Neuroendocrine carcinoma of vagina with prolonged survival

Abstract

We report the case of a woman in her 70s with a stage IVA small cell neuroendocrine carcinoma of the vagina. The patient started chemotherapy with cisplatin and etoposide followed by concurrent chemoradiotherapy and adjuvant chemotherapy. Pelvic MRI after completion of treatment did not show residual disease. Three years and 8 months after definitive treatment, the patient remains on regular follow-up without evidence of disease.

Background

Small cell neuroendocrine carcinoma (SCNC) is a highly proliferative disease. It commonly arises in the lung and only 2.5%–5% are extrapulmonary.^1–3 Primary SCNC of the female genital tract constitutes less than 2% of all gynaecological cancers.^4–6 It has been reported in the cervix, endometrium, ovary, vagina and vulva. SCNC of the vagina is a very rare entity with a dismal prognosis.² The mean age at diagnosis is 59 years,⁶ and the most common symptom is postmenopausal bleeding.⁷ Due to its rarity and lack of data, there are no established treatment guidelines. We report a case of SCNC of the vagina, its treatment and follow-up.

Case presentation

We report the case of a woman in her 70s, gravida 4, para 1, stillbirth 1 and abortus 3, with Eastern Cooperative Oncology Group performance status of 0, with a medical history of hypertension, transient ischaemic attack, peripheral vertigo and bilateral oophorectomy and hysterectomy 25 years earlier, for unknown reasons. No family history of cancer was found.

The patient presented with pruritus and vaginal bleeding for 1 month, with no pain or abnormal smell. On gynaecological examination, a haemorrhagic lesion was observed in the anterior wall of the vagina and a biopsy was performed. Pathology identified small cells with dispersed chromatin nuclei and visible nucleolus, scarce cytoplasm with undefined limits in a lobulated growth, extensive necrosis and high mitotic index (60 mitoses per 10 high-power fields), with atypical mitoses. On immunohistochemistry examination, tumour cells were positive for AE1/AE3, CD56 and synaptophysin, and negative for chromogranin, CD10, CD45, CD99, vimentin, desmin and actin. Ki67 index was >90% (figure 1). Therefore, the histology was consistent with SCNC.

Figure 1.

Histology showed a high-grade carcinoma with positive neuroendocrine markers, abundant mitotic figures and a proliferative index of >90%, consistent with SCNC. SCNC, small cell neuroendocrine carcinoma.

Rectal examination showed no involvement of the parametrium. A pelvic MRI revealed a 60 mm lesion with external bladder invasion and regional lymph nodes involvement (figure 2). Cystoscopy revealed no extramural transgression. A positron emission tomography scan showed a lesion in the vagina, enlarged bilateral external iliac lymph nodes and no evidence of metastatic disease. Therefore, the final diagnosis was a stage cT4N1M0–IVA SCNC of the vagina.

Figure 2.

Pelvic MRI with a 60 mm lesion (T2 sagittal), external bladder invasion (T2 sagittal) and regional lymph node involvement (T2 axial).

Tumour board discussion proposed concurrent chemotherapy and radiotherapy. The patient underwent two cycles of intravenous cisplatin 80 mg/m² on D1 and etoposide 100 mg/m² on D1–D3, followed by concurrent chemotherapy (two cycles of 3 weekly cisplatin and etoposide) in addition to radiation therapy with 28 external beam fractions to the tumour and lymph nodes of 1.8 Gy each and a boost of 8 fractions of 2 Gy each on the tumour. After concurrent chemoradiotherapy, the patient received two more cycles of cisplatin and etoposide.

Despite acute grade 1 asthenia and grade 1 peripheral sensory neuropathy, the treatment was well tolerated, and the patient became asymptomatic from the presenting symptoms. No dose reduction or interruption was necessary.

Outcome and follow-up

Pelvic MRI performed 6 weeks after completion of treatment did not show residual disease. She was kept on regular follow-up, with gynaecological examination every 4–6 months and pelvic MRI and chest and abdominal CT scans every 6 months. Three years and 8 months after definitive chemoradiotherapy, the patient has no evidence of disease, remaining asymptomatic with good quality of life.

