Primary vaginal small cell carcinoma is an extremely rare disease. There have been only 25 previously reported cases in the English literature. Regardless of the extent of disease at presentation, most patients die within two years of diagnosis from distant metastatic disease.
A 39 year old Hispanic woman presented to our institution with vaginal pain. A firm mass was palpated on the distant vaginal wall on gynecological examination. Examination of the vagina with speculum confirmed the presence of an ulcerated mass. Biopsy of this suspicious mass revealed small cell carcinoma suggestive of metastasis from a lung primary. She was subsequently diagnosed with Stage 1 (T1N0M0) small cell carcinoma of the vagina. Immunohistochemistry showed tumor cells positive for cytokeratin, chromogranin, synaptophysin, NSE and thyroid transcription factor 1 (TTF1). She received chemoradiation and is alive and without evidence of disease 10 months after diagnosis.
To our knowledge this is the first reported case of a primary vaginal small cell carcinoma in a patient with Hepatitis C and is the second case in the literature with tumor cells positive for TTF1. Primary small cell neuroendocrine carcinoma of the vagina has histologic, immunohistochemical and ultrastructural features similar to those of its pulmonary counterpart. Because thyroid transcription factor 1 can be positive, it should not be used to differentiate primary from metastatic disease. Concurrent chemoradiation is superior in local control and progression free survival and thus should be considered as primary treatment approach for the management of this extremely aggressive disease.
Primary small cell carcinoma of the vagina is an extremely rare and aggressive malignancy with propensity to early metastases. Only 5 % of small cell carcinomas arise in extra pulmonary sites, 1 accounting for 1-2 % of gynecologic malignancies. 2 3 These tumors have been reported to originate in the cervix, 1 2 endometrium, 3 4 5 6 ovary, 7 vagina, 8 9 10 11 12 13 14 and vulva 15 in decreasing frequency. To our knowledge only 25 cases of small cell carcinoma arising as a primary in the vagina have been reported in the English literature to date. These neoplasms share the same histological, neuroendocrine and immunohistochemical profiles as small cell carcinomas originating elsewhere. We report a case of primary small cell carcinoma of the vagina in a patient with hepatitis C whose tumor cells stained positive for thyroid transcription factor 1 (TTF1). We discuss the light and electron microscopic features with associated immunohistochemical characteristics and present a review of the literature.
A 39 year old Hispanic female G0P0 presented to the gynecology clinic complaining of right sided vaginal pain of one month duration. On review of systems the pain was postcoital. She denied any bleeding or discharge. Her past medical history was significant for a history of syphilis treated when she was 15 years old. She was positive for Hepatitis C diagnosed four years earlier. History was also significant for active intravenous heroin and crack cocaine use. She was an ex smoker. The patient was a homosexual and had been with the same sexual partner for the last 14 years. An HIV test done in the recent past was reported negative. The patient was 5 feet tall, 152 lbs. Physical examination revealed normal external genitalia. Vaginal examination under speculum revealed a 2.5 cm x 2.4 cm distal vaginal lesion, slightly ulcerated and firm. There was no evidence of any sidewall involvement. Colposcopic visualization of the cervix was unremarkable. The uterus was 7.5 cm. There was no evidence of uterine tenderness, adnexal tenderness or masses. Of note, a PAP smear done was negative. The rest of her physical examination was unremarkable. Biopsy of the vaginal lesion revealed small cell carcinoma suggestive of metastasis from a lung primary.
The patient underwent imaging studies to assess extent of disease. Transvaginal ultrasound showed a bicornuate uterus with duplication of the endometrial stripe but otherwise normal thickness and no focal abnormality at the level of the endometrial stripe and normal sized ovaries. There were simple cysts within the left ovary and no adnexal masses. Chest X ray and chest CAT scan were both negative. CAT scan of abdomen and pelvis with contrast were significant for a 2.5 cm X 2 cm round low density area in the upper pelvis of unclear etiology. PET scan showed intense hypermetabolic focus in right midvaginal wall compatible with neoplasm at the site of the lesion, otherwise negative. Brain MRI was negative for metastasis.
The patient was started on concurrent chemotherapy and radiation. She received four cycles of carboplatin and etoposide. Pelvic external radiation therapy with an intensity modulated radiation therapy technique was given followed by an interstitial plane implant in the right vaginal wall. She received a total dose of 6800 cgy radiation. After completion of treatment PET/ CT scans reveal she is without evidence of disease 10 months after diagnosis.
The biopsy of the vaginal mucosa showed extensive proliferation of small malignant cells which showed pleomorphic dark staining nuclei with inconspicuous nucleoli and scant cytoplasm. Many apoptotic cells and mitoses were seen. Diffuse infiltration of small, closely packed, darkly stained cells arranged in nests, trabeculae and rosettes were seen. These tumor cells showed pleomorphic hyperchromatic nuclei with finely granular powdery chromatin, inconspicuous nucleoli, very scanty cytoplasm and ill-defined cell borders. Nuclear molding, mitoses and individual cell necrosis with nuclear dusts were frequently seen. The intervening stroma was scanty and vascular with few lymphoplasmacytic infiltrate. The overlying squamous mucosa showed focal areas of ulceration with fibrinous exudate.
