A 68-year-old woman comes to the office due to blood-tinged vaginal discharge. The patient has had intermittent, slightly malodorous discharge for the past several weeks but has not passed large clots or had heavy vaginal bleeding. Medical history is significant for exposure to diethylstilbestrol in utero that resulted in infertility. She underwent menopause at age 55 and has used combined menopause hormone therapy for several years. Her mother was diagnosed with endometrial cancer at age 54, and her uncle was diagnosed with colorectal cancer at age 70. The patient has smoked a pack of cigarettes daily for the last 40 years and drinks a few glasses of wine each week. BMI is 32 kg/m². Pelvic examination demonstrates a blood-tinged watery discharge and a 3-cm ulcerated lesion on the posterior vaginal wall; the cervix appears normal. Transvaginal ultrasound shows a 2-mm endometrial stripe. Biopsy of the lesion demonstrates squamous cell carcinoma. Which of the following is the greatest risk factor for this patient's diagnosis?

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11ec25c8_d9f2_af5d_bc81_3f50236b5b0e_MD0003_00 This postmenopausal woman has biopsy-confirmed vaginal squamous cell carcinoma. Although many women are diagnosed with vaginal cancer on routine screening, those with large, symptomatic lesions often have vaginal bleeding and malodorous vaginal discharge. Additional clinical features that are suggestive of metastatic disease can include pelvic pain, urinary symptoms (eg, hematuria), and bulk symptoms (eg, constipation). Lesions typically appear as an irregular plaque or ulcer in the upper third of the posterior vagina, as seen in this patient. As with cervical cancer, vaginal cancer is due to persistent human papillomavirus (HPV) infection with high-risk types 16 and 18. Chronic tobacco use decreases the immune response and prevents viral clearing. This increases the risk of persistent HPV infection and thereby allows continued viral replication and eventual metaplastic changes within the vaginal squamous cell epithelium. Diagnosis is with biopsy of the lesion to evaluate for depth of invasion and help determine management options. (Choices A and D) Obesity (BMI ≥30 kg/m²) and a possible hereditary cancer syndrome (particularly Lynch syndrome) increase the risk of endometrial cancer. Advanced-stage endometrial cancer can present as a vaginal lesion; however, patients would have a concomitant thickened (>4 mm) endometrial stripe. In addition, biopsy for endometrial cancer shows endometrioid adenocarcinoma. ² (Choice C) Diethylstilbestrol was previously used for spontaneous abortion prevention but was discontinued due to multiple adverse effects (eg, infertility due to anatomic defects). Women who were exposed to this medication in utero are at increased risk of vaginal clear cell adenocarcinoma, not squamous cell carcinoma. (Choice E) Infertility, particularly in patients who are nulliparous despite ovulatory cycles, increases the risk of epithelial ovarian cancer due to recurrent damage and subsequent malignant transformation of the ovarian epithelium from ovulation. Infertility does not increase the risk of vaginal cancer. (Choice F) Menopause hormone therapy is associated with an increased risk of endometrial cancer in patients who receive estrogen-only therapy and have a uterus and an increased risk of breast cancer. There is no association with vaginal cancer. Educational objective: Vaginal squamous cell carcinoma is due to persistent infection with human papillomavirus (HPV) infection high-risk types 16 and 18. Chronic tobacco use decreases the normal immune response, which allows for persistent HPV infection and squamous cell metaplastic changes. References: A population-based study of squamous cell vaginal cancer: HPV and cofactors. (http://www.ncbi.nlm.nih.gov/pubmed/11812085) Smoking cessation counseling in women with genital intraepithelial neoplasia. (http://www.ncbi.nlm.nih.gov/pubmed/22366589)

A 68-Year-Old Woman Comes to the Office Due to Blood-Tinged