Primary poorly differentiated carcinoma of the vagina with focal neuroendocrine differentiation: a tumour with aggressive behaviour

Abstract

Primary vaginal neuroendocrine tumours are extremely rare but aggressive. We report a case of primary poorly differentiated vaginal carcinoma with focal neuroendocrine differentiation. The clinical stage was cT3N1M0, FIGO stage III. The patient received six cycles of cisplatin-based concurrent chemoradiation therapy (CCRT) followed by six cycles of adjuvant chemotherapy (IEP protocol: ifosfomide, epirubicin and cisplatin). Pelvic MRI scans obtained after treatment completion revealed no residual tumour in the vagina. However, the patient experienced severe dyspnoea 2 months later. Chest X-ray revealed a reticulonodular interstitial pattern over bilateral lungs with suspicion of lymphangitic carcinomatosis. Further chest, abdominal and pelvic CT scans showed bilateral lung metastases with multiple mediastinal, left lower neck and left axilla, intra-abdominal and pelvic lymphadenopathies. For this rare tumour, cisplatin-based CCRT followed by IEP protocol adjuvant chemotherapy may have a limited treatment effect. Further studies are necessary to provide more information on clinical management.

Background

Primary vaginal cancer is rare and consists of only 1%–2% of all malignant neoplasms of the female genital tract.^{1 2} However, the vagina is a common site of metastatic gynaecological cancer (eg, cervical cancer and endometrial cancer) either by direct extension or through haematogenous/lymphatic spread. Non-gynaecological tumours can also metastasise or directly extend to the vagina, while the origin of the tumours includes not only nearby organs, such as the bladder and rectum but also occasionally distant organs, such as the lung and breast.^{1 3} Therefore, primary vaginal malignancies should be classified only after excluding possible metastatic tumours of other origin.²

Primary gynaecological neuroendocrine tumours (gNETs) are also rare. According to the Surveillance, Epidemiology and End Results (SEER) cancer registry from 1987 to 2012 in the United States, gNET accounted for only approximately 2% of all gynaecological malignancies, and the cervix was the most frequent site, followed by the ovaries and uterus.⁴ Gibbs et al found that approximately 7% (39 of all 559 cases) of women with gNET had neuroendocrine tumours (NETs) of the vulva, vagina or other unspecified gynaecological sites. Moreover, the overall incidence of gNET increased over time (0.3 per million in 1987 to 1.30 per million in 2012), but no statistically significant improvement in survival was observed despite continuous progress in cancer-related therapy.⁴

Case presentation

A middle-aged woman was presented with a small, round, pink-coloured, exophytic, firm and tender mass over the posterior orifice of the vagina for 2 months. The tumour had no significant change in size after discovery, and had a tendency to bleed during contact or wiping after urination. The patient had no fever episodes and denied decreased appetite, body weight loss, night sweats, urinary symptoms or gastrointestinal complaints.

The patient had a gynaecological history of endometrioid endometrial adenocarcinoma, pT1aN0M0, grade 2, FIGO stage IA diagnosed 9 months earlier. She had received standard comprehensive staging surgery (including total hysterectomy, bilateral salpingo-oophorectomy, collection washings of the pelvic cavity, pelvic lymph node dissection and para-aortic lymph node sampling) and 2-week courses of adjuvant intravaginal brachytherapy (with 5 Gy to 5 mm submucosa of the vaginal stump, total 20 Gy/4 Fx) and regular follow-up at 3-month intervals. Tumour marker CA-125 was 34.6 U/mL at diagnosis of endometrial adenocarcinoma and ultimately reduced to 6.9 U/mL after intravaginal brachytherapy. Follow-up vaginal Papanicolaou (Pap) smear conducted 6 months after the staging surgery revealed negative results for malignant cells. The patient was also a hepatitis B carrier, and her body mass index was approximately 37 kg/m² (162.1 cm, 97.3 kg). She was sexually inexperienced, a non-smoker and had menarche at age 12. There was no history of gynaecological cancer or breast cancer in her family, and she had an HPV vaccination injection 6 years ago.

Physical examination of the external genitalia showed a small (approximately 2×2 cm), round, pink-coloured, exophytic mass with a smooth surface at five o'clock over her vaginal orifice on inspection (figure 1). There was no abnormal vaginal discharge, erythema or vulvar ulceration. Lymph nodes over her inguinal region were not palpable. On vaginal examination, several (more than three) firm and round masses were palpated in the middle-to-lower third, both anterior and posterior wall of the vagina, and the largest mass was approximately 3 cm in diameter. A vaginal Pap smear was positive for malignant cells (carcinoma).

Figure 1.

The gross appearance of tumour at the lower third and posterior wall of the vagina.