Immunohistochemical stains for cytokeratin (AE1/AE3), chromogranin, synaptophysin and neuron-specific enolase were positive on tumor cells. TTF1 stain was positive for nuclear staining pattern. Stains for leukocyte common antigen, S-100 and vimentin were all negative.
Extra pulmonary primary vaginal small cell carcinoma are extremely rare. Scully et al in 1984 were first to describe an adenocarcinoma of the vagina associated with invasive small cell carcinoma. Since then only 25 cases have been reported in literature. (Table 1) –
|SR.NO (REFERENCE)||NO OF PATIENTS||AGE/RACE||PRESENTATION||PREVIOUS GYN SURGERY||SIZE OF PRIMARY TUMOR(LARGEST DIAMETER IN CM’S)||STAGE (TNM)|
|1 (*)||1||39/L||Vaginal pain||No||2.5||I (T1 N0 M0)|
|2 (32)||3 -I||74/W||Vaginal bleed||TVH+BSO||7.5||IV (T3 N1 M1)|
|-II||55/L||Vaginal spotting||PAP with AGUS||7.0||III ( T2 N1 M0)|
|-III||38/B||Rectal pain||No||10.0||IV (T4 N0 M0)|
|3 (8)||1||69/W||Vaginal spot||No||4.0||I (T1 N0 M0)|
|4 (18)||1||51/A||Vaginal Bleed||No||4.0||I (T1 N0 M0)|
|5 (9)||1||57/N/A||Post menopausal bleed||No||8.0||III ( T3 NoMo)|
|6(13)||1||32/N/A||Dyspareunia||No||10.0||III ( T3 NoMo)|
|7 (10)||1||59/?N/A||Post coital bleed||TAH+BSO||3.5||I ( T2 N0 M0 )|
|8(10)||1||78/N/A||Vaginal discharge||TAH||3 Nodules||III(T1or2N0M0)|
|9 (14)||1||34/N/A||Routine D&C||Vaginectomy||3.0||II (T2 N0 M0)|
|10 (11)||1||65/W||Abnormal PAP||TAH||0.5||I ( T1 N0 M0 )|
|11 (20)||1||63/W||Vaginal Bleed||TAH||2.0||II (T2 N0 M0)|
|12 (21)||2 -I||78/W||Constipation||No||4.0||II (T2 N0 M0 )|
|-II||74/W||Post menopausal bleed||TAH + BSO||3.0||II (T2 N0 M0 )|
|13 (12)||3 -I||41/ B||Post coital bleed||No||4.0||II (T2 N0 M0 )|
|-II||68/B||Post menopausal bleed||TAH||IV( T? N? M1)|
|-III||73/W||Vaginal discharge||TAH||N/A||IV ( T? N? M1)|
|14 (22)||1||32/W||N/A||N/A||3.0||II ( T2 N0 M0)|
|15(23)||5||61 yrs(m)||N/A||N/A||N/A||II (2)#|
TAH indicates Total abdominal hysterectomy; BSO, Bilateral Salpingo Oophorectomy;AGUS, Atypical Glandular Cells of Undetermined Significance; N/A, Not Available; (*) Present study, W, White; L, Latin American; B, Black; (m), Median age. No 16 & 17 were only histopathologic studies, no other information available about the ;# indicates No of patients with the mentioned staging.
Of 23 patients for which there is clinical and pathological information, the mean age of presentation is 57 years ranging from 32 to 78 years. Of the reported cases, 10 presented with vaginal bleeding, two with vaginal discharge, two with pain, one after an abnormal PAP smear, one in the setting of weight loss and one was diagnosed on routine dilatation and curettage after a miscarriage. Four cases presented with Stage I disease, eight with Stage II, six with Stage III and five cases with Stage IV disease. Median survival of the patients was 11 months ranging from 4 months to 41 months. All patients but one died of metastatic disease. Only one patient (Hayashi et al in 2000) was reported alive more than 41 months after diagnosis without evidence of disease. Considering the aggressive nature of this malignancy, biopsy of suspicious lesions found on gynaecological examinations is an important means of early diagnosis and therefore treatment.
