General
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• Primary squamous cell carcinoma arising in vagina without involvement of surrounding structures, such as cervix or vulva

Epidemiology
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• Comprises 1-3% of all gynecological cancers (Int J Gynecol Cancer 1994;4:389, Gynecol Oncol 2013;131:380, Gadducci: Critical Reviews in Oncology / Hematology, 2014)
• 80-90% of primary vaginal cancers are squamous cell carcinomas (Gadducci: Critical Reviews in Oncology / Hematology, 2014))
• Usually in 6th decade of life (median age 58 to 68) but can also be seen in younger patients (Int J Gynecol Cancer 1994;4:389, Gynecol Oncol 2013;131:380)

Sites
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• Most common in upper half of vagina (Int J Gynecol Cancer 1994;4:389, Gynecol Oncol 2013;131:380, Critical Reviews in Oncology / Hematology)
• Tumor may be missed on initial examination if small and involves lower 2/3 of vagina (Int J Gynecol Cancer 1994;4:389)

Pathophysiology
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• In some cases, vaginal intraepithelial neoplasia (VAIN) can be found prior to invasive squamous cell carcinoma
• History of prior hysterectomy in up to 50% of cases
• Also sassociated with vaginal or utero-vaginal prolapse (Critical Reviews in Oncology / Hematology)

Etiology
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• Strong relationship with high risk human papilloma virus (HPV), especially HPV16 (seen in up to 80% of cases), HPV18 and HPV31
• More common in smokers, because smoking increases the risk of high grade VAIN in women with oncogenic HPV (Critical Reviews in Oncology / Hematology)

Clinical features
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• Most common symptom is vaginal bleeding or discharge (Int J Gynecol Cancer 1994;4:389, Gynecol Oncol 2013;131:380, Critical Reviews in Oncology / Hematology)
• Other symptoms include urinary symptoms and lower abdominal pain (Int J Gynecol Cancer 1994;4:389)
• May remain asymptomatic, especially if small

Diagnosis
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• Clinical history along with histological features on biopsy/resection specimen
• A tumor involving both the vagina and the cervix should be classified as a cervical carcinoma; similarly a tumor involving both the vagina and the vulva should be considered a vulvar carcinoma

Radiology
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• Imaging required to determine extent of disease and to look for distant metastasis

Prognostic factors
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• FIGO stage is most important predictor of overall survival
• Tumor size >4 cm associated with decreased local control and lower overall survival, while total radiation dose in excess of 70 Gy is associated with improved local control of disease and improved overall survival (Gynecol Oncol 2013;131:380, Critical Reviews in Oncology / Hematology)
• Vaginal squamous cell carcinoma can spread to vulva, cervix, bladder, rectum and through lymphatics can metastasize to obturator, hypogastric, external iliac and groin nodes
• Rarely distant metastasis to liver, lungs, bones and brain (Critical Reviews in Oncology / Hematology)

Case reports
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• 28 year old woman with invasive squamous cell carcinoma of vagina during pregnancy (Obstet Gynecol 2002;100:1105)
• 39 year old woman with primary vaginal squamous cell carcinoma arising in a squamous inclusion cyst (Cesk Patol 2012;48:153)
• 59 year old woman with vaginal cancer and complicated prolapse history (Female Pelvic Med Reconstr Surg 2014;20:295)
• 68 year old woman with vaginal cancer and multiple liver and pulmonary metastases (Obstet Gynecol Sci 2013;56:416)
• 84 year old woman with carcinoma of vagina in utero-vaginal prolapse (JNMA J Nepal Med Assoc 2012;52:82)
• Aggressive primary invasive vaginal carcinoma associated with HPV61 (Tumori 2012;98:57e)
• Synchronous papillary cystadenocarcinoma of ovary and squamous cell carcinoma of lower vagina (BMJ Case Rep 2013 Jan 11;2013)

Treatment
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• Various treatment modalities are used including external beam radiation therapy/EBRT, interstitial brachytherapy, intracavitary brachytherapy, chemotherapy and surgical resection
• The mainstay of treatment is typically definitive radiation therapy with external beam radiation or brachytherapy (Gynecol Oncol 2013;131:380, Int J Clin Oncol 2013;18:314, Critical Reviews in Oncology / Hematology)
• Surgical resection is recommended for early stage cancer involving upper posterior vagina (Gynecol Oncol 2013;131:380)
• For stage I disease, surgery consists of radical hysterectomy, upper vaginectomy and pelvic lymphadenectomy (Critical Reviews in Oncology / Hematology)
• Cisplatin-based chemotherapy can be administered with radiation therapy (Gynecol Oncol 2013;131:380)

Gross description
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• Exophytic or ulcerative with necrosis

Micro description
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• Histologically graded as well differentiated (G1), moderately differentiated (G2), poorly differentiated or undifferentiated (G3) (Critical Reviews in Oncology / Hematology)
• Well differentiated tumors have polygonal squamous cells with ample eosinophilic cytoplasm, abundant keratin pearls and intercellular bridges
• Poorly differentiated tumors have small cells with scant cytoplasm and hyperchromatic nuclei
• Nuclear pleomorphism and mitotic activity increases from well to poorly differentiated
• Moderately differentiated tumors have histological features intermediate between well and poorly differentiated
• HPV+ tumors are more frequently of non-keratinizing, basaloid or warty-type than HPV- tumors (84% versus 14.3%; p < 0.001), and more often showed diffuse p16 immunereactivity (96% versus 14.3%, p < 0.001)

Micro images
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Multiple squamous pearls

Poorly differentiated

Cytology description
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• Keratinizing squamous cell carcinomas have polygonal cells with bizarre shapes including spindle shaped and tadpole cells, with dense orangeophilic/eosinophilic cytoplasm
• Cells can present singly or in small groups in a dirty necrotic background

Positive stains
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• Cytokeratin, p16

Differential diagnosis
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• Non-keratinizing SCC needs to be differentiated from repair and adenocarcinoma

Additional references
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• Int J Clin Oncol 2013;18:314, Gynecol Oncol 2012;125:194, Int J Cancer 2008;122:2827

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