Marc van Beurden Vulval cancer accounts for approximately 4% of all gynaecological malignancies and 1% of all cancers in women. Ninety per cent of vulval cancer consists of squamous cell carcinoma (SCC). Vulval squamous cell carcinoma (VSCC) is the fourth most common gynaecological cancer, following cancer of the uterine corpus, ovary, and cervix. The incidence is 2.6 per 100 000 women per year and is rising by an average 0.6% each year. Approximately 0.3% of women will be diagnosed with VSCC at some point during their lifetime. VSCC is mainly diagnosed in elderly women, with a mean age at diagnosis of approximately 70 years, but 15% are younger than 50 years of age and the median age of onset has decreased over the past few decades. VSCC is diagnosed in stage I/II in 60% of patients, stage III in 27%, and stage IV in 6%. Another 6% are unstaged. The 5‐year overall survival (OS) rate decreases with increasing 2009 FIGO stage and number of LN metastasis. FIGO stage I, II, III, and IV patients had 5‐year OS rates of 84.0%, 74.6%, 47.8%, and 9.4%, respectively [1]. The disease had spread to the regional lymph nodes in 27%, and in 6% it metastasised to distant sites. Therefore, the earlier VSCC is diagnosed, the better the chance of survival. The 5‐year OS is 84.5% for patients without LN metastasis, but is only 30.1% for those with three or more LN metastases [1]. Mortality rates have been stable in younger women but have declined in older women, and the percentage of VSCC deaths is highest among women over 85 years of age [2–5, 6]. Morbidity is high despite the move to less invasive surgical procedures, which has not changed survival but has decreased the complication rate and improved the quality of life. This is particularly important as the rate of VSCC in younger women has increased dramatically in the past 50 years due to the rise in human papillomavirus (HPV)‐related VSCC. Two independent pathways of carcinogenesis in VSCC currently exist, both with their own premalignant and invasive histological forms. One type is related to lichen sclerosus (LS), and the second type is related to HPV infection (Figure 43.1). Risk factors associated with HPV infection include early age at first intercourse, multiple sexual partners, human immunodeficiency virus (HIV) infection, and cigarette smoking. The most common type of VSCC occurs in elderly women on a background of LS often with differentiated VIN (dVIN) and leads to mostly keratinising carcinoma (see Chapter 41). The HPV prevalence in dVIN is only 2% [7]. Differentiated VIN is underreported and probably has a relatively short intraepithelial phase before progression. Since dVIN is known to develop in patients with LS, biopsies should be taken from lesions not responding to therapy for LS, or with a suspicious clinical appearance. Adequate sampling is of importance, as VSCC is often diagnosed adjacent to dVIN [8]. VSCC arising in the background of dVIN has a poorer prognosis and recurs more commonly than VSCC associated with high‐grade squamous intraepithelial lesion (HSIL) [9, 10]. DNA sequencing shows that the key mutation in HPV‐negative vulvar carcinoma concerns TP53 [11, 12]. Figure 43.1 Overview of the multistage evolution of vulval squamous cell carcinoma (VSCC), depicting its two distinct pathways. The human papillomavirus (HPV)‐driven pathway starts with an HPV infection, for which the lifetime risk for women is 80%. 20% of these infections persist, of which half causes vulval high‐grade squamous intraepithelial lesion (vHSIL). A small percentage of vHSIL develops into HPV‐positive VSCC. The HPV‐independent pathway is associated with lichen sclerosis, which can develop into DVIN, commonly after TP53 mutation. DVIN is considered a direct precursor of HPV‐negative VSCC, which accounts for 80% of all VSCC cases. Source: From Abdulrahman, Z., Kortekaas, K.E., De Vos Van Steenwijk, P.J. et al. The immune microenvironment in vulval (pre)cancer: Review of literature and implications for immunotherapy. Expert Opin Biol Ther. 2018 Dec; 18(12): 1223–1233. The other type of VSCC generally affects younger women and consists mainly of non‐keratinising carcinomas. It is caused predominantly by HPV16 and 18 infections resulting in HSIL, and these women tend to present with early‐stage disease. In