Squamous cell carcinoma of the vulva (vSCC) is relatively rare but is the most common malignant tumor of the vulva, comprising 95 % of malignancies in this organ with malignant melanoma being second most common. The incidence is 1–2 per 100,000 women annually [1]. In 2013, the American Cancer Society estimated that there were 4,700 new cases of vulvar cancer and 990 vulvar cancer-related deaths in the United States [2]. Some have shown that the incidence of VIN has increased over time while the incidence of vSCC has remained stable [3, 4]. Others report that incidence of vSCC has increased over time [5, 6]. White and non-Hispanic women are more frequently affected, with the incidence among African-American and Hispanic women being one third lower [7]. African-American women present at a significantly younger age than white women [8]. Incidence increases with age at diagnosis such that women 70 and older are most at risk [9]. However, there is a trend toward decreased age at diagnosis of VIN and vSCC [10, 11].

The development of vSCC can frequently be attributed to one of two distinct etiologic pathways: HPV related or non-HPV related. Women who develop HPV-related vSCC are typically younger (35–65 years) than those women who develop non-HPV-related vSCC (55–85 years) [12]. Risk factors for developing HPV-related squamous cell carcinoma include known indicators of high-risk HPV exposure: infection with HPV type 16 [13], history of anogenital warts [9], smoking [9, 13, 14], and alcohol consumption [9]. Infection with herpes simplex virus (HSV) type 2 is a risk factor [13]. Number of years in school is inversely associated with risk [9]. Non-HPV-related vulvar squamous cell carcinoma is associated with vulvar dermatoses, especially lichen sclerosus (LS). LS is a chronic dermatologic condition commonly affecting perimenopausal women that causes vulvar pruritus and is associated with epithelial thinning and distinctive dermal changes (Fig. 10.1). Chronic LS often alters vulvar anatomy with loss of distinction between the labia majora and minora and loss of the clitoral hood. Women with a long-standing history of LS are at risk for developing vSCC. Approximately 3–15 % of women with LS will eventually develop invasive squamous cell carcinoma [15–19]. In women with LS, the risk of invasive squamous cell carcinoma increases with age and clinical evidence of localized hyperkeratosis [20, 21].

Patients with vSCC most commonly present with one or more of the following vulvar symptoms and signs: pruritus, pain, discharge, bleeding, dysuria, foul odor, and mass. The presenting signs and symptoms are nonspecific, overlapping with numerous benign vulvar diseases including infectious diseases and vulvar dermatoses. Vulvar squamous cell carcinoma can appear as exophytic or papillomatous masses, occasionally mimicking condyloma acuminatum. A small percentage of women (13.8 %) presents with persistent vulvar ulcers that ultimately prove to be squamous cell carcinoma (Fig. 10.2) [22]. As a result, clinicians should have a low threshold for biopsy of patients (especially postmenopausal women) with persistent ulcers and other atypical vulvar lesions. Definitive diagnosis of vSCC is frequently delayed either because patients do not seek medical attention when signs and symptoms first appear or their lesions are not biopsied at the time of initial clinical presentation.

The labia majora, labia minora, and clitoris are the most commonly affected sites. The majority of patients present with a solitary localized mass; however, patients occasionally present with more than one focus of invasive squamous cell carcinoma (Fig. 10.3). Multifocal vSCC is more frequently seen in patients with HPV-related tumors. Many tumors are larger than 2 cm at presentation. Tumors are locally destructive and can invade adjacent perineal structures such as the urethra, vagina, bladder, and rectum. The primary lymph node group that drains the vulva is the superficial inguinal lymph nodes. The deep femoral lymph nodes are the secondary lymph nodes, while the deep pelvic lymph nodes are the last group. The incidence of positive inguinal or pelvic lymph nodes ranges from 21 % to 50 %, and the incidence of positive pelvic lymph nodes decreases to 4.6–16.1 % [23]. Surgery (wide local excision/partial vulvectomy) is the mainstay of treatment for patients with resectable disease, corresponding to patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I-II disease. Sentinel lymph node mapping can be used in the setting of early stage disease to determine which patients require locoregional lymphadenectomy [24]. Intraoperative pathologic assessment of sentinel lymph nodes is optional but allows the surgeon to perform completion lymphadenectomy in one procedure when the sentinel lymph node is positive at frozen section. In one study, up to one third of women with T1-T2 vSCC had a positive sentinel lymph node [25]. The risk of non-sentinel lymph node metastasis increases with the size of sentinel lymph node metastasis [25]. There are no standard protocols for pathologic assessment of sentinel lymph nodes. One group bivalved then quadrisected each sentinel lymph node half for routine histologic examination; this was followed by ultrastaging for all negative sentinel lymph nodes [25, 26]. For ultrastaging, three slide pairs were taken per millimeter. A hematoxylin and eosin (H&E) slide and a cytokeratin slide were evaluated for each pair. There is currently no evidence to suggest that ultrastaging of sentinel lymph nodes or special handling of sentinel lymph nodes is necessary. Years of experience with sentinel lymph node biopsy in women with breast cancer have shown that while ultrastaging does indeed reveal small metastatic tumor deposits that may have otherwise been missed by usual pathologic examination, the tumor deposits identified as a result of ultrastaging do not affect prognosis or change clinical management. Women with vSCC in the midline have an increased risk of bilateral lymph node metastasis, representing a large proportion of false-negative sentinel lymph nodes. Patients with metastasis to two or more lymph nodes are treated with adjuvant radiation or chemoradiation, while patients with locally advanced/metastatic disease may be treated with surgical resection (including rarely pelvic exenteration) if resectable in addition to chemoradiation therapy [27].

