ORIGINAL RESEARCH ARTICLE: VULVA AND VAGINA Small Cell Carcinoma of the Vagina: First Systematic Review of Case Reports and Proposal of a Management Algorithm Sira Capote, MD,1 Marta Domènech, MD,2 Lorena Valdivieso, MD,3 Victoria Tuset, MD,4 Myriam Sanchez, MD,1 Elvira Carballas, MD,5 Iris Teruel, MD,2 David Durany, MD,6 Gloria Moragas, MD,7 Carlos Molina, MD,1 Judith Lleberia, MD, PhD,1 Sergio Martínez-Roman, MD, PhD,5 and Margarita Romeo, MD, PhD2 achieve better outcomes. Human papillomavirus could be related to the de- Objectives: Small cell carcinoma of the vagina (SmCCV) is an extremely velopment of SmCCV. A diagnostic-therapeutic algorithm is proposed. rare disease. Evidence-based data and specific guidelines are lacking. We conducted the first systematic review of case reports to provide the most Key Words: neuroendocrine tumors, vaginal cancer, small cell carcinoma, overall picture of SmCCV. cancer of vagina, human papillomavirus, molecular characterization Materials and Methods: Literature search in PubMed and Scopus was (J Low Genit Tract Dis 2023;27: 56–67) performed using the terms “small cell carcinoma” and “vagina.” English-language case reports of primary SmCCV up to January 2022 were included. Results: Twenty-nine articles describing 44 cases met our inclusion criteria. We report a new case of our hospital. The global median overall survival S mall cell carcinomas (SmCCs) are high-grade neuroendocrine tumors that emerge from neuroendocrine cells or result from the dedifferentiation of an aggressive nonneuroendocrine tumor.1 (mOS) was 12.00 months (95% CI = 9.31–14.69). The mOS was not reached Most commonly, SmCCs arise in the lung (SmCLC),2 and only 5% for stage I, and it was 12.00, 12.00, 9.00, and 8.00 months for stages II, III, are extrapulmonary. An SmCC from the female genital tract (usu- IVA, and IVB, respectively (statistically significant differences between ally cervix)3 constitutes less than 2% of all gynecologic cancers,4 stage I and stages II, III, or IVA [log rank p = .003–.017]). Thirty-five cases showing poorer prognosis than other carcinomas. A small cell car- received local treatments (77.8%). The mOS of patients treated with cinoma of the vagina (SmCCV) is a rare neoplasm with less than 50 surgery ± complementary chemotherapy, radiotherapy ± complementary cases reported to date (the first in 1984).5 Herein, we report our own chemotherapy, chemoradiation ± complementary chemotherapy, and sur- case and we present, to our knowledge, the first systematic review gery + radiotherapy ± complementary chemotherapy were 11.00, 12.00, of case reports and a diagnostic-therapeutic algorithm. 17.00, and 29.00 months, respectively. The use of adjuvant or neoadjuvant chemotherapy (64.5%, mostly platinum + etoposide) showed longer mOS (77.00 vs 15.00 months). Four of 5 tested cases presented human papillo- Case Presentation mavirus infection, 3 of them presenting type 18. A 55-year-old patient was admitted to our hospital in July Conclusions: Small cell carcinoma of the vagina shows dismal prognosis. 2018 for postmenopausal bleeding. She had an active type 2 dia- Multimodal local management plus complementary chemotherapy seems to betes mellitus and no family history of malignancy. Her general physical examination was normal and vaginal ex- 1 Gynecology Department, Fundació Hospital de l'Esperit Sant, Barcelona, Spain; amination revealed a 2-centimeter polypoid mass depending from 2 Medical Oncology Department, B-ARGO Group, Institut Català d'Oncologia, the upper third of vagina without involving cervix (1 cm apart). Barcelona, Spain; 3Pathology Department, Hospital Universitari Germans Trias i Pujol, Autonomous University of Barcelona, Barcelona, Spain; 4Radiation- Biopsy of the vaginal polypoid mass showed infiltration of Oncology Department, Institut Català d'Oncologia, Barcelona, Spain; 5Gyne- subepithelium by isles of malignant cells with a high nuclear- cology Department, Hospital Universitari Germans Trias i Pujol, Autonomous cytoplasmic ratio, hyperchromatic nuclei, and scanty eosinophilic University of Barcelona, Barcelona, Spain; 6Radiodiagnostic Department, Hos- cytoplasm. Immunohistochemical staining showed positivity for pital Universitari Germans Trias i Pujol, Autonomous University of Barcelona, Barcelona, Spain; and 7Nuclear Medicine Department, Hospital Universitari chromogranin A, synaptophysin, and low–molecular weight cytokeratins Germans Trias i Pujol, Autonomous University of Barcelona, Barcelona, Spain (CKCAM 5.2, CK7, CK20). The pathologic diagnosis was small Reprint requests to: Margarita Romeo MD, PhD, Medical Oncology cell carcinoma. Type 18 human papillomavirus (HPV) was de- Department, B-ARGO Group, Institut Català d'Oncologia, Carretera del tected in biopsy specimen, and an intense nuclear p16 expression Canyet s/n, 08916, Badalona, Spain. E-mail: mromeo@iconcologia.net S.C. and M.R. participated in the conceptualization and methodology of the was observed (see Figure 1). study and writing of the article. S.C. and M.R. performed the data Gynecologic transvaginal ultrasound scan proved normal and collection. M.R. performed the data analysis. S.C., M.D., L.V., V.T., M.S., discarded invasive disease in cervix or paracervix. Laboratory re- E.C., D.D., G.M., C.M., J.L., S.M.