HSIL, significant histological atypia is seen with positivity for p16 [13]. More than 80% of HSILs have been reported to be HPV positive, frequently detected genotypes being high‐risk HPV16 (77%), HPV33 (11%), and HPV18 (3%) [7, 13]. However, these high rates of HPV positivity have not been found in VSCC. Only 29% of cases from an international cohort of 1709 VSCCs were found to contain HPV, with HPV16 detected in 75% of these [14]. Other studies have reported 15–79% HPV positivity in VSCC [15]. These high‐risk oncogenic HPV types lead to carcinogenesis primarily via the oncoproteins E6 and E7, which interfere with the functioning of tumour suppressor retinoblastoma protein (pRB), and p53. Loss of pRB potentially leads to p16INK4a overexpression [16]. Clinical outcomes in a cohort of 236 patients show that the local recurrence rate was 5.3% for HPV‐positive VSCC and 16.3–22.6% in HPV‐negative tumours. This is independent of clinicopathological variables, which may provide an opportunity to reduce overtreatment in VSCC [11]. This is illustrated in two clinical examples (Figure 43.2a,b). Figure 43.2 (a) Vulvar squamous cell carcinoma (VSCC) on the background of lichen sclerosus. This patient was diagnosed at the age of 49 with VSCC FIGO stage 4B with inguinofemoral and pelvic lymph node metastasis, for which she underwent a radical local excision, IFL, and pelvic lymph node dissection, followed by radiotherapy. The lichen sclerosus was infrequently treated with ultrapotent topical corticosteroids. In the 20 years of follow‐up, no recurrence occurred. (b) VSCC on the background of human papillomavirus (HPV)‐related HSIL. This patient was diagnosed with VSCC FIGO stage 1B at the age of 37. She was treated with a radical local excision and a sentinel node (SN) procedure in both groins. No metastases were found. In the 20 years of follow‐up, she was operated four times for a local VSCC recurrence. Patients may be asymptomatic at the time of diagnosis and just notice a nodule or ulcer on the vulva (Figure 43.3). Common symptoms are pain and pruritus, but bleeding, discharge, and dysuria can occur. The presence of an enlarged inguinal lymph node is less common at presentation but is suggestive of advanced disease. VSCC can occur anywhere on the vulva, but the labia majora, clitoris, and periclitoral areas are the most common sites. About 15% arise at the posterior fourchette or perineum. The most common presentation is a vulval plaque or friable nodule, which often ulcerates and then bleeds. Multifocal disease is possible. VSCC can metastasise in different ways. There may be direct extension of tumour to adjacent structures, lymphatic spread to regional lymph nodes, or distant dissemination via the bloodstream. Unilateral lesions usually spread only to the ipsilateral nodes. The risk of invasion is related to the depth of invasion, with lesions less than 1 mm not thought to have a metastatic risk. With lesions between 1 and 2 mm in depth, there is an 8% risk of lymph node involvement, which rises to 34% in lesions over 5 mm deep. Lymphatic spread is first to the inguinal nodes. This can occur with small lesions and may be present even if nodes are not clinically palpable. Physical examination alone is therefore insufficient to detect metastatic disease, and imaging is an essential investigation. Figure 43.3 Invasive squamous cell carcinoma (SCC) arising from a plaque of high‐grade squamous intraepithelial lesion (HSIL) at the fourchette. Haematogenous spread to liver, lung, and bones occurs as a late event and is unusual in those without nodal involvement. The histology of VSCC is the same as that of SCC elsewhere. They have been classified into various subtypes: large‐cell (typical) keratinising (approximately 65%), basaloid (approximately 30%), and warty (5–10%) [17]. Typical large‐cell keratinising carcinomas are characterised by the formation of squamous pearls in the invasive nests and cords. Well‐differentiated tumours are composed predominantly of nests of relatively bland squamous cells with central maturation. Amorphous keratin may be conspicuous, constituting most of the tumour. Mitotic figures are infrequent, may be atypical, and are usually limited to the periphery of the nests. Most of the tumours appear to have a pushing invasive pattern, but focal