Primary small cell carcinoma of the vagina: a rare instance of prolonged survival

Abstract

Small cell carcinoma (SmCC) of the vagina is a rare and aggressive tumour. It comprises only 1% –2% of all gynaecological malignancies 85% of the patients with SmCC vagina die within a year of diagnosis. Here we report the case of a 65-year-old woman with stage III primary neuroendocrine carcinoma of vagina who was treated with chemoradiotherapy. The patient survived 1 year and 10 months after the initial presentation. SmCC of the vagina is very rare and despite being aggressive, the local disease can be controlled with a chemoradiation regimen.

Background

Small cell carcinoma (SmCC) comprises only 1%–2% of all gynaecological malignancies.¹ The median survival is 11 months.² Eighty-five per cent of the patients with SmCC vagina die within 12 months of diagnosis.³ SmCC is a well established and common histological variant in carcinoma lung. But extra-pulmonary SmCC is rare and accounts for only 2.5% –5% of all SmCCs reported in the USA and an even meagre 0.1%–0.4% of all cancers.⁴ After an extensive search in the PubMed and MEDLINE database, we could find only 31 reported cases of primary SmCC of the vagina.^5–7 Since the entity is so rare and sparsely studied, there is no established line of management. In this case report, we discuss the investigations, histopathology, and treatment options for this condition. This patient has been treated with the SmCC-2 protocol which was originally used to treat SmCC of the cervix.⁸

Case presentation

A 65-year-old woman who was a known case of hypertension and diabetes presented with pain in the vulval region and difficulty passing stools for 5 months. She had occasional white discharge from the vagina. She denies any history of blood in stools or difficulty in passing flatus.

She had no family history of malignancy.

Investigations

On examination, a growth was palpable in vagina involving the posterior wall reaching close to the introitus. The growth was not extending to involve the cervix. The right para-vaginal tissue was involved up to the pelvic sidewall and the left was involved medially. The growth was protruding into the rectum but the rectal mucosa was uninvolved.

Colonoscopy showed an extraneous mucosal bulge ~6 cm starting from anal verge along the anterior wall. Mucosa overlying the bulge was normal.

Contrast-enhanced computerised tomography (CECT) revealed that the mass is ill-defined and heterogeneously enhancing with infiltration of right lateral fornix and loss of fat plane with anterior rectal wall without the involvement of bladder neck and urethra.

MRI showed a 6.6×7×9 cm mass involving the posterior, lateral walls of the vagina, bilateral paravaginal tissues and anterior wall of the rectum without involving the rectal mucosa. The cervix was free of any disease.

Several enlarged nodes were seen in obturator, inguinal and bilateral external iliac lymphatic stations, largest being an external iliac node of 2×1.4 cm (figure 1, figure 2).

Figure 1.

MRI showing growth in the posterior vaginal wall indenting onto the anterior wall of the rectum. The cervix is visualised to be free of the growth.

Figure 2.

CECT image showing heterogeneously enhancing growth involving the posterior vaginal wall.

A biopsy from the vaginal growth when examined, showed fragments partly lined by stratified squamous epithelium. Subepithelium shows infiltration by rent and island of malignant cells with a high nuclear-cytoplasmic ratio, hyperchromatic nuclei with scanty to moderate eosinophilic cytoplasm. Mitotic figures are 2–3/high power field, suggestive of primary neuroendocrine carcinoma. Immuno-histochemistry staining is positive for synaptophysin and CD 56 and negative for p63 (figure 3, figure 4). Bone marrow aspirate showed no evidence of spread to the marrow. Markers for HIV and HBsAg were negative.

Figure 3.

Pleiomorphic cells with hyperchromatic nuclei.

Figure 4.

Cells showing synaptophysin positivity.