-R.S., and M.R. participated in writing of sults were unremarkable, including tumor markers (cancer antigen the article. All authors approved the final manuscript. M.D. has received honoraria from advisory board (Novartis) and travel grants 12.5 [CA125], cancer antigen 19.9 [CA19.9], and squamous cell for attending to medical congresses (Seagen, Roche, Bristol Meyers carcinoma[SCC] antigen). A positron emission tomography–computed Squibb, Novartis, MDS, AstraZeneca, Lilly). I.T. has received honoraria for tomography (PET-CT) discarded distant dissemination. Thus, speaking (Novartis) and inscription grant for attending medical congresses the final diagnosis was primary small cell carcinoma of the vagina (AZ) in the last year. S.M.R. has received honoraria from advisory boards AstraZeneca, TESARO, and ROCHE. M.R. has received honoraria from (SmCCV) stage I, according to the 2009 International Federation of advisory boards (AstraZeneca/MSD, GSK, Merck and Clovis) and travel Gynecology and Obstetrics (FIGO) clinical staging system. grants for attending medical congresses (Pfizer) in the last year. The other Concurrent external beam radiation therapy (EBRT) with 50 authors have declared they have no conflicts of interest. grays and weekly cisplatin 40 mg/m2 was started. After completing The present study was exempt from institutional board review. Oral and written informed consent was obtained for case publication of the patient reported by our group. EBRT, chemotherapy with cisplatin 75 mg/m2 on day 1 plus etopo- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on side 100 mg/m2 on days 1–3 every 3 weeks was continued until behalf of the ASCCP. This is an open-access article distributed under the completing 6 cycles. An episode of febrile grade 4 neutropenia oc- terms of the Creative Commons Attribution-Non Commercial-No Derivatives curred after administration of cycle 2 and grade 2 radiation-related License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any colitis after cycle 4. Complete response was achieved. way or used commercially without permission from the journal. The patient underwent strict follow-up with physical examina- DOI: 10.1097/LGT.0000000000000712 tion and full-body CT every 3 months. Six months after finishing 56 Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 Vaginal Neuroendocrine Cancer: A Review FIGURE 1. Pathological study of vaginal tumor. Histologic examination shows (A) a bluish submucosal proliferation growing in a solid fashion close to the resection margins. Molding and smudging phenomena, especially in the periphery of the lesion and around the vessels, are a distinctive feature (hematoxylin-eosin [H&E], 2). Diffuse areas and (B) well-defined nests are observed (H&E, 20). C, A relatively monotonous population of small round cells with finely stippled “salt and pepper” nuclear chromatin, inconspicuous nucleoli, and scant cytoplasm constitutes the lesion. A thin delicate fibrovascular stroma is also noted (H&E, 40). D, Immunohistochemistry reveals the neuroendocrine nature of the tumor cells with a diffuse membrane expression of synaptophysin. E, The neoplasm is also positive for chromogranin A with a perinuclear dot-like pattern. F, An intense nuclear p16 expression is identified. Cytokeratin positivity was demonstrated with (G) CAM.5, CK7, and CK20 stains. chemotherapy, mediastinal adenomegalies were observed in full-body SYSTEMATIC REVIEW OF THE LITERATURE CT scan, without signs of local recurrence in the gynecological exam- AND ANALYSIS ination. A fine-needle puncture-aspiration assessment (PAAF) guided by endobronchial ultrasound was conclusive for sarcoidosis. Methods In January 2020, 14 months after finishing chemotherapy, a vaginal mass of 1 cm in upper vaginal location was detected on phys- Search Strategy, Selection Criteria, Study Design, and ical examination. The biopsy confirmed local recurrence. A PET-CT Endpoints. A systematic review of the literature was performed scan showed the vaginal nodule (maximum standardized uptake following the Preferred Reporting Items for Systematic Reviews value of 5) and 2 infracentimetric pulmonary nodules (located in left and Meta-Analyses guidelines. PubMed and Scopus were search lower and right upper lung lobes, both maximum standardized uptake using the combination of the key words “small cell carcinoma” value of 5). A salvage vaginal surgery and an excisional biopsy of the and “vagina” (see Figure 2). Search ended on January 23, 2022. lung nodules, followed by chemotherapy, were planned. The patient Articles had to meet the following inclusion criteria: English underwent laparoscopic-robotic assisted radical hysterectomy with manuscripts, human