Investigations

Laboratory investigations showed normal haemogram and blood biochemistry values. Tumour marker CA-125 was 5.7 U/mL. Pelvic MRI scan revealed an infiltrative tumour involving the whole vaginal stump, more predominantly in the anterior wall (figure 2). Bilateral inguinal and pelvic sidewall (PSW) lymph node enlargement was also detected, in favour of metastatic lymphadenopathy. Recurrent endometrial cancer was highly suspicious due to her medical history. Further evaluation, including cystoscopy and colonoscopy revealed no tumour invasion in the bladder or rectum. Preoperative assessments, including chest X-ray and ECG, were unremarkable.

Figure 2.

Sagittal view and axial view (T2-weighted image) of the pelvis before treatment shows postoperation status of the comprehensive staging surgery of endometrial cancer and infiltrative tumour involving the whole vaginal stump. Recurrence of endometrial cancer was highly suspicious initially.

Local excision of the visible tumour at the lower third and posterior wall of the vagina was performed under general anaesthesia. Microscopic findings of the specimen revealed tissue with solid nests of poorly differentiated carcinoma cells, which were mainly located in the subepithelial tissue with focal epithelial involvement (figure 3). The tumour is mainly composed of small round tumour cells with scant cytoplasm and vesicular nuclei containing indistinctive nucleoli. Nuclear pleomorphism and mitotic activity are frequently seen with the presence of tumour necrosis (figure 4). Immunohistochemical (IHC) staining of the surgical specimens, including CK7, CK20, synaptophysin (SYP), insulin-associated protein 1 (INSM1), thyroid transcription factor-1 (TTF-1), oestrogen receptor (ER), progesterone receptor (PR), PAX8, neurofilaments and GCDFP15, was conducted and focally positive for CK20, neurofilaments, SYP and INSM1 but negative for the other above specimens (figure 5). The previous specimen of endometrioid endometrial adenocarcinoma was reviewed and showed different morphological features. The above histopathological features were most consistent with poorly differentiated neuroendocrine carcinoma. The final diagnosis was primary poorly differentiated carcinoma of the vagina with focal neuroendocrine differentiation, and the clinical stage was cT3N1M0, FIGO stage III.

Figure 3.

Tissue with solid nests of poorly differentiated carcinoma cells is mainly located in the subepithelial tissue.(H&E stain).

Figure 4.

The tumour is composed of small round tumour cells with scanty cytoplasm and vesicular nuclei containing indistinctive nucleoli. Nuclear pleomorphism and mitotic activity are frequently seen (Papanicolaou stain).

Figure 5.

Immunohistochemical stains for the tumour cells are focally positive for synaptophysin.

Differential diagnosis

The first impression of several exophytic lesions of the vaginal stump after treatment for endometrial adenocarcinoma within 1 year must include recurrent endometrial metastatic cancer, based on our clinical experiences and documentation. The interpretation of pelvic MRI scans was consistent with our suspicion. However, previous endometrioid adenocarcinoma of endometrial specimens revealed different morphological features. In addition, exclusion of several common causes of vaginal bleeding, such as bleeding from other genital tract sites, vaginal atrophy, infection, inflammation and trauma, should also be evaluated. The differential diagnoses mentioned above were excluded by history taking, laboratory tests and pathological analysis.

Treatment

A multidisciplinary treatment approach involving radiation oncologists and gynaecological oncologists suggested a treatment plan including six cycles of weekly low-dose cisplatin-based CCRT followed by six cycles of adjuvant chemotherapy at an interval of 3 weeks. The protocol of chemotherapy was the IEP regimen (ifosfomide, epirubicin and cisplatin).

After discussion with the patient, she underwent CCRT treatment (7200 Gy/33 Fx for vaginal stump tumour, 6600 Gy/33 Fx for bilateral inguinal lymphadenopathies, and 5040 Gy/28 Fx for pelvic lymphadenopathies combined with weekly cisplatin 80 mg infusion for total of 6 weeks) 2 weeks after the pathological diagnosis. The patient had side effects of anal pain and blood-tinged stool with tenesmus 2–4 times a day within 2 days after radiation therapy, which were likely related to acute radiation reaction. After an interval of 2 weeks, she then received six cycles of adjuvant chemotherapy (IEP regimen) for 16 weeks. Mild side effects with nausea and fatigue for 1 day were noticed after each cycle of chemotherapy.

