Clinical questions

1. 1. How does immunosuppression (prognostic factor) contribute to the development of preinvasive or invasive cancer (outcome) in women (population )?

Search Strategy

• MEDLINE and EMBASE: (immunosupp*): explode vulvar cancer OR vaginal cancer AND (immunosupp* OR immunosupp*.mp) AND population studies AND cohort studies AND meta‐analysis.
  
• Hand‐searching (immunosuppression): references listed in the articles obtained.

Vulvar and vaginal cancers and their preinvasive precursors are considered to be highly associated with the human papillomavirus (HPV). An estimated 40–50% of vulvar cancers and 64–91% of vaginal cancers have been linked to HPV [3]. Although at least 70% of women are infected with HPV in their lifetime, most infections are asymptomatic and spontaneously clear within 12–18 months. Less than 10% of women have a persistent infection, which in turn may develop into invasive cancer [4].

Since the majority of vulvar and vaginal cancers are HPV‐related, an immunocompromised state can render one’s immune system unable to clear the infection, thereby increasing the risk of developing these cancers. The majority of the data on immunosuppression and vulvovaginal cancers are on patients with HIV infections and acquired immune deficiency syndrome (AIDS), with an increasing number of studies on patients after organ transplantations and patients on renal dialysis. Due to the rarity of vulvar and vaginal cancers, epidemiologic studies require a large cohort of patients to adequately assess for potential risk factors. Thanks to large HIV/AIDS and transplant registries and databases, these types of population studies can be conducted [5–12].

Table 17.1 lists the results of several multicenter cohort studies and the reported standardized incidence ratios (SIRs) of preinvasive and invasive vulvovaginal cancers, comparing their incidence rates in immunosuppressed patients and the general population. The SIRs vary considerably among the studies, and this variance is likely due to the overall low incidence of vulvar and vaginal cancers. However, the SIRs are consistently high throughout the studies: the lowest SIR is still over two for vaginal cancer in Engels et al. [10], and the highest SIR is over 26 for vulvar cancer in Adami et al. [6]. These studies strongly suggest a potential role of an impaired immune system in increasing the rate of development of invasive vulvar and vaginal cancers.

In addition, multiple studies have demonstrated associations between low CD4 counts and increased risks of both invasive and preinvasive vulvar and vaginal cancers [9, 13–15]. Chaturvedi et al. in their study of cancer registry data found an elevated relative risk of 4.91 (95% confidence interval 1.02–23.60) with each 100 cells mm⁻³ decline in CD4 count, suggesting that there may be a relationship between the severity of immunosuppression and cancer risk. The authors also compared patients who were 4–27 months after AIDS onset and 28–60 months after onset and discovered that vulvar and vaginal cancer incidences were significantly elevated in the 28–60 month group but not in the 4–27 month group [9]. This may be due to both the role of long‐term immunosuppression in increasing cancer risk as well as the natural slow progression of HPV infection to invasive disease.

Smoking, which has been considered to enhance immunosuppression, is also a known risk factor for vulvovaginal cancers. Daling et al. in a tumor‐based registry study found that 59.5% of vulvar cancer patients and 42.0% of vaginal cancer patients were current smokers compared with 26.8% of control patients [16]. Mabuchi et al. saw an increasing risk associated with an increasing number of cigarettes smoked a day [17]. Madsen et al. categorized vulvar cancer cases by high‐risk HPV involvement and discovered that tobacco smoking had only a significant risk on the incidence of high‐risk HPV‐associated vulvar cancer and not on HPV‐negative vulvar cancer cases. The authors suggested that the role of tobacco smoking is limited to vulvar cancer associated with HPV, possibly due to a biologic interaction between tobacco smoking and viral proteins [18]. The exact mechanisms of how smoking increases the risk of vulvovaginal cancer has yet to be elucidated, but early studies have implicated that smoking decreases the numbers of T‐cell lymphocytes which produce cytokines that ultimately combat HPV infections [19].

Additionally, the therapeutic role of imiquimod, an immune response modulator, demonstrates the role of the immune system in clearing HPV‐infected cells when used as medical management of vulvovaginal dysplasia. Imiquimod in vivo raises levels of various cytokines to increase the potency of natural killer cells and also activates T cells and Langerhans cells to target HPV‐infected cells [20]. Two randomized controlled trials have shown objective responses with imiquimod compared to placebo control: Van Seters et al. found a 35% response rate with imiquimod compared with a 0% response rate with placebo [21] and Mathiesen et al. achieved an 81% response rate with imiquimod compared with 0% response with placebo [22].

The causative role of HPV infections with high‐risk subtypes allows for specific targeting of these viruses to prevent HPV‐related cancers including cervical and anal malignancies. There are now three available HPV vaccines in the United States: the bivalent Cervarix^® which protects against HPV‐16 and ‐18, the quadrivalent Gardasil that includes HPV‐6, ‐11, ‐16, and ‐18, and the recently approved nonavalent Gardasil‐9 that adds HPV‐31, ‐33, ‐45, ‐52, and ‐58 to the quadrivalent Gardasil. The phase III randomized controlled FUTURE I trial showed that the quadrivalent vaccine was 100% effective in preventing vaginal, vulvar, perineal, and perianal intraepithelial lesions with an average follow up of three years [23]. Saraiya et al. found in the Center for Disease Control (CDC) Cancer Registry Data that universal administration of the bivalent HPV vaccine can prevent 55.1% of vaginal cancers and 48.6% of vulvar cancers in the United States and report that many more cancer cases could be avoided with the nonavalent vaccine [24]. Given the promising data on HPV vaccines, many organizations including the CDC, the American College of Obstetrics and Gynecology, and the Society of Gynecologic Oncology have endorsed the universal administration of HPV vaccines to females 9–26 years of age. The HPV vaccine consists of recombinant HPV L1‐specific DNA fragments, and therefore can be safely given to immunocompromised patients without risk of infection.

In summary, immunosuppression significantly increases the risk of preinvasive and invasive vulvar and vaginal cancers as demonstrated in multiple large cohort studies. This relationship is likely due to a decreased ability to clear HPV infections, thereby allowing HPV infections to progress to preinvasive then invasive cancers. The severity of immunosuppression indicated by low CD4 counts may correspond to higher rates of vulvar and vaginal cancers. HPV vaccines can be safely administered to immunocompromised patients and can potentially prevent the development of these neoplasms.

1. 2. In patients with early stage vulvar cancer (population), what is the role of sentinel lymph node dissection (intervention) compared to inguinofemoral lymph node dissection (comparison) in detecting lymph node metastasis (outcome)?

Search Strategy

• MEDLINE and EMBASE: (sentinel node): explode vulvar cancer OR vaginal cancer AND (sentinel node OR sentinel node.mp) AND clinical trial AND cohort studies AND meta‐analysis
  
• Hand‐searching (sentinel node): references listed in the articles obtained.

Classical standard treatment for early‐stage vulvar carcinoma with a depth of invasion of greater than 1 mm consists of wide local excision or partial/complete vulvectomy with complete inguinofemoral lymphadenectomy (CIL). The procedure is efficacious but CIL is associated with significant morbidity including lymphedema, cellulitis, and wound breakdown. Previous studies have reported lymphedema rates of 19–37.2%, cellulitis rates of 4.5–39%, and wound breakdown rates of 7.4–29.0% [25–28]. Although the complication rates are high, only 25–35% of patients with early stage disease will have lymph node metastases [29–31

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