patients diagnosed with primary SmCCV, bilateral adnexectomy and upper colpectomy, with an unremarkable and original nonduplicated data. Two authors (S.C. and M.R.) re- postoperative course. Suddenly, world pandemic for COVID-19 viewed independently the retrieved articles and clarified dubious started, and thoracic surgery was postponed. The patient started chemo- cases with VT and SM before deciding on the definitive inclusion therapy, using cisplatin 75 mg/m2 day 1 plus etoposide 100 mg/m2 days or exclusion for the review. As expected, only case reports were 1–3 every 3 weeks, and completed 4 cycles. The CT scan after che- identified. First reported case dates from 19845 and the last one motherapy showed stable disease. The excision of the 2 lung nod- was reported in December 2021.6 Data regarding pathological ules was planned in 2 surgical times with 1 month of difference. and clinical features, as well as medical management approaches The anatomopathological study of both nodules revealed metasta- and outcomes, were extracted. Progression-free survival (PFS) tic SmCCV, with margins free of lesion. was lacking in many reports. Overall survival (OS) was the only In January 2021, she was admitted in hospital because of com- outcome that could be measured. Those patients who were staged plete bowel obstruction and intense dorsal pain. Relapse in the according to the American Joint Committe on Cancer Cancer stag- peritoneum, liver, and multiple bones was detected. She received ing and Tumor Node Metastases staging system were modified to palliative decompressing radiotherapy on D5–D6 and began again meet the definitions of the 2009 FIGO clinical staging system. cisplatin plus etoposide on February 15, 2021. Malignant bowel obstruction resolved, and she was discharged from hospital. She Statistical Analyses. Clinical information is summarized in Tables 1 continued chemotherapy up to 6 cycles. Unfortunately, in June and 2 according to the FIGO stages. All possible variables were 2021, systemic progression occurred, and the patient decided to quantified and summarized using percentages, means, or medians travel to her homeland and abandoned medical controls. when appropriate. We used the Kaplan-Meier method to estimate © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 57 Capote et al. Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 FIGURE 2. Flow chart of studies retrieved and finally included in the meta-analysis. survival curves and the log rank test to compare survival differences. Figure 2). All cases, including our own, are summarized in Tables Overall survival was calculated from time of diagnosis until death 1 and 2. or last contact alive. Global median OS (mOS), mOS according to the FIGO stage, and mOS according to different therapeutic Clinical Presentation approaches were analyzed. Analysis was performed using the The mean age at diagnosis was 55.29 years (n = 42, range Statistical Package for Social Science software (IBM SPSS Statistics 32–81 years). Most commonly, SmCCV presented with postmen- 15.0; IBM Corp, Armonk, NY) for Windows, and p values less opausal vaginal bleeding and an exophytic vaginal polypoid mass. than .05 were considered statistically significant. Lymphatic dissemination was reported in 10 cases, affect- ing groin nodes, pelvic, and/or para-aortic nodes, according to RESULTS radiological and/or surgical findings. Interestingly, we identi- Until January 23, 2022, our search identified 29 articles fied 3 patients with para-aortic dissemination without pelvic or describing 44 different cases that met our inclusion criteria (see inguinal involvement. 58 © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. TABLE 1. Clinical and Pathological Information of Patients Diagnosed With Small Cell Carcinoma of the Vagina N Ref Year Age, y Clinical features Tumor size, cm Imaging staging HPV Lymph M1 Immunohistochemical staining Stage I FIGO 2009 (n = 9) 7 1 1992 65 HSIL 0.5 CT scan, chest x-ray — No NSE 8 2 1997 59 AVB + Cushing syndrome 3.5  3 CT scan Np No — Negative for ACTH 9 3 2000 51 AVB 43 MRI, CT scan Np No CK, NSE, chr-A and 5HT 10 4 2009 53 Ns Ns Ns Np No NS 11 5 2013 81 AVB — MRI + PET-CT Np No Chr-A and SYN 12 6 2016 NS NS 4.5  2.5  2 Ns Np No Ns 13 7 2018 56 Vaginal mass 3 PET-CT +(Other) No Ns 14 8 2020 51 AVB 0.5 MRI, CT scan Np No Chr-A and CD56 9 Ours 2021 53 AVB 221 PET-TC + (18) No LMW CK, chr-A, and SYN Stage II FIGO 2009 (n = 12) 15 10 1985 61 (m) Ns Ns Ns Np No Ns 15 11 1985 61 (m) Ns Ns Ns Np No Ns 16 12 1986 32 AVB 332 Chest x-ray, CT scan, proctoscopy Np No 5HT 17 13 1989 41 AVB 43 Chest x-ray, cystoscopy, sigmoidoscopy Np No Np 18 14 1989 78 Tenesmus, malaise 4 CT scan Np No Np 18 15 1989 74 AVB 3 CT scan Np No Np 19 16 1990 62 AVB 2 — Np No — 20 17 1992 34 Vaginal mass 3 CT scan Np No Chr-A 21 18 2013 41 Vaginal discharge 22 MRI Np No CK AE1/AE3, CD57, chr-A Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 12 19 2016 Ns Ns 4  4  1.5 Ns Np No Ns 22 © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 20 2018 34 Vaginal mass 11 PET-CT Np Ns LMW CK and SYN 4 21 2019 43 Vaginal mass — — Np No Ns Stage III FIGO 2009 (n = 10) 15 22 1985 61 (m) Ns Ns Ns Np Ns Ns 15 23 1985 61 (m) Ns Ns Ns Np Ns Ns 23 24 1992 78 Vaginal discharge 3 nodes (1.2–4) CT scan, chest x-ray Np Yes NSE, PGP 9.5, chr-A, SYN, CD57, and LMW CK 24 25 1998 32 Vaginal mass 10  8 Np No SYN, NSE, neurofilament, CD57, chr-A 25 26 2000 57 AVB 8 CT scan Np No NSE and SYN 26 27 2004 55 AVB 733 CT and bone scan Np Yes TTF-1, LMW CK, chr-A, SYN 27 28 2005 50 AVB — Ns Np Yes NSE, chr-A 28 29 2018 51 Ns Ns Ns Np Yes SYN, CD56, Chr-A 29 30 2018 54 AVB 1.5 MRI, PET-CT Np Yes CD56, CK7 30 31 2019 65 Vaginal pain 79 MRI and CT scan Np Yes SYN and CD56 6 32 2021 70 AVB 3 Yes (ns) + (18) Yes CK19, SYN, Chr-A, p16 Stage IVA FIGO 2009 (n = 5) 15 33 1985 61 (m) Ns Ns Np Ns Ns Continued next page Vaginal Neuroendocrine Cancer: A Review 59 Capote et al. Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 5HT indicates serotonin; abd US, abdominal ultrasound; AVB, abnormal vaginal bleeding; Chr-A, chromogranin A; CK, cytokeratins; HSIL, high-grade squamous intraepithelial lesion; LMW, low molecular weight; M1 CK AE1/AE3, vimentin, Ki-67 (50%), SYN, and CD99 Two of 42 patients (5%) with clinical information presented metastases; m, median; N, number; Np, not performed; Ns, nonspecified; NSE, neuron-specific enolase; PGP 9.5, protein gene product 9.5; Ref, reference; SYN, synaptophysin; TTF-1, thyroid transcriptor factor 1. central nervous system metastases at diagnosis. Endocrinologic disorders were present in 4 of 42 patients (10%), specifically ec- topic Cushing syndrome (n = 2, 5%) and syndrome of inappropri- Immunohistochemical staining ate antidiuretic hormone secretion (n = 2, 5%). LMW CK, chr-A, CEA, SYN, CD56. Pathologic Study The only macroscopic pathological description observed “a CK19, CK20, SYN, Chr-A, p16 yellow and hemorrhagic mass” after resection.24 The mean larger LMW CK, chr-A and SYN LMW CK, chr-A and SYN diameter of the vaginal masses was 3.15 cm (range = 0.5–10 cm, n = 30). Microscopically, high mitotic rate, extensive areas of necrosis, NSE, SYN, chr-A and frequent lymph-vascular space invasion were usually reported. Immunohistochemical staining was described in 26 cases (60%, n = 45). Chromogranin A (n = 17, 65%), synaptophysin SYN, CD56 (n = 17, 65%), low–molecular weight cytokeratin (n = 11, 42%) and neuron-specific enolase (n = 7, 27%) were the most frequently positive markers. Np Np Histopathologic study without clinical details (detected by cfDNA testing) Human Papillomavirus Infection and Lymph M1 Molecular Studies Yes Yes Yes Yes Yes No No Ns Ns Only 5 cases were reported to be tested for HPV: 1 negative,7 1 positive for a high-risk type different to 16–18 (not specified),13 Histopathologic study without clinical details Histopathologic study without clinical details and 3 positive for 18 type (2 cases reported in 20216 and our case). + (18) The 3 cases HPV18+ positive were reported to be p16+ with a dif- HPV Np Np Np Np Np Np Np — fuse pattern in the immunochemistry study. Moreover, 2 of them6 were studied by next-generation sequencing analysis of a panel of 60 major cancer-related genes, finding low tumour mutational burden (TMB), low microsatellite instability score, and no TP53 (tumor protein p53) or retinoblastoma gene mutations in both cases. One of them harbored a mutation in NF1 (neurofibromato- Imaging staging sis type 1) gene (NF1 p.T4671) and the other case harbored a mu- tation in AR (androgen receptor) gene (AR p.C327Y). Chest x-ray and abd US CT and bone scan CT and bone scan Staging and Global Prognosis Primary vaginal tumors are clinically staged, but imaging Chest x-ray techniques help determine their real local and distant extension.37 CT scan CT scan CT scan Yes (ns) Twenty-seven of 45 patients (64.2%) reported information about imaging techniques. Pelvic magnetic resonance imaging (MRI), Ns which is the best technique for evaluating the real tumor size and invasion of neighboring tissues,37 was performed in 6 patients Tumor size, cm 2.5  1.5  1 (22.2%). Distant metastatic disease was evaluated with a CT in 18 10  8  8 932 1.5  1 cases (66.7%) and/or a PET-CT scan in 5 cases (18.5%). 