Differential diagnosis

The most probable diagnosis with the above presentation, especially in Indian women will be carcinoma cervix, as it is the second most common malignancy in the women of India. The absence of a cervical growth makes the diagnosis of carcinoma cervix unlikely. The next more common differential diagnosis would be carcinoma of the vulva which is also free of disease in this case. It is highly unlikely that a benign condition presents with such a clinical picture of infiltration into surrounding structures.

Treatment

She was planned to receive a regimen of SMCC-2 protocol (table 1).

Table 1.

Details of the regimen used

Cycle #	Drugs	Dosage	Regimen
Cycle A	Inj. paclitaxel IV	175 mg/m2	Day 1
	Inj. cisplatin IV	60 mg/m2	Day 1 and 2
Cycle B	Inj. cisplatin IV	60 mg/m2	Day 21 and 22
	Inj. etoposide IV	75 mg/m2	Day 21 and 22
	Tab. etoposide PO	100 mg	Days 23–25
Cycle C		XBRT 46Gy/23 # f/b 7Gy x 2# linear HDR f/b 10Gy/5# Posterior oblique boost
	Concurrent Inj. cisplatin IV	60 mg/m2	Days 42, 56, 70, 84
Cycle D	Inj. paclitaxel IV	175 mg/m2	Day 98
	Inj. carboplatin IV	AUC-5	Day 98
Cycle E	Tab. etoposide PO	100 mg	Days 126 and 130
	Inj. carboplatin IV	AUC-5	Day 126

IV, intravenous; PO, per oral.

She received neoadjuvant chemotherapy (NACT) with taxane and cisplatin followed by cisplatin and etoposide. After the completion of NACT, she received concurrent chemoradiotherapy, 46Gy in 23 fractions which were followed up with two linear high dose rate (HDR) brachytherapy applications of 7Gy each and finally a posterior oblique boost of 10Gy in five fractions. Concurrently with external beam irradiation, she received cisplatin every 2 weeks at a dose of 60 mg/m². The external beam radiotherapy was delivered using three dimensional conformal radiotherapy and brachytherapy was delivered using a point based plan. Following concurrent chemoradiation, she received adjuvant chemotherapy with paclitaxel and etoposide which was succeeded by another cycle of cisplatin and etoposide.

External beam radiation target volumes

Gross tumor volume (GTV) tumor – Contrast enhancing gross disease visualised in the simulation images.

Clinical target volume (CTV) tumor – 2 cm margin to the GTV tumour in all directions excluding bone and muscles.

CTV nodes – Includes bilateral common iliac, external iliac, internal iliac, obturator, presacral and inguinal regions with standard margins around the vessels making sure that all the involved nodes are engulfed by the volume.

CTV – Combination of CTV tumour and CTV nodes.

PTV – 1 cm margin to CTV in all directions.

She received a dose of 46 Gy in 23 fractions to the PTV (figure 5, figure 6).

Figure 5.

Coronal section showing the external beam radiotherapy dose deposition.

Figure 6.

Sagittal section showing the external beam radiotherapy dose deposition.

After the completion of cycle C, a local examination showed a clinical partial response with a residual lesion of 2×3 cm, involving posterior vaginal wall with induration of right paravaginal tissue medially. The rest of the vaginal walls and the left paravaginal tissue were free of the growth.

Outcome and follow-up

CECT after 6 months of treatment completion showed a nodular thickening of the lower vagina with an ill-defined nodule ~1.2×2.2×1.5 cm with intact fat planes with the anal canal (figure 7).

Figure 7.

Post-treatment CECT image showing resolution of the vaginal wall lesion.

Biopsy from the nodule showed acanthotic stratified squamous epithelium and areas of haemorrhage with no evidence of dysplasia or malignancy.

Twenty-two months after the diagnosis, the patient has no evidence of disease and symptomatically normal. She developed grade two proctitis after 3 weeks of radiotherapy and was managed conservatively.

Owing to the aggressive nature of the disease and higher chances of distant failure, we plan to keep her in close follow-up and imaging every 6–8 months. Though frequent imaging is noted to increase the risk of over-treating the patient, we feel this is a risk worth taking in such aggressive tumours.