areas of diffusely invasive small nests and cords may be present, particularly at the periphery. Moderately differentiated tumours have a greater degree of pleomorphism and nuclear atypia with prominent nucleoli, and a brisk mitotic index (Figure 43.4). Squamous differentiation is less conspicuous than in well‐differentiated tumours. Poorly differentiated carcinomas are composed predominantly of sheets or confluent and anastomosing nests of large cells with marked pleomorphism, with prominent nucleoli or diffusely infiltrative cords of small to moderately sized cells with pleomorphic nuclei with dense chromatin and scant cytoplasm, similar to those at the edge of some moderately differentiated carcinomas. Mitotic figures, often atypical, are usually easily identified, and there is usually an absence of keratinisation. The well and moderately differentiated keratinising tumours are generally associated with differentiated VIN in the adjacent epithelium, whereas the moderately differentiated non‐keratinising and poorly differentiated carcinomas are usually associated with HSIL. Figure 43.4 Moderately differentiated large‐cell keratinising carcinoma with keratin pearl rimmed by cells with hyperchromatic nuclei with increased nuclear–cytoplasmic ratio unlike well‐differentiated carcinoma. Basaloid carcinomas usually have little mature‐appearing squamous elements, and squamous pearls are rare. The tumours are composed of infiltrating anastomosing broad islands, with cords and nests of small atypical basaloid cells. Mitotic figures are easily identified and are often atypical. The tumours may be misdiagnosed as basal cell carcinomas in small biopsy specimens, and staining with Ber EP4 (positive in basal cell carcinomas) may be helpful in differentiating the two. Like basaloid carcinomas, the so called ‘warty’ carcinomas are usually HPV positive and occur on a background of HSIL. The tumours have an exophytic surface with condylomatous features, and the underlying invasive tumour is composed of infiltrating, irregularly shaped nests of large atypical cells which frequently have central maturation. Atypical mitotic figures are commonly found. Other variants of squamous carcinoma are uncommon and include adenoid or acantholytic, giant cell, and spindle cell variants. However, in well‐sampled tumours, there are almost always areas of more conventional squamous carcinoma. The depth of invasion is taken from the deepest invasive tumour to the tip of the nearest dermal papilla [18]. In cases where the tumour is ulcerated, the depth of invasion cannot be measured, and only a tumour thickness can be estimated. In this case, the depth of the tumour from the base of the ulcer is measured and added to the estimated depth of the ulcer to arrive at a thickness. For all intents and purposes, ulcerated tumours are assumed to have a depth of invasion greater than 1 mm. Distinguishing between tangentially cut full‐thickness HSIL and stage Ia tumours can be difficult, but the presence of invasion is usually characterised by small irregular nests of cells that lack the peripheral palisading that is present in the accompanying HSIL (Figure 43.5). This is an uncommon form of VSCC which has also been referred to as a Buschke Lowenstein tumour [19]. They tend to occur in older women and are very slow growing. They form condylomatous growths which can cover most of the vulva (Figure 43.6). They are composed of an exophytic papillary component with broad invasive bulbous nests with a pushing rather than diffusely infiltrative margin. The degree of cellular atypia is mild, and mitotic figures are rare. There is no HSIL at the margins. Diagnosis can be difficult if the biopsy specimen is small, and sometimes multiple deeper biopsies are required to confirm the diagnosis. Figure 43.5 Low magnification of early invasive squamous carcinoma with pushing invasion of variably sized islands of basaloid cells that connect to the surface and have central maturation Figure 43.6 Verrucous carcinoma with extensive warty vulval plaque. These are a type of low‐grade squamous carcinoma which present with exophytic growths. Mild to moderately atypical koilocytes are seen, and invasion tends to be superficial. Diagnosis at an early stage is difficult if invasive nests have not developed, and