75 34 3.8 Ns — According to the 2009 (FIGO) staging system, 9 patients were stage I (23.7%), 12 stage II (31.6%), 11 stage III (26.3%), 5 stage IVA (13.2%), and 3 stage IVB (5.3%), of 40 cases with staging information. AVB+ Cushing syndrome The median follow-up of the whole series was 12 months Vaginal mass + AVB Clinical features (minimum–maximum = 4–77, n = 38; mean = 17.65). Twenty-two Vaginal discharge Vaginal discharge Vaginal bleeding Vaginal mass deaths were described (59.5%, n = 38), all caused by disease progres- Rectal pain sion. The mOS was 12.00 months (95% CI = 9.31–14.69). The most AVB AVB frequent sites of metastases were lung (n = 5), liver (n = 3), lymph Case was excluded for survival analyses. nodes (n = 3), bones (n = 3), brain (n = 1), and occipital scalp (n = 1; see Tables 1, 2). The mOS was not reached for stage I, and it was 12.00, 12.00, 9.00, and 8.00 months for stages II, III, IVA, and IVB, respectively (see Figure 3). Survival differences between Stage IVB FIGO 2009 (n = 2) Year Age, y stage I and stages II, III, or IVA were statistically significant (log rank Stage not specified (n = 5) 43 68 73 74 38 70 61 50 50 p ranging from .003 to .017). TABLE 1. (Continued) 2016 43a 35a 1986 1984 1989 1989 2004 2004 2021 2008 2013 45a 36a 2018 2011 Primary Treatment and Outcomes Treatment approaches were very heterogeneous among the 42 cases with some kind of information regarding management Ref 17 17 26 26 31 32 33 34 5a 6 (see Tables 1, 2). Local treatments (surgery and/or radiotherapy) were used in 35 cases (83.3%), chemotherapy alone in 4 cases (10%, a 41a 42a 44a 34 35 36 37 38 39 40 with 2 radiological responses described), and best supportive care N 60 © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. TABLE 2. Treatment and Survival Outcomes of Patients With Small Cell Carcinoma of the Vagina Survival, N Ref Surgical treatment Radiation, Gy Chemotherapy (no. cycles) Resp Recur Site of recurrence/P Recur/progress treatment mo Stage I (n = 9) 7 1 Lump excision BT (70) Vin + DXR + CFM (6) CR No 24 (A) 8 2 — EBRT (45)conc CDDP + ETO (1) conc CR Yes Liver — 17 9 3 — EBRT (ns) CDDP + THP + CFM (5) CR No 41 (A) 10 4 Yes (ns) EBRT (50) CBP + ETO (4) CR No 36+ 11 5 — EBRT + BT (63) No CR No 20 (A) 12 6 — EBRT + BT (51) CDDP + ETO (4) conc CR No 7 (A) conc CBP + PTX (2) 12 7 Va + BILND Ns Ns CR Ns Ns (A) 14 8 Lump excision — Irinotecan + CDDP (6) CR No 11 (NED) 9 Ours — EBRT (50) conc Weekly CDDP, then CDDP + ETO (6) CR Yes Vaginal, lung CDDP + ETO + surgery. P 26 (A) (bones, peritoneum liver) Stage II (n = 12) 10 15 — — Yes (ns) Ns Ns — 12 (md) 11 15 — — Yes (ns) Ns Ns — 12 (md) 12 16 — EBRT + BT (80) — CR Yes Lung and liver P-chemo (ns) 12 13 17 Lump excision EBRT + BT (90) — CR Yes Occipital scalp, bones Br radiation +CDDP + Vin 29 14 18 — EBRT (40) — CR Yes Lung, vagina 5-Fluoracil 15 15 18 — EBRT + BT (100) — CR Yes Bony, lung Palliative EBRT. 11 Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 16 19 EBRT (ns) CDDP + ETO (5) P P-Chemo (ns) (refused 8 CDDP + ETO) © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 20 17 Va + BILND EBRT + BT (ns) CDDP + ETO (3) CR Yes Ns — 6 21 18 — EBRT + BT (ns) CDDP + ETO (6) CR No 5 (A) 12 19 RH + partial Va + BILND EBRT + BT (ns) CDDP + ETO (6) CR Ns Ns (A) 22 20 RH + partial Refused Refused CR Yes 1 pelvic mass (5 mo) 1 TPT + PTX + Bev + IMRT 34 Va + RSO + RPLND 2 retroperit LN + brain 2 TPT + DTX + Bev (28 mo) 4 21 CKC + Va + BILND — PTX + CBP (2) CR Yes Ns Ns 77 Stage III (n = 11) 22 15 — — — Ns Ns — 12 (md) 23 15 — — — Ns Ns — 12 (md) 24 23 Modified R hemi Va-Vu — — CR Yes Paravaginal and Vu-va and RR 10 pararectal 24 25 — EBRT (ns) CDDP + ETO (6) CR No 6 (A) 25 26 — EBRT (54) conc CBP + ETO (6) CR Yes Liver, lung Ns 14 (AE, low dose, TED) Continued next page Vaginal Neuroendocrine Cancer: A Review 61 TABLE 2. (Continued) 62 Survival, N Ref Surgical treatment Radiation, Gy Chemotherapy (no. cycles) Resp Recur Site of recurrence/P Recur/progress treatment mo Capote et al. 26 27 Radical Vu + partial Va Refused Refused CR Yes Vaginal, bone and CDDP + ETO 4 supraclav LN 27 28 Anterior PE + BPLND — CDDP + ETO + DXR (ns) CR Yes Para-aortic LN Ns 11 28 29 — EBRT (ns) conc CDDP + ETO + PTX (5) CR Yes Lung RRx-001 + CDDP + 7 ETO + Nivolumab 29 30 — EBRT + BT CDDP (5) conc CR No 12 (NED) 30 31 — EBRT + BT (70) PTX + CDDP (1), CDDP + ETO (1), CDDP (2), CR No 22 (A) conc PTX + CBP (1), CBP + ETO (1) 6 32 — RT conc (ns) Ns (conc) PR 8 (A) Stage IVA (n = 5) 33 15 — — — Ns Ns — 12 (md) 34 17 — EBRT (52) ADR + CFM (1) P — Lung Palliative EBRT 5 35 17 — — CDDP + MTX (ns) CR Yes Ns 9 36 26 — EBRT (ns) conc CDDP + ETO (2.AE)conc P — 4 37 26 — EBRT + BT (ns) CDDP + ETO➔ CDDP (3) only conc CR No 15 (A) conc Stage IVB (n = 3) 38 31 — — CDDP + ETO (4.AE) PR Early Epi 8 P 32 39 — EBRT + BT (ns) CDDP + PTX (6) CR No 21 (A) conc 6 40 TH + BSO + Va — Yes (ns) PR No 8 (A) Not specified (n = 5) 41a 33a Lump excision Ns Ns Ns Ns Ns Ns Ns 42a 34a Lump excision Ns Ns Ns Ns Ns Ns Ns 43a 35a Histopathologic study without clinical details 44a 5a Histopathologic study without clinical details 45a 36a Histopathologic study without clinical details a Case was excluded for survival analyses. (A) indicates alive at the moment of reporting the case; ADR, adriamycin; AE, adverse effect; Bev, bevacizumab; BILND, bilateral inguinal lymph node dissection; BPLND, bilateral pelvic lymph node dissection; BSO, bilateral salpingo-oophorectomy; BT, brachytherapy; CBP, carboplatin; CDDP, cisplatin; CFM, cyclophosphamide; CKC, cold knife conization; CR, complete response; DTX, docetaxe; DXR, doxorubicin; ETO, etoposide; Epi, epirubicin; IMRT, intensity-modulated radiation therapy; LN, lymph