Outcome and follow-up

After completing CCRT treatment, a pelvic CT scan with contrast (9 weeks after pathological diagnosis) revealed that the soft tissue mass at the vaginal stump decreased in size with mild perifocal fat stranding, compatible with post-treatment changes. There was also a regressive change in metastatic lymphadenopathy, including small lymph nodes at the bilateral inguinal, bilateral internal iliac and retroaortic regions. Pelvic MRI scan obtained after whole treatment completion (26 weeks after pathological diagnosis) revealed no definite vaginal tumour and only one borderline-sized lymph node at the left internal iliac region with no significant interval change (figure 6). Vaginal Pap smear revealed negative results for malignant cells. A consensus of intensive surveillance at the gynaecology outpatient department at intervals of 12 weeks after completion of the treatment course was reached with the patient. However, the patient experienced severe dyspnoea 2 months later, and she visited a pulmonologist. Initial chest X-ray revealed a reticulonodular interstitial pattern over bilateral lungs (figure 7). Further chest, abdominal and pelvic CT scans showed bilateral lung metastases with multiple mediastinal, left lower neck, left axilla, intra-abdominal and pelvic lymphadenopathies. Lymphangitic carcinomatosis was the favour diagnosis. Prompt cancer treatment was suggested by the pulmonologist to relieve her respiratory symptoms. She was admitted for first cycle of immunotherapy (pembrolizumab) and target therapy (bevacizumab) 5 days after the findings of CT scan. However, dyspnoea still deteriorated despite cancer-related treatment, bronchodilator and usage of non-rebreathing mask. Acute respiratory distress syndrome occurred 2 weeks after admission, the patient was intubated and transferred to intensive care unit (ICU). In ICU, bronchodilator and empirical antibiotics with piperacillin/tazobactam were administrated. The patient expressed her wish of endotracheal tube withdrawal during clear consciousness. After informing poor prognosis to her family, they agreed with terminal withdrawal of mechanical ventilation and extubation was applied 7 days after transferring to ICU. The patient was pronounced dead in her family’s presence on the same day.

Figure 6.

Sagittal view and axial view (T2-weighted image) of the pelvis. Complete resolution of the vaginal tumour after treatment completion.

Figure 7.

Chest X-ray revealed a reticulonodular interstitial pattern over bilateral lungs with suspicion of lymphangitic carcinomatosis within 2 months after treatment completion.

Discussion

Primary neuroendocrine carcinoma of the vagina is rare and documented in only approximately 30 cases in the English literature.⁵ Given the low incidence of this malignancy, no standard treatment or guidelines have been established, and the majority of current treatment protocols was extrapolated from retrospective case reports or adopted from the treatment of neuroendocrine carcinoma of the cervix.⁶ A multidisciplinary meeting including clinical, pathological and radio-oncological attendants, is crucial for reaching the correct diagnosis and formulating the appropriate and customised treatment plan.

With regard to the immunohistochemical biomarkers of neuroendocrine tumours (NETs), a conventional panel including chromogranin A (CGA), SYP and CD56 is useful for reaching a diagnosis.^{7 8} However, challenges in differential diagnosis may occur due to small or unqualified samples, especially in cases with few cells, crush artefacts or uncertain staining with traditional neuroendocrine biomarkers. Fortunately, recent studies have suggested that insulinoma-associated protein 1 (INSM1) plays an essential role in the development of neuroendocrine differentiation in various tissues and therefore provides an exceptional diagnostic value for NETs.^{7 8} The major advantage of INSM1 is its high sensitivity, specificity and reliability compared with other traditional neuroendocrine biomarkers.

According to the 2021 National Comprehensive Cancer Network (NCCN) guidelines for extrapulmonary poorly differentiated neuroendocrine carcinoma, surgical resection followed by CCRT with chemotherapy or chemotherapy/radiation therapy alone is the first-line treatment.⁹ For locoregional unresectable lesions, CCRT with adjuvant chemotherapy or chemotherapy alone is recommended. By retrospectively reviewing a series of similar case reports of vaginal neuroendocrine tumours after year 2000 (table 1), CCRT or surgical intervention is the preferred first-line treatment in most conditions, usually followed by chemotherapy or radiation therapy. In terms of chemotherapy, the most frequently used regimen is etoposide and cisplatin/carboplatin (EP regimen) alone or combined with other chemotherapy agents, similar to the chemotherapy protocol used for small cell lung cancer.¹⁰ Kombathula et al referred to the SMCC-2 protocol (cisplatin, etoposide and paclitaxel), the EP-based regimen used originally for cervical small cell carcinoma (SmCC) by Hoskins et al, to treat a case of stage III vaginal small cell carcinoma, which left no evidence of disease 22 months after the diagnosis.^{11 12} Considering other possible treatment options, Kostamo et al used the results of the gene expression profile of tumour tissue and decided on a salvage chemotherapy protocol (topotecan, paclitaxel, and bevacizumab) for vaginal neuroendocrine tumours.¹³ In this case, the patient had a 14-month progression-free survival. Therapy based on molecular profiling may provide a potential benefit in cancer-related treatment.

Table 1.