Of the 18 cases with documented treatment, 11 were treated with combination chemoradiotherapy, four with radiotherapy, two with surgery, and one with chemotherapy alone. Our patient presented at the age of 39 with vaginal pain. She was diagnosed at Stage I. She was treated with aggressive chemoradiation and is alive with no evidence of disease 10 months after diagnosis. See Table 2 for details on treatment and outcomes.
|SR.NO (REFERENCE)||NO OF PATIENTS.||PRIMARY TREATMENT GIVEN.||RESPONSE||OUTCOME||SURVIVAL (MONTHS)|
|1 (*)||1||CTx ( Carboplatin + Etoposide ) + RTx||Ongoing Rx||Alive||9|
|2 (32)||3 – I||CDDP ( Cis-diaminedichloroplatinum ) + Etoposide + Pelvic radiation||PR||Died||4|
|-II||Surgery (radical vulvovaginectomy) & lymph node dissection||PR||Died||4|
|– III||CDDP + Etoposide + External beam RTx followed by brachytherapy (Vag cyllinder)||Ongoing Rx||Alive with disease||>5|
|3 (8)||1||Chemoradiation to pelvis ( 4500 rads in 2500 fractions ). CTx Cispaltin + Etoposide.||Persistent local disease||Died||13|
|4 (18)||1||Combination CTx (Cyclophosphamide + pirarubicin + cisplatinCDDP + GCSF)||CR||Alive without disease||>41|
|5 (9)||1||Concurrent chemoradiation with carboplatin & Etoposide||CR||Died||>13|
|6 (13)||1||Combination CTx ( Cisplatin + Etoposide )& whole pelvis RTx||CR||Alive without disease||>6|
|7 (10)||1||Combination CTx ( Cisplatin + VP 16 )& Whole pelvis RTx.||CR||Died||26|
|8 (19)||1||Modified Rt Vulvovaginectomy & Rt sided inguinal lymph node dissection.||CR||Died||10|
|9(14)||1||Vaginectomy with B/L Inguinal lymphnode dissection + Cispaltin, Etoposide + RTx||CR||Died||6|
|10(11)||CTx with Vincristine, Doxorubicin, Cyclophosphamide + RTx||CR||Alive without disease||>26|
|11 (20)||1||Sequential CTx with Etoposide and Cisplatinum +RTx||Focal disease||Died||8|
|12 (21)||2 -I||RTx||NED 1M||Died||15|
|13(12)||1 -I||RTx ( External pelvis irradiation& brachy therapy)||No mention||Died||29|
|-II||Whole pelvis RTx CTx (adriamycin + cytoxan)||No mention||Died||5|
|-III||CTx ( Cisplatin + Dichloromethotrexate )||No mention||Died||9|
|16 (17)||1||Details N/A|
|17 (24)||1||Details N/A|
CTx indicates Chemotherapy; RTx, Radiotherapy; CR, Complete responce; PR, Partial response; Rx, Treatment; NED, No evidence of disease; 5FU, 5 Fluro Uracil; (*), Present study.
The histological findings in our patient are identical to those of pulmonary small cell carcinoma consisting of tightly packed small, round, oval and spindle cells with scant cytoplasm, ill-defined cell borders, fine granular, nuclear chromatin and absent or inconspicuous nucleoli. Argyrophilia, immunoreactivity for neuron specific enolase, chromogranin, synaptophysin, detection of amines ( e.g. serotonin ) and polypeptides demonstrate neuroendocrine differentiation. These characteristic light microscopic features of small cell carcinoma are complimented by neurosecretory dense core granules on electron microscopy which support the neuroendocrine nature of the tumor. Immunohistochemical staining for cytokeratin is often required to confirm the epithelial origin and exclude other small blue cell tumors such as lymphoma and sarcoma. Leucocyte common antigen negativity also readily excludes the possibility of a lymphoma. The positive staining with argyrophil stains and immunoperoxidase satins for chromogranin A supports the diagnosis.
Human TTF 1 is a 38-kd homeodomain transcription factor of the NKx2 family that is almost exclusively expressed in normal thyroid and lung and their metastasis. 25 TTF 1 is a sensitive but not absolutely specific marker for small cell carcinoma. It has been reported to be expressed in non pulmonary small cell carcinomas that have originated in the gastrointestinal tract, urinary bladder and uterine cervix. 25 To our knowledge, this is the second report of the expression of TTF 1 in a patient with primary vaginal small cell carcinoma, indicating that TTF 1 is not a specific marker for small cell lung carcinoma and should not be used to distinguish primary from metastatic pulmonary small cell carcinoma. 26
Extra pulmonary small cell carcinoma is recognized as a clinicopathologic entity distinct from small cell lung cancer, however the aggressive nature of these tumors is similar to that of their pulmonary counterpart. Because of the rarity of vaginal primary small cell carcinoma the treatment has been based on modalities active in the management of small cell carcinoma of the lung. These tumors have the propensity for early systemic spread in the form of micro metastasis and therefore systemic therapy should be instituted in combination with pelvic radiation. In pulmonary small cell carcinoma combination chemotherapy has been demonstrated to be superior to single agent chemotherapy. Concurrent rather than sequential radiation has been shown to be better.
Primary vaginal small cell carcinoma is a rare aggressive tumor with propensity for early dissemination. Patients with this disease should be regarded as having micrometastasis at diagnosis. Although no consensus has been reached regarding the optimal therapy, we recommend aggressive multimodality therapy even in the setting of early stage disease.
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