Discussion

SmCC vagina generally occurs in the postmenopausal age group and presents with vaginal discharge, metastatic symptoms or leucorrhoea.^{5 9} This patient presented to us with difficulty in passing stools due to the obstruction of the lumen by the extraneous mass.

Examination of the patients commonly reveals a vaginal growth. The only documented case with multiple vaginal nodules was reported by Miliauskas and Leong in 1992.¹⁰

Bing et al, in their review of the reported SmCC vagina cases, reported that only 2 out of 23 cases reported until 2004 had lymph nodal involvement, one of which had distal metastases also. They also noted that 3 out of 23 had distant metastases at diagnosis and 6 cases had unknown nodal status while there were three cases with no documentation regarding the status of distal metastases. The most common mode of treatment failure is distant metastasis.¹¹ This patient had pelvic and inguinal lymphadenopathy at presentation.

Since the condition is very rare, standard guidelines have not yet been formulated. The general modality of treatment with a radical intent has been surgical excision with dissection of involved fields of nodes followed by adjuvant chemoradiation depending on the performance status of the patient. When treated with palliative intent, the modality has been chemoradiation. The cases reported until now have tried out several variations in the lines of management for this condition. Hayashi et al, have treated a case of stage I SmCC vagina with a combination chemotherapy regimen (cyclophosphamide, pirarubicin and cisplatin) and the patient achieved complete response with a disease-free survival of 41 months, the longest documented survival with this disease.¹²

The cases presenting with lymph nodal or distant metastases have had a low median survival (<6 months) despite the multimodality treatment. This points to a correlation between the stage of the disease and survival. The cases belonging to stage III discussed in the review by Bing et al had a maximum survival of 13 months.¹¹ Relative to the finding, this patient has survived for 22 months.

Kaminski et al have reported the first case of SmCC vagina having a residual disease post concurrent chemoradiation.¹³ The residual disease was boosted with a brachytherapy regimen.

In 2011, Society of Gynaecologic Oncology released a clinical document discussing the neuroendocrine tumours of gynaecological tract in which, it was suggested to treat SmCC vagina with radical excision in suitable cases and with platinum and etoposide-based chemotherapy in advanced cases.³ In accordance to it, we followed the SMCC-2 protocol used originally for SmCC cervix by Hoskins et al.⁸ SmCC, whichever the organ of origin may be, is more predisposed to cause paraneoplastic syndromes, particularly Cushing’s syndrome. Until, there have been two reported cases of SmCC vagina presenting with Cushing’s syndrome due to ectopic production of ACTH by tumour cells.^{14 15} This condition may be fatal and warrants vigilance from the treating physician (table 2).

Table 2.

Summary of similar case reports

Report	Stage	Treatment	Survival
Miliauskas and Leong10	T2N0M0	Right hemivagino-vulvectomy and right-side inguinal node dissection	10 months
Kaminski et al 13	T1N0M0	Chemoradiation with cisplatin and etoposide	13 months
Colleran et al 14	T2N0M0	Chemoradiation with cisplatin and etoposide	17 months
Weberpals et al 15	T3N1M1	Chemotherapy with cisplatin and etoposide	8 months
Bing et al 11	T3N1M0	Palliative radiotherapy alone	4 months
Bing et al 11	T2N1M0	Radical vagino-vulvectomy and bilateral node dissection	4 months
Bing et al 11	T4N0M0	Chemotherapy with cisplatin and etoposide	>5 months

TNM, tumour, node, metastases.

Learning points.

• Small cell carcinoma of the vagina is an aggressive entity with a very short median survival.

• Clinical examination plays a vital role in the diagnosis of carcinoma vagina.

• Advanced stage primary small cell carcinoma of the vagina can be treated with concurrent chemoradiation combined with anterior and posterior chemotherapy.

• Clinicians should be wary of such lesions presenting with paraneoplastic manifestations.