Discussion

SCNC of the vagina was first reported by Scully et al in 1989.⁸ It is a very rare and aggressive disease with no standard treatment and the majority of the patients die within a year of diagnosis.³ Since female genital tract and lung SCNC have similar pathological features,⁴ treatment of non-metastatic disease often includes a combination of etoposide/platinum-based chemotherapy and radiotherapy.³ Due to its rarity, there is no consensus about the optimal therapy of SCNC of the vagina. There are other described therapeutic options according to staging, such as radiation therapy of the lung and prophylactic cranial irradiation, which may cause cognitive impairment and compromise quality of life.⁹

A summary of the literature regarding SCNC of the vagina is shown in table 1. Forty-nine patients with primary SCNC of the vagina have been reported in 38 English-language articles to date, with a mean age at diagnosis of 54 years. The most common symptom at presentation was bleeding (23 patients). Of the described patients, 12 were International Federation of Gynecology and Obstetrics (FIGO) stage I, 12 FIGO stage II, 12 FIGO stage III and 11 FIGO stage IV. Twenty-four patients died, 15 of them (63%) within 1 year of diagnosis.

Table 1.

Summary of SCNC of the vagina case reports in literature

Literature	Year of publication	No of patients	Age range (years)	Presentation	FIGO stage	Primary therapy	Chemotherapy used	Secondary therapy	Outcome	Survival (months)
Scully et al8	1984	1	Histopathological study without clinical details
Peters et al10	1985	5	60s (mean)	ND	II (2) III (2) IV (1)	ND		ND	Died	12 (median)
Fukushima et al11	1986	1	30s		II	RT		CT	Died	12
Ulich et al12	1986	1	Histopathological study without clinical details
Hopkins et al13	1989	3	40s 60s 70s	Bleeding Bleeding Mucoid discharge	II IVB IVB	RT, BT RT, CT CT	Doxorubicin, cyclophosphamide cisplatin, methotrexate	CCRT	Died Died Died	29 5 9
Chafe14	1989	2	70s 70s	Constipation Tenesmus bleeding	II II	RT RT		CT RT	Died Died	15 11
Rusthoven and Daya15	1990	1	60s	Bleeding	II	CT, RT	Etoposide, cisplatin	RT	Died	≈8
Joseph et al16	1992	1	60s	Asymptomatic	I	S, CT, BT	Vincristine, doxorubicin, cyclophosphamide		Alive	24 or more
Prasad et al17	1992	1	30s	Asymptomatic	II	S, CT, BT	Cisplatin, etoposide		Died	6
Miliauskas and Leong18	1992	1	70s	Vaginal discharge	III	S		S	Died	10
Colleran et al19	1997	1	50s	Bleeding	I	CCRT	Cisplatin, etoposide		Died	26
Mirhashemi et al20	1998	1	30s	Dyspareunia	III	CT, RT	Cisplatin, etoposide		Alive	6 or more
Elsaleh et al21	2000	1	50s	Bleeding	III	CCRT	Carboplatin, etoposide		Died	14
Hayashi et al4	2000	1	50s	Bleeding	I	CT	Cyclophosphamide, pirarubicin hydrochloride, cisplatin		Alive	41 or more
Kaminski et al22	2003	1	60s	Spotting	I	CCRT, BT	Cisplatin, etoposide	CT	Died	13
Bing et al23	2004	3	70s 50s 30s	Bleeding Spotting Rectal pain	IVB III IVA	CCRT S CCRT, CT, BT	Cisplatin, etoposide cisplatin, etoposide	CT	Died Died Alive	4 4 5 or more
Petru et al24	2005	1	50s	Bleeding	II	S, CT	Cisplatin, etoposide, epirubicin		Died	11
Coleman et al25	2006	1	60s	Pain, bleeding	IVB	RT, CT	Cisplatin, etoposide	CT	Died	8
Weberpals et al26	2008	1	60s	Vaginal discharge, bleeding	IVB	CT	Cisplatin, etoposide		Died	8
Bhalodia et al27	2011	1	50s	Difficulty in urination	I	S			ND	ND
ElNaggar et al28	2012	1	30s	Dyspareunia, bleeding, vaginal discharge	IVB	CT	Cisplatin, etoposide	CT, RT	Died	11
Khurana et al5	2013	1	30s	Bleeding	I	S, CT, RT	Cisplatin, etoposide		Alive	12 or more
Oliveira et al29	2013	1	40s	Vaginal discharge	III	CT, RT, BT	Cisplatin, etoposide		Alive	5 or more
Tamura et al30	2013	1	80s	Bleeding	I	RT			Alive	20 or more
Jain et al31	2016	2	30s ND	ND ND	II I	S, CT, RT S±adjuvant treatment	Cisplatin, etoposide		Alive Alive	67 or more 31.7 (median)
Vatankulu et al32	2016	1	30s	Pain, bleeding	IVA	CT	Cisplatin, etoposide		ND	ND
Yan et al33	2016	1	40s	Vulvar mass, bleeding	IVB	CCRT, BT, CT	Paclitaxel, cisplatin		Alive	21 or more
Brzezniak et al34	2017	1	50s	ND	III	CCRT	Cisplatin, etoposide	IO	Died	7.5
Haykal et al35	2018	1	50s	Bleeding	I	CT, CCRT	Cisplatin, etoposide		Alive	Under treatment
Kostamo et al7	2018	1	30s	Asymptomatic	II	S		CT, RT	Died	34
Kusunoki et al36	2018	1	50s	Bleeding	III	CCRT, BT	Cisplatin		Alive	17 or more
He et al37	2019	1	40s	Mass	II	S, CT	Paclitaxel, carboplatin		Died	77
Kombathula et al3	2019	1	60s	Pain	III	CT, CCRT, BT	Taxane, cisplatin, etoposide		Alive	22 or more
Shimazaki et al38	2020	1	50s	Bleeding	I	S, CT	Irinotecan, cisplatin		Alive	11 or more
Kitazono et al39	2021	2	70s 70s	Bleeding Bleeding	I IVB	CCRT S to primary, CT			Alive Alive	8 or more 8 or more
Kumari et al2	2021	1	50s	Bleeding	III	RT, CCRT	Cisplatin, etoposide	BSC	Died	14
Inzani et al40	2022	1	40s	Bleeding	I	S			ND	ND
Mai et al41	2022	1	Middle-aged	Mass	III	S, CCRT, CT	Cisplatin, ifosfamide, epirubicin	IO, TT	Died	21
Present study	2022	1	70s	Pruritus, bleeding	IVA	CT, CCRT	Cisplatin, etoposide		Alive	44 or more
Total	39 articles	50 patients

