinoma, infiltrating the vaginal wall. The tumor presented a papillary architectural pattern with solid areas, nuclear grade 3, high mitotic count, mucinous areas, and intense fibroblastic stromal reaction with vascular neoformation and lymphoid aggregates. Tumor-infiltrating lymphocytes stromal (TILs) was 15%, tumor necrosis foci <5%, without peritumoral vascular embolization. The immunohistochemical profile was positive for PAX-8, CEA, napsin, HNF1B (HNF1 homeobox B (hepatocyte nuclear factor 1 homeobox B), and p53 (Figure 2). The morphological findings and immunohistochemical profile indicated a primary gynecological site. A PET-CT in March 2020 showed an increase in glycolytic metabolism in a heterogeneous expansive lesion in the anterior compartment of the pelvic excavation, determining incarceration of the urethra, without a cleavage plane with the vesical floor, as well as the vaginal canal, with also hypermetabolic bilateral pelvic and left inguinal lymph node disorders, compatible with secondary neoplastic involvement. The patient was then submitted to chemoradiotherapy treatment with weekly cisplatin from 04/01/2020 to 05/01/2020, with improved vaginal bleeding since radiotherapy started. PET-CT for response assessment, performed on 05/22/2020, showed a marked increase in glycolytic metabolism, more irregular and expressive than in the previous study in an expansive lesion in the anterior compartment of the pelvis, with increased dimensions, as well as pelvic and bilateral inguinal lymph nodes increased in number and measurements compared to the previous study, compatible with disease progression based on RECIST 1.1. The patient remained in excellent general condition, except for the locally advanced neoplasia, which was not amenable to surgical resection without an exenterative procedure. The patient initiated chemotherapy (3 cycles of carboplatin and paclitaxel) and presented no objective response. Faced with a rare disease, a patient already exposed to treatment with chemotherapy and radiotherapy without objective response, and based on positive results observed with immunotherapy in clear cell cancer from different tumor sites, the oncology team opted for immunotherapy. In August/2020, nivolumab 480mg monthly was started. Response evaluation tests were performed in October/2020, with suspected pulmonary progression on computed tomography (CT) of the chest, due to the appearance of bilateral pulmonary nodules. On the other hand, an excellent local response was achieved with an MRI of the abdomen and pelvis showing a reduction from 14.3 cm³ to 3.0 cm³ in the lesion volume involving the urethra and the middle and distal thirds of the vagina (Figure 3). There was also a slight reduction in other secondary lesions and secondary lymph nodes. She continued on immunotherapy, with excellent response in exams of April/2021, with chest CT no longer visualizing bilateral pulmonary nodules, and MRI of the abdomen and pelvis also not evidencing the lesion involving the urethra. Other secondary lesions reduced in size, including secondary lymph nodes, the biggest in the right lateral anterior aspect close to the pubic symphysis, measuring 1.4 x 1.0 cm ( previously 2.4 x 1.3 cm). The patient remained in excellent condition, asymptomatic, and without toxicities from the immunotherapeutic treatment. PETCT was performed on 06/25/21 with complete response in all sites and increased glycolytic metabolism in the paraaortic lymph node, measuring 6.2 x 9.5 mm with SUVmax 4.66, previously absent, suggesting a secondary neoplastic implant. Abdomen and pelvis MRI of 07/28/21 showed reduction of all lymph nodes, including the one shown in PET-CT, measuring 4.0 x 6.0 mm. There was no appearance of new lesions. The patient remains on immunotherapy, with no evidence of disease in the last control exams.

Figure 1: Lesion involving the urethra, volume 14.3 cm³, close to the anterior wall of the distal half of the vaginal canal.

Figure 2: Immunohistochemical profile of tumor cells showing A) negative estrogen receptor contrasting with positive stromal cell; B) p53 wild type characterized by weak to moderate nuclear staining in part of cells; C) negative WT-1 (positive internal control of endothelial cells); D) positive PAX-8; E) HNF1B diffusely positive; F) positive napsin with a dot-like pattern of staining.