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Chapter 2.6 ■ Therapy for Vulvar Cancer: Radiation, Systemic Therapy, and Treatment of Persistent and Recurrent Disease 19

4. Muigai J, Jacob L, Dinas K, Kostev K, Kalder M. Potential delay in the diagnosis of vulvar cancer and associated risk factors in women treated in German gynecological practices. Oncotarget . 2018;9(9):8725-8730. 5. de Bie RP, van de Nieuwenhof HP, Bekkers RL, et al. Patients with usual vulvar intraepithelial neoplasia-related vulvar cancer have an increased risk of cervical abnormalities. Br J Cancer . 2009;101(1):27-31. 6. Expert Panel on GYN and OB Imaging, Lakhman Y, Vargas HA, et al. ACR Appropriateness Criteria® staging and follow-up of vulvar cancer. J Am Coll Radiol . 2021;18(5S):S212-S228. 7. Olawaiye AB, Cotler J, Cuello MA, et al. FIGO staging for carcinoma of the vulva: 2021 revision. Int J Gynaecol Obstet . 2021;155(1):43-47.

R eferences 1. Kim KW, Shinagare AB, Krajewski KM, et al. Update on imaging of vulvar squamous cell carcinoma. AJR Am J Roentgenol . 2013;201(1):W147 -W157. https://pubmed.ncbi.nlm.nih.gov/23789687/ 2. Lanneau GS, Argenta PA, Lanneau MS, et al. Vulvar cancer in young women: demographic features and outcome evaluation. Am J Obstet Gyne col . 2009;200(6):645.e1-645.e5. 3. Vandborg MP, Christensen RD, Kragstrup J, et al. Reasons for di agnostic delay in gynecological malignancies. Int J Gynecol Cancer . 2011;21(6):967-974.

2.6 c h a p t e r

Therapy for Vulvar Cancer: Radiation, Systemic Therapy, and Treatment of Persistent and Recurrent Disease

Diane C. Ling and Sushil Beriwal

Invasive Vulvar Squamous Cell Carcinoma: Management of the Primary Tumor Early-Stage Tumors Tumors demonstrating a DOI of 1 mm or less have minimal risk for lymphatic dissemination (4-6). Excisional procedures that in corporate a 1-cm normal tissue margin are likely to provide cu rative results. Patients in this category represent the only subset for whom surgical evaluation of the inguinal LNs can be omitted. These superficially invasive carcinomas tend to arise in younger patients with HSIL/VIN lesions that are commonly associated with oncogenic HPV infections. Occult invasion in lesions thought to be intraepithelial is common (132,133,7,8). Consequently, the entire lower genital tract and vulva should be carefully evaluated before surgical resection of these lesions is attempted. The risk of vulvar recurrence or development of a new lesion at another vulvar site is significant. After primary therapy, these patients should undergo frequent follow-up examinations. Management of clinical stage I and II vulvar cancer includes wide radical excision of the primary tumor with unilateral or bi lateral sentinel lymph node biopsy (SLNB), with or without in guinofemoral lymphadenectomy. SLNB should be offered as an alternative to inguinofemoral lymphadenectomy for women with tumors of size 4 cm or less, with no suspicious LNs on physical ex amination or imaging and no prior groin surgery or radiation that might interfere with lymphatic drainage pathways. The primary tumor is removed with a wide radial margin of normal skin (2 cm), along with a deep margin to the deep perineal fascia; thus, the vulvar specimen will contain tumor, skin, subcu taneous fat, vascular perforators, and dermal lymphatics. This ap proach provides excellent long-term survival and local control in approximately 88% of patients (9). Every attempt should be made to preserve structures such as the clitoris and urethral meatus. Deep margins are rarely a problem except on the perineum, where there is little or no subcutaneous fat. In this case, removal of the capsule of the anus or some of the sphincter muscle itself can be performed without loss of anal function. Vulvar defects for small primary tumors can usually be closed with simple mobilization of the skin and fat surrounding the vulva. In cases where primary closure is not possible, any one of a number

G eneral M anagement High-Grade Vulvar Intraepithelial Neoplasia Vulvar LSILs (previously called VIN-1) are not precancerous le sions and do not require treatment unless symptomatic. HSIL (HPV dependent by definition according to 2020 WHO classifi cation; previously called u-VIN, or VIN-2 and VIN-3) and d-VIN (HPV independent) both require treatment, and the goal of treat ment is both symptom relief and prevention of progression into invasive disease. Distinguishing between HPV-associated and HPV-independent lesions has important implications for treatment and progno sis. d-VIN and steroid-resistant VAM are treated with excision, whereas HSIL may be treated with topical imiquimod, ablation, or excision (1). In general, excision is preferred because of the risk for occult invasive disease, especially in the setting of prior vul var HSIL, d-VIN, LS, or immunosuppression. Careful assessment of surgical margins is imperative given the high risk of recurrence following positive margins. Extensive or diffuse HSIL may require a wider excision and is sometimes treated with partial vulvectomy of the superficial skin. Vulvar skin should be sutured primarily if possible, but sometimes a split-thickness skin graft is required. In the setting of extensive multifocal disease, CO 2 laser ablation or argon beam coagulation can be considered after extensive sam pling to rule out invasive disease. This can also be considered for lesions that involve the clitoris, urethra, anus, or vaginal introitus. These methods may spare the patient a morbid surgery, but do not yield a specimen for histology. Topical treatments such as imiquimod or 5-fluorouracil (5-FU) cream can be used in select cases. Imiquimod is an immune modula tor that is believed to affect the function of the Toll-like receptor (Tlr) as a costimulatory molecule for T-cell-mediated immune response to malignant cells. It has well-documented activity for treatment of genital warts as well as vulvar dysplasia. It is often the initial treat ment for recurrent vulvar HSIL (2). It is typically applied 3 to 5 times per week for a total duration of 16 weeks. Side effects include local inflammation at the application site resulting in mild-to-moderate erythema or erosions. Although 5-FU cream is very effective, it is used rarely because of significant side effects (3).

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