Summary of similar case reports of vaginal neuroendocrine carcinoma after year 2000

Report	Age	Pathology	Stage	Initial treatment	Outcome	Survival duration after diagnosis
Hayashi et al14	51	Small cell carcinoma	cT1N0M0 stage I	Chemotherapy (cyclophosphamide, pirarubicin and cisplatin)	Stable	≥41 months
Kaminski et al15	69	Small cell carcinoma	cT1N0M0 stage I	CCRT (cisplatin and etoposide) with brachytherapy adjuvant chemotherapy (cisplatin and etoposide)	Died	13 months
Bing et al16	74	Small cell carcinoma	cT3N1M1 stage IV	Chemotherapy (cisplatin and etoposide)	Died	4 months
Bing et al16	55	Small cell carcinoma	pT2N1M0 stage III	Surgery (radical vulvectomy, partial vaginectomy and bilateral inguinal LNs dissection)	Died	4 months
Bing et al16	38	Small cell carcinoma	cT4N0M0 stage IV	CCRT (cisplatin) with both EBRT & brachytherapy	Newly diagnosed	Not determined
Weberpals et al17	61	Small cell carcinoma	cT4N1M1 stage IV	Chemotherapy (cisplatin and etoposide, complicated with diabetes mellitus & retinal haemorrhages, then shifted to epirubicin)	Died	8 months
Khurana et al5	37	No description	pT1N0M0 stage I	Surgery (total vaginectomy and pelvic lymphadenectomy) Adjuvant chemotherapy (cisplatin and etoposide) Adjuvant EBRT	Stable	≥12 months
Kostamo et al13	34	Small cell carcinoma	pT2N0M0 stage II	Surgery (radical hysterectomy, right salpingo-oophorectomy, left oopexy, partial vaginectomy and right pelvic lymphadenectomy)	Died	34 months
Kusunoki et al18	54	Small cell carcinoma	cT1N1M0 stage III	CCRT(cisplatin) with both EBRT & brachytherapy	Stable	≥17 months
Kombathula et al12	65	Small cell carcinoma	cT3N1M0 stage III	Neoadjuvant chemotherapy (cisplatin, etoposide and paclitaxel) CCRT (cisplatin) with both EBRT & brachytherapy Adjuvant chemotherapy (cisplatin, etoposide and paclitaxel)	Stable	≥22 months
Shimazaki et al19	51	Small cell carcinoma	pT1NXM0 stage I	Surgery (resection of vaginal wall including vaginal cut edge) Adjuvant chemotherapy (cisplatin and irinotecan)	Stable	≥15 months

CCRT, concurrent chemoradiation therapy.

In our case, local excision of the visible tumour was conducted rather than total vaginectomy and pelvic lymphadenectomy due to the locally advanced stage. IHC staining of the tumour was focally positive for CK20, neurofilaments, SYP and INSM1, enhancing the accuracy of the diagnosis of neuroendocrine tumours. A consensus on a multimodality therapeutic plan was six cycles of weekly low dose cisplatin-based CCRT and six cycles of adjuvant chemotherapy (IEP regimen) postoperatively. The tumour appeared to have a good response to our therapeutic strategy initially, as the follow-up pelvic MRI scan obtained after treatment completion revealed no residual tumour in the vagina. However, recurrence of this aggressive malignancy occurred within 2 months and the patient died 1 month after recurrence. For this case, cisplatin-based CCRT followed by IEP protocol adjuvant chemotherapy may have had limited therapeutic effects.

In conclusion, CCRT or surgical intervention is by far the most commonly used first-line treatment for vaginal neuroendocrine carcinoma, usually followed by chemotherapy. However, there is no established chemotherapy regimen for patients with vaginal neuroendocrine carcinoma, although etoposide and cisplatin/carboplatin (EP regimen) alone or combined with other chemotherapy agents is the most frequently used regimen, and IEP protocol adjuvant chemotherapy may have had limited therapeutic effects based on our experience in this case. The standard treatment strategy based on randomised trials for vaginal neuroendocrine tumours is also limited given the condition’s rarity, and further studies are necessary to provide more information on clinical management.

Learning points.

• No standard treatment strategy or guidelines have been established for vaginal neuroendocrine carcinoma. Concurrent chemoradiation therapy (CCRT) or surgical intervention is the most preferred first-line treatment to date, usually followed by adjuvant chemotherapy or radiation therapy.

• A multidisciplinary meeting including clinical, pathological and radio-oncological attendants, is crucial for reaching the correct diagnosis and formulating the appropriate and customised treatment plan.

• For vaginal neuroendocrine carcinoma, cisplatin-based CCRT followed by IEP (ifosfomide, epirubicin and cisplatin) protocol chemotherapy may have limited treatment effect.

Ethics statements

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