Two distinct pathways for development of vulvar squamous cell carcinoma have been delineated: HPV related and non-HPV related. Regardless of the pathway, squamous cell carcinoma is frequently identified adjacent to its precursor lesion, VIN. The progression of VIN to squamous cell carcinoma is not well understood. One systematic review of 3,322 patients reported a 6.5 % progression rate of VIN III/high-grade squamous intraepithelial lesion (HSIL) to squamous cell carcinoma [28].

HPV-related vSCCs are most commonly histologically non-keratinizing squamous cell carcinomas, warty or basaloid type [29], frequently identified adjacent to usual (warty and basaloid)-type VIN. The proportion of HPV-related squamous cell carcinomas ranges from 19 % to 79 % [9, 29–40]. The largest study to date reported 25 % of the more than 1,700 cases of vSCC were HPV related [29]. The variable distribution of HPV-related vSCCs can be attributed to geographic variances of viral incidence and technical differences of molecular diagnostic testing methods. HPV type 16 is the most common HPV type detected in vSCC [30–32, 34–38, 40]. HPV types 18, 31, 33, 45, 52, 53, and 62 have also been detected in these tumors [29, 39, 41].

Non-HPV-related vSCCs are most commonly histologically keratinizing squamous cell carcinomas and can be identified in association with differentiated (simplex)-type VIN and/or LS. The specific mechanism of carcinogenesis in non-HPV-related squamous cell carcinoma is not completely understood, but TP53, a tumor suppressor gene on chromosome 17, is thought to play a role. Lichen sclerosus shows p53 overexpression as demonstrated by immunohistochemistry, which has been attributed by one group as an ischemic stress response [42]. The association between LS and squamous cell carcinoma has largely been established based on the frequent observation of LS adjacent to squamous cell carcinoma [19, 37, 43, 44]. Women with LS develop vulvar cancer at a rate more than 300-fold higher than women without LS of similar age [45]. Differentiated (simplex)-type VIN is the precursor of non-HPV-related squamous cell carcinoma [46]. Because differentiated (simplex)-type VIN is infrequently diagnosed, the data on progression to invasive squamous cell carcinoma is limited. However, the few available reports suggest a higher rate of progression to invasive carcinoma and a shorter time interval between diagnosis of differentiated (simplex)-type VIN and detection of invasion than uVIN. Compared to usual VIN, women with differentiated VIN are reported to have a 5.6-fold higher rate of developing squamous cell carcinoma [21]. The majority of differentiated (simplex)-type VIN is HPV negative [46] and expresses increased p53 nuclear expression by immunohistochemistry in the basal and suprabasal epithelial layers [46, 47]. Vulvar squamous cell carcinoma also contains TP53 mutations and expresses p53 antigen by immunohistochemistry [47, 48]. Allelic losses at the TP53 locus are frequently identified in HPV-negative squamous cell carcinomas with loss of heterozygosity being more common in HPV-negative carcinomas [49]. Further, common TP53 mutations identified both in differentiated (simplex)-type VIN and in squamous cell carcinoma have been demonstrated [48]. Alteration of the TP53 gene is therefore thought to play a role in development of differentiated (simplex)-type VIN and subsequent keratinizing squamous cell carcinomas. This interpretation is not universally accepted, and it has alternately been suggested that p53 overexpression is reactive rather than causal [50].