node; md, median; MTX, methotrexate; N, number; ns, nonspecified; P, progression; Pal, palliative; p-Chemo, palliative chemotherapy; PE, pelvic exenteration; PR, partial response; PTX, paclitaxel; R, right; Rad, radical; Recur, recurrence; Ref, reference; Resp, response; RH, radical hysterectomy; RPLND, right pelvic lymph node dissection; RR, rectosigmoid resection; RSO, right salpingo-oophorectomy; seq, sequential; Supraclav, supraclavicular; TED, thromboembolic disease; THP, pirarubicin; TPT, topotecan; Va, vaginectomy; Vin, vin- cristine; Vu, vulvectomy. © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 Vaginal Neuroendocrine Cancer: A Review FIGURE 3. Overall survival curve of our series according to the FIGO staging. in 3 cases (7.5%). None of them received prophylactic brain radi- To enable a more detailed analysis, patients with survival infor- ation. The retrospective nature of data hampers determining the mation (n = 31) were categorized in 4 subgroups, as shown in Table 3: palliative or curative intention of treatment in all cases. surgery ± chemotherapy (n = 7, 22.6%), radiation ± sequential che- Of the 38 patients with survival information, there were 15, motherapy (n = 10, 32.2%), surgery followed by radiation ± sequential 4, and 3 deaths described for each subgroup. The mOS were chemotherapy (n = 4, 12.9%), concurrent chemoradiation ± sequential 29.00 (95% CI = 5.21–52.79), 9.00 (95% CI = 6.39–11.61), and chemotherapy (n = 10, 32.2%). The mOS of each subgroup were 12.00 months (95% CI = unavailable because of sample size), re- 11.00, 12.00, 29.00, and 17.00 months, respectively, without statisti- spectively. We will describe the first subgroup with more detail. cally significant differences among them. Of note, most local relapses occurred among operated patients without postoperative radiation. Patients Treated With Local Therapies (n = 35). Among No one received surgery plus concurrent chemoradiation. them, best recorded response was complete response in 29 cases, Twenty patients (64.5%) underwent chemotherapy sequentially partial response in 3 cases, and progression in 3 cases. to local treatments (mean number of cycles 6), whereas 14 patients Surgery was performed in 15 cases (42.8%), ranging from did not (including 5 patients who only received chemotherapy lumpectomy to anterior pelvic exenteration. Regional lymphade- concurrently to radiation). The mOS was 77.00 (95% CI = unavail- nectomy was only purposely mentioned in 7 patients. Considering able because of limited sample size) versus 15.00 months (95% cases with survival information, mOS of operated patients was CI = 9.02–20.98), respectively (log-rank p = .390). Either as systemic 77.00 months (95% CI = unavailable because of sample size, treatment alone or used concurrently to radiation, regimens of chemo- n = 11) versus 17.00 months (95% CI = 12.04–21.96, n = 19) in therapy were mostly platinum based, usually in combination with eto- nonoperated patients (log-rank p = .586). Considering patients poside (see Tables 1, 2). Only 2 cases reported chemotherapy-related who underwent surgery with available information regarding ad- serious adverse events: grade 3 gastrointestinal toxicity in 1 patient re- juvant treatments and follow-up, those who received surgery alone ceiving cisplatin-etoposide concurrently to radiation26 and persistent had an mOS of 10.00 months (95% CI = 0.40–19.60, n = 3), hypomagnesemia and hypokalemia as well as retinal hemorrhages in whereas those who also received complementary treatments (ra- one patient receiving cisplatin-etoposide as a systemic treatment alone. diotherapy and/or chemotherapy) had an mOS of 29.00 months In both cases, further chemotherapy was discarded.31 Dosages of (95% CI = 0.00–69.80, n = 7, log-rank p = .374). No surgical com- cisplatin-etoposide were not described in most cases. plications were reported. Pelvic radiotherapy was performed in 25 of 42 patients with information management (71.4%), only 7 of them also operated. Recurrent Disease The mean administered grays were 64.11 (SD = 18.284, n = 14), Among those who achieved complete response after local thera- usually by combining EBRT and brachytherapy. Considering pies (n = 29), 15 relapsed (51.7%). Recurrence site was reported only cases with survival information, mOS of patients who received ra- in 13 patients. Rates of local, local and distant, and distant relapses diotherapy was 17.00 months (95% CI = 3.02–30.98, n = 24) ver- were 8% (2 of 13), 31% (3 of 13), and 61% (8 of 13), respectively. sus 11.00 months (95% CI = 0–51.21, n = 7) in those who did not Both isolated local recurrences identified were treated surgically, (log-rank p = .951). There were no grade III–IV toxicity associated and one patient presented afterward distant metastasis.22 A variety of with radiotherapy reported. second-line chemotherapy regimens have been used (see Tables 1, 2). © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 63 Capote et al. Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 TABLE 3. Survival Outcomes According to Local Approach Treatment in Patients With Small Cell Carcinoma of Vagina Treated With Radical Intention Mean diameter No. cases Median OS No. case of primary tumor FIGO stages who received for the whole according to Subgroups of local treatment No. cases (min–max), cm (no. cases) adjuvant CT subgroup, mo Tables 1–3 Surgery ± chemotherapy 7 4 (1–7, n = 4) I (1) 1 11 8, 20a, 21, 24a, 27a, II (2) 1 28, 40 III (3) 1 IVB (1) 1 Radiotherapy ± chemotherapy 10 4 (2–10, n = 7) I (2) 2 12 3, 5, 12, 14a, 15, 16, II (5) 3 18, 25, 30, 34 III (2) 0 IVA (1) 1 Chemoradiation ± chemotherapy 10 5.6 (2–10, n = 9) I (3) 1 17 2, 6, 9a, 26, 28, 29, III (3) 2 31, 32, 36, 37 IVA (2) 1 IVB (2) 1 Surgery plus radiotherapy ± chemotherapy 4 2.5 (0.5–4, n = 3) I (2) 1 29 1, 4, 13, 17 (not concurrent) II (2) 1 a Local relapse. max indicates maximum; min, minimum. In one case, a chemosensitivity and radiosensitivity gene-profiling Contrary to squamous vaginal cancers, the association of HPV test suggested better response to topoisomerase-1 inhibitors and and SmCCV remains largely unexplored. In this review, 3 cases pre- antifolate therapies than to platinum agents or gemcitabine. Thus, sented HPV18 and another case presented a high-risk nonspecified a second line (after savage pelvic radiotherapy) using a combination subtype. Noticeably, high-risk HPV type infection in SmCCC ranges of topotecan, docetaxel, and bevacizumab was chosen, obtaining 50% to 100%, being the HPV18 the more prevalent type.40–42 Con- 14 months of PFS and 34 months of OS.22 sidering that HPV 18 presents highest affinity for glandular and neuroendocrine cells, its hypothetical etiological relationship with SmCCV warrants further research. DISCUSSION According to our results, both surgery and radiation positively An SmCCV is an extremely rare and dismal disease that raises impact on OS, and multimodal local approaches seem to be associ- a diagnostic-therapeutic challenge with scarce literature available. ated with longer survival than any of them alone. Remarkably, mOS In our systematic review based in all English-reported cases of of those who received surgery plus radiation was 29 months and, for SmCCV in Scopus and PubMed, this entity showed a global mOS those who received concurrent chemoradiation, 17 months. On the of 12 months. Nevertheless, most stage I patients were alive at time contrary, those patients treated with one only local approach, either of report, while all patients diagnosed of stage II–IVB died from me- surgery or radiotherapy, ranged 11–12 months (see Table 3). These tastatic extension (see Figure 3). Remarkably, we found a case with a observations are consistent with literature: chemoradiation has stage II disease treated with local therapies and only 2 cycles of classically shown its superiority to radiation alone in other SmCC carboplatin/paclitaxel that survived 77 months.4 Noticeably, diagno- and locally advanced squamous cervical carcinomas, and recent sis was done in a routine gynecologic examination (without prior re- reports of SmCCC showed that postoperative radiation seems to ported symptoms), and tumor diameter is undescribed. achieve better outcomes compared with surgery alone.43,44 In ad- One hypothesis for this dismal prognosis, accepted for other dition, lower locoregional failure and higher OS rates (5-year SmCC, is that subclinical metastatic focus could be present even 78%) have been described for SmCCC patients who received pri- in apparently stage II disease. Importantly, we identified 3 patients mary chemoradiation in comparison with primary surgery (5-year with para-aortic dissemination without pelvic or inguinal nodal in- OS 46%), except for tumors less than or equal to 2 cm and no volvement (see Tables 1, 2). Therefore, we strongly recommend lymph-vascular space invasion (5-year OS of 89% with primary performing a complete gynecologic examination and a full-body surgery).45 However, the role of postoperative radiation in gyne- PET-CT scan, also according to general recommendations of the cologic SmCC, particularly when there is a negative lymphade- Society of Gynecologic Oncology for gynecologic SmCC.38 His- nectomy, remains to be defined. torical data of this review (back to 1984) would explain the low re- We found that complementary platinum-based regimens ported percentage of performed PET-CT, as well as of MRI. seem to improve OS in locally treated SmCCV, consistent with A PET-CT also allows to rule out other SmCC primaries with the well stablished role of complementary/adjuvant chemotherapy higher incidence, because SmCCV is a diagnosis of exclusion. in other SmCC,46,47 particularly cisplatin plus etoposide. This reg- Neuroendocrine markers, despite not being mandatory for the diag- imen was, in fact, the most frequently used in this series, also con- nosis of a neuroendocrine carcinoma in the last 2014 World Health currently to pelvic radiation (similarly to schemas used for con- Organization