the presence of significant atypia and atypical mitoses in any architecturally typical condyloma should raise the suspicion of this tumour. These have classically been considered benign neoplasms, but are often classified as indolent low‐grade squamous carcinomas that fail to metastasise. They are rare in the vulva and occur in the hair‐bearing portions [20]. They present as a rapidly growing nodule that usually has a central crater. Typically, keratoacanthomas will enlarge over a period of about 6 weeks and then spontaneously regress. However, as there is such difficulty in distinguishing them clinically and histologically from an invasive tumour, they are usually excised. Histologically, there is an exophytic proliferation of squamous epithelium that pushes into the underlying dermis. A central keratin‐filled crater is present that extends from the surface to the central portion that is composed of nests of mildly atypical squamous cells with a peripheral layer of bland basaloid cells. Mitotic figures may be numerous, but they are limited to the periphery of the nests, and abnormal forms are not present. Unlike invasive squamous carcinomas, the invasive margin is smooth, and there is often a collarette at the periphery that appears to confine the proliferation, and, unlike verrucous carcinoma, there is an absence of papillomatosis. If a patient is suspected of having vulval cancer, the diagnosis should be established by a deep punch or incisional biopsy. The histological type and depth of invasion should be mentioned in the pathology report [21]. The depth of invasion is defined from the epithelial–stromal junction of the most superficial adjacent dermal papilla to the deepest point of invasion of the tumour [18]. An excisional biopsy for initial diagnosis may obstruct further treatment planning and should therefore be avoided. In cases where there are multiple vulval lesions, they all should be biopsied separately with clear documentation of mapping. After the diagnosis, all patients should be referred to a gynaecological oncology centre and treated by a multidisciplinary gynaecological oncology team. Staging should be done according to FIGO [22, 23, 24, 25] (Table 43.1) and/or TNM classification [26, 27] (Table 43.2). The size of the lesion; distance to the midline, clitoris, anus, vagina, and urethra; and palpation of lymph nodes should be documented, preferably with a picture or drawing. The cervix, vagina, and anus should be examined. The groins should be palpated [28], and thereafter imaging is done by ultrasound, PET‐CT, or MRI [29] to identify potential lymph node metastases. A fresh needle aspiration of suspicious nodes should be performed and in cases of a suspicious or proven nodal metastasis or in advanced disease, a CT of the thorax and abdomen should be performed. Table 43.1 FIGO staging for vulval cancer. Table 43.2 TNM staging system for vulval cancer.
43
Vulval Squamous Cell Carcinoma
Epidemiology
Pathophysiology
Clinical features
Histology
Variants of SCC
Verrucous carcinoma
Condylomatous carcinoma
Keratoacanthoma
Diagnosis
I
Tumour confined to the vulva
Ia
Lesions 2 cm or less in size confined to the vulva or perineum, and with stromal invasion 1 mm or less. No nodal metastasis
Ib
Lesions 2 cm or greater in size or with stromal invasion greater than 1.0 mm, confined to the vulva or perineum, with negative nodes
II
Tumour of any size with extension to adjacent perineal structures (lower third of urethra and/or the vagina or anus) with negative nodes
III
Tumour of any size with or without extension to adjacent perineal structures (lower third of urethra and/or the vagina or anus) with positive inguinofemoral nodes
IIIa
With 2 lymph node metastases <5 mm
IIIb
With 2 or more lymph node metastases >5mm or with 3 or more lymph node metastases <5 mm
IIIc
With positive nodes with extra‐capsular spread
IV
Tumour invades other regional (upper 2/3 of urethra or vagina) or distant structures
IVa
Tumour invades any of the following:
Upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or
Fixed or ulcerated inguinofemoral lymph nodes
IVb
Any distant metastasis including pelvic lymph nodes
Primary tumour
FIGO stage
T1
Lesions 2 cm or less in size confined to the vulva or perineum
T1A
Ia
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