Additional possible precursor markers of malignant transformation of LS to vSCC have been suggested [50]. Ki-67, a marker of cellular proliferation, has increased expression in LS and vSCC but is also increased in HPV-related uVIN and vSCC [50]. γ-H2AX expression, a molecule involved in DNA repair, is significantly increased in LS, HSIL, differentiated (simplex)-type VIN, and vSCC compared with normal vulva, suggesting that γ-H2AX may represent an early event in carcinogenesis [51]. Other markers such as MCM3, an essential protein for DNA function and replication; Cyclin D1, a cell cycle regulation protein; and angiogenesis may be useful markers of malignant transformation, but additional studies are warranted [50].

Prognosis in vSCC is primarily determined by tumor stage, based upon surgical and pathological findings. Tumor size, depth of invasion, tumor extension to adjacent structures, presence of lymph node metastasis, and/or presence of distant metastasis are all assessed to assign a pathologic tumor stage. Inguinal lymph node status and tumor size are primary independent prognostic factors [52] with the most important prognostic factor being presence of lymph node metastasis [52–54]. Staging information is commonly reported using the tumor-node-metastasis (TNM) system outlined in the American Joint Commission on Cancer (AJCC) staging manual, seventh edition (Table 10.2) [55]. Alternatively, the FIGO staging system can be used (Table 10.2). Survival data is presented in Table 10.3. Patients with disease localized to the vulva (FIGO stage I or II) have a 5-year survival of 86 %; involvement of the regional lymph nodes (FIGO stage III) lowers the 5-year survival to 54 %. Patients with FIGO stage IV disease have a dismal prognosis, with a 5-year survival of only 15 %. Only 5 % of patients are FIGO stage IV at presentation, however [56].

Patients with tumor depth of invasion less than 1 mm have essentially no risk for lymph node metastasis and are almost always cured by local excision [57]. Patients with a tumor depth of invasion greater than 1 mm have an associated increased risk of lymphatic/vascular invasion, lymph node metastasis, and recurrence leading to worse survival rates [57]. Histologic patterns of invasion are also prognostic factors. Tumors with a spray or finger-like invasion pattern portend poorer survival compared to pushing invasion (Fig. 10.4) [58]. Risk of lymph node metastasis increases with age, tumor size, depth of invasion, and tumor grade [54]. Extracapsular extension of lymph node metastases and size of metastatic vSCC are predictors of poor survival [59–61]. Women with two or more positive lymph nodes also have poor survival [59]. Bilateral lymph node involvement in vSCC is not more important than number of lymph nodes with metastases [62].

Local recurrences are common in vSCC. Regular follow-up for early detection is important. Approximately 23–33 % develop local recurrences [63–65], and older age (age > 74 years) is an independent risk factor for recurrence [65]. Recurrences detected at regularly scheduled posttreatment follow-up appointments (every 3 months for 2 years, biannually until the 5th year, and then annually thereafter) were significantly smaller than recurrences detected at interval appointments [63]. Patients who develop one recurrence are at a significantly increased risk for development of a second recurrence (72 %) and should be closely monitored for subsequent recurrences [65].

The College of American Pathologists (CAP) has developed recommendations to unify the information included in vSCC pathology reports; these are listed in Table 10.4 [66]. Both depth of invasion and tumor thickness are among the recommended criteria. It is important that these measurements be performed in a standardized fashion. The World Health Organization (WHO) defines depth of invasion as the distance (in millimeters) from the epithelial-stromal junction of the nearest adjacent superficial dermal papilla to the deepest point of invasion [66, 67] and tumor thickness as the distance (in millimeters) from the surface of the tumor to the deepest point of invasion [66, 67]. Tumor thickness can be considerably larger than depth of invasion in a given tumor, particularly if it is exophytic, but depth of invasion is the measurement used for staging. In practice, determining the depth of invasion can be challenging. Figure 10.5 demonstrates both tumor thickness (left) and depth of invasion (right). One could argue that the measurement for depth of invasion could logically be taken in several different ways, highlighting the difficulty of determining accurate depth of invasion in some cases. Even tumors with very early invasion can arguably be greater than 1 mm deep if the depth of invasion definition is strictly followed. Close communication with surgeons and oncologists is necessary in these situations to prevent overly aggressive treatment of very small tumors.