classification, may be also useful. Of note, positivity current chemoradiation in SmCLC). However, gastrointestinal of CD56, chromogranin A, and synaptophysin could potentially dif- toxicity is the most relevant adverse event to take into consider- fer from SmCC of the cervix (SmCCC, 18.3%, 63.6%, and 63.6%, ation when evaluating pelvic chemoradiation with this schema. vs 90%, 90%, and 90%, respectively) or SmCLC (90%, 90%, and Although very few reports included in this review specified dos- 60%),39 but this issue remains to be fully explored. ages, MD Anderson's protocol for gynecologic SmCC consists 64 © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 Vaginal Neuroendocrine Cancer: A Review of cisplatin 60 mg/m2 day 1 plus etoposide 100 mg/m2 days 1–3 Regarding follow-up, the Society of Gynecologic Oncology every 3 weeks, up to 6 cycles (2 concurrent to radiation).48 Figure 4 guidelines38 for gynecologic SmCC emphasize the importance of summarizes authors' recommendations regarding diagnostic and a close surveillance, including vaginal, cervical, rectal, inguinal, treatment of SmCCV, integrating our findings and information and supraclavicular examinations, as well as body imaging (CT or from other SmCC. Because only 6% of patients in this series pre- PET-CT scan). We think that HPV test could be recommended if sented central nervous system metastases (n = 3) compared with it was positive at diagnosis.51 20%–60% of SmCLC patients,49,50 we do not recommend pro- For relapsed SmCCV patients, individualized management phylactic brain radiation. would be recommended.38 For isolated local relapses, salvage FIGURE 4. Proposal of staging and management algorithm for patients with SmCCV. BGLND, bilateral groin lymph node dissection; BPLND, bilateral pelvic lymph node dissection; BT, brachytherapy; CDDP, cisplatin; EBRT, external beam radiation therapy; ETO, etoposide; IMRT, intensity-modulated radiation therapy; M, metastases; N, ganglionar status; RH, radical hysterectomy; T, tumor. *The FIGO 2009 stage. **If possible 6 cycles of chemotherapy. © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP. 65 Capote et al. Journal of Lower Genital Tract Disease • Volume 27, Number 1, January 2023 surgery and/or radiotherapy could be considered, always followed 4. He Y, Zhao H, Li XM, et al. A clinical analysis of small-cell by systemic treatment. Unfortunately, most relapsed patients will neuroendocrine carcinoma of the gynecologic tract: report of 20 cases. Arch eventually die because of distant progressions. Regarding systemic Gynecol Obstet 2019;299:543–9. treatment, after progression to platinum or if it is not an option (i.e., 5. Scully RE, Aguirre P, DeLellis RA. Argyrophilia, serotonin, and peptide in case of renal impairment), single agents used in SmCLC such hormones in the female genital tract and its tumors. Int J Gynecol Pathol as topotecan, paclitaxel, or docetaxel can be considered, despite 1984;3:51–70. their poor outcomes.52 Of note, the combination of topotecan 6. Kitazono I, Akahane T, Sakihama M, et al. Human papilloma virus 18– (0.75 mg/m2 on days 1–3), paclitaxel (175 mg/m2 on day 1), and positive submucosal small cell neuroendocrine carcinoma of the vagina: an bevacizumab (15 mg/kg on day 1 on a 21-day cycle) was associated immunohistochemical and genomic study. Int J Surg Pathol 2021;29: with a significant improvement in PFS (8 vs 4 months)52 compared 870–6. with other regimens in a retrospective analysis of 33 patients with 7. Joseph RE, Enghardt MH, Doering DL, et al. Small cell neuroendocrine SmCCC treated with primary chemotherapy. Outstandingly, the carcinoma of the vagina. Cancer 1992;70:784–9. case 3022 of this review used a similar combination (topotecan, docetaxel, and bevacizumab) in a relapsed patient, based on a 8. Colleran KM, Burge MR, Crooks LA, et al. Small cell carcinoma of the gene-profiling test, obtaining a PFS of 14 months. vagina causing Cushing's syndrome by ectopic production and secretion of ACTH: a case report. Gynecol Oncol 1997;65:526–9. Improving the efficacy of systemic treatments is a priority for all SmCC. Currently, immunotherapy is being intensively investi- 9. Hayashi M, Mori Y, Takagi Y, et al. Primary small cell neuroendocrine gated in this area,53,54 also for recurrent gynecological SmCC.55 carcinoma of the vagina. Marked effect of combination chemotherapy: a In our study, we identified a report on RRx-001 (a M2-to-M1 mac- case report. Oncology 2000;58:300–4. rophage stimulating agent) as maintenance after cisplatin/etoposide 10. Ochsenreither S, Marnitz-Schultze S, Schneider A, et al. Extrapulmonary as first line,28 but progression was observed after 6 weeks of treat- small cell carcinoma (EPSCC): 10 years' multi-disciplinary experience at ment. Importantly, HPV-related carcinogenesis could be the rational Charité. Anticancer Res 2009;29:3411–5. to further develop immunotherapy. 11. Tamura R, Yokoyama Y, Kobayashi A, et al. 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