BSC, best supportive care; BT, brachytherapy; CCRT, concurrent chemoradiation therapy; CT, chemotherapy; FIGO, International Federation of Gynecology and Obstetrics; IO, immunotherapy; ND, no description; RT, radiotherapy; S, surgery; SCNC, small cell neuroendocrine carcinoma; TT, target therapy.

Cisplatin–etoposide was the most common chemotherapy regimen, used in 21 cases (42%), in the adjuvant setting, with concurrent radiotherapy or in metastatic setting. Due to the heterogeneity of the reported cases, the rarity of the disease and the absence of prospective studies, it is difficult to conclude which should be the preferred treatment.

Our patient was treated with cisplatin–etoposide chemotherapy followed by concurrent chemoradiotherapy with an external beam radiotherapy boost. Surgery was not an option as this was a locally advanced disease with bladder invasion (FIGO stage IVA), whose cases are associated with less favourable outcomes with surgery as primary treatment modality. A radiotherapy boost was given after taking into consideration tumour size, bladder invasion and constraints in the availability of interstitial brachytherapy. Despite the locally advanced disease, she remains free of relapse after 44 months.

Learning points.

• Small cell carcinoma of the vagina is a rare disease with a dismal prognosis.

• There is no established standard treatment of small cell neuroendocrine carcinoma of the vagina.

• Locally advanced small cell carcinoma of the vagina can be treated with cisplatin and etoposide concurrent chemoradiotherapy.

Ethics statements

Patient consent for publication

Obtained.