Type of vulvar SCC
Usual (warty/basaloid) types
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 . 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 . 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 . African-American women present at a significantly younger age than white women . Incidence increases with age at diagnosis such that women 70 and older are most at risk . 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) . Risk factors for developing HPV-related squamous cell carcinoma include known indicators of high-risk HPV exposure: infection with HPV type 16 , history of anogenital warts , smoking [9, 13, 14], and alcohol consumption . Infection with herpes simplex virus (HSV) type 2 is a risk factor . Number of years in school is inversely associated with risk . 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].
Lichen sclerosus is a chronic dermatologic disease characterized microscopically by epithelial thinning with loss of the rete ridges, homogenization of the superficial dermis, and underlying band of chronic inflammatory infiltrate
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) . 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.
This patient presented with an ulcerated squamous cell carcinoma and no prior history of predisposing disease (Reprinted with permission of Stanley J. Robboy and Robboy Associates LLC)
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 % . 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 . 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 . The risk of non-sentinel lymph node metastasis increases with the size of sentinel lymph node metastasis . 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 .
Bilateral vulvar squamous cell carcinoma was identified in the bilateral labia majora of a woman with a history of lichen sclerosus (Reprinted with permission of Stanley J. Robboy and Robboy Associates LLC)
Etiology and/or Pathogenesis
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 .
HPV-related vSCCs are most commonly histologically non-keratinizing squamous cell carcinomas, warty or basaloid type , 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 . 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 . 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 . Differentiated (simplex)-type VIN is the precursor of non-HPV-related squamous cell carcinoma . 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 . The majority of differentiated (simplex)-type VIN is HPV negative  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 . Further, common TP53 mutations identified both in differentiated (simplex)-type VIN and in squamous cell carcinoma have been demonstrated . 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 .
Additional possible precursor markers of malignant transformation of LS to vSCC have been suggested . Ki-67, a marker of cellular proliferation, has increased expression in LS and vSCC but is also increased in HPV-related uVIN and vSCC . 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 . 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 .
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  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) . 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 .
Staging of vulvar malignancy
Primary tumor (T)
Primary tumor cannot be assessed
No evidence of primary tumor
Carcinoma in situ
Lesions 2 cm or smaller confined to the vulva perineum and with stromal invasion 1.0 mm or less
Lesions larger than 2 cm or any size tumor with greater than 1 mm stromal invasion
Any size tumor with extension to adjacent perineal structures (lower/distal 1/3 urethra, lower/distal 1/3 vagina, anal involvement)
Any size tumor with extension to any of the following: upper/proximal 2/3 urethra, upper/proximal 2/3 vagina, bladder mucosa, rectal mucosa, or fixed to pelvic bone
Regional lymph nodes (N)
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
One or two regional lymph nodes with the following features:
One lymph node metastasis 5 mm or smaller
One lymph node metastasis 5 mm or larger
Regional lymph node metastasis with the following features:
Three or more lymph node metastases each smaller than 5 mm
Two or more lymph node metastases 5 mm or larger
Lymph node metastasis with extracapsular spread
Fixed or ulcerated regional lymph node metastasis
Distant metastasis (M)
No distant metastasis
Distant metastasis (including pelvic lymph node metastasis)
Vulvar cancer survival rates
Relative 5-year survival rate (%)
Relative 10-year survival rate (%)
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 . 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 . 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) . Risk of lymph node metastasis increases with age, tumor size, depth of invasion, and tumor grade . 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 . Bilateral lymph node involvement in vSCC is not more important than number of lymph nodes with metastases .
Malignant cells invade the stroma in small nests and individually in a spray pattern. Note the marked desmoplastic stromal response and chronic inflammatory infiltrate
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 . 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 . 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 .
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 . 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.
Recommended elements of synoptic reporting of vulvar squamous cell carcinoma
Specimen type and size
Tumor site, size, thickness, and focality
Histologic type and grade
Depth of invasion
Lymph node status
Tumor thickness is measured from the tumor surface to the deepest point of invasion (left line). Depth of invasion is measured from the epithelial-stromal junction of the nearest adjacent superficial dermal papilla to the deepest point of invasion (right line); this measurement is difficult and could arguably be made in several different places in this particular tumor
Histologic Features and Differential Diagnosis
Keratinizing Squamous Cell Carcinoma
Keratinizing squamous cell carcinoma is the most common histologic subtype of vSCC. As noted above, keratinizing squamous cell carcinoma is frequently identified in older women with LS and differentiated (simplex)-type VIN.
Invasive squamous cell carcinoma is defined by stromal invasion of malignant-appearing squamous epithelium (Fig. 10.6). In keratinizing squamous cell carcinoma, the malignant cells frequently have eosinophilic cytoplasm, enlarged nuclei with prominent nucleoli, increased nucleus to cytoplasm ratio (N/C), and increased mitotic activity. Well-differentiated squamous cell carcinoma commonly displays paradoxical maturation characterized by abundant eosinophilic cytoplasm within the tumor cells; increased mitotic activity may only be identified at the leading edge of invasion. The histologic hallmark of keratinizing squamous cell carcinoma is demonstration of keratin production. Keratin production can be in the form dyskeratotic cells (Fig. 10.7), keratin pearls (Fig. 10.8), or parakeratotic cells. Keratinizing squamous cell carcinomas are defined by the presence of keratin production in the absence of features of warty carcinoma such as fibrovascular papillary architecture and koilocyte-like malignant cells.
Keratinizing squamous cell carcinoma demonstrates keratin production. Abundant keratin pearls are surrounded by nests of malignant squamous epithelium. At the leading edge of invasion, small nests of invasive tumor are identified in a background of desmoplastic stromal response
Individual dyskeratotic cells may be identified in keratinizing and non-keratinizing squamous cell carcinomas. Dyskeratotic cells are small cells with brightly eosinophilic and dense cytoplasm and a hyperchromatic, pyknotic nucleus
Keratin pearl formation is the hallmark of keratin production, identified in keratinizing squamous cell carcinomas but is absent in non-keratinizing squamous cell carcinomas. Keratin pearls are characterized by whorls of brightly eosinophilic keratin material which may or may not contain parakeratotic nuclei. The nests of keratin are surrounded by malignant-appearing squamous epithelium
Keratinizing squamous cell carcinoma should be differentiated from several benign and malignant entities (Table 10.5).
Differential diagnosis of squamous cell carcinoma (SCC)
Basal cell carcinoma
Small cell carcinoma
Merkel cell carcinoma
Patients with VIN may or may not be symptomatic. Those with symptoms present with pruritus and possibly dyspareunia. Lesions are clinically identified using visual inspection with the aid of colposcopy. Biopsies are taken to establish a diagnosis and to rule out invasive squamous cell carcinoma. Treatment depends on extent of disease and is either ablative or surgical.
The histological distinction between VIN and invasive squamous cell carcinoma can be challenging. When frankly invasive squamous cell carcinoma is identified, the diagnosis is straightforward. In cases with patchy VIN and epithelial acanthosis or cases with atypical epithelial nests suspicious for invasion (Fig. 10.9), distinguishing between VIN and well-differentiated or superficially invasive squamous cell carcinoma can be extremely difficult. In fact, interobserver agreement between 11 gynecologic pathologists for diagnosis of the presence of early invasion was only fair (kappa = 0.24) , reflecting the diagnostic dilemma commonly encountered.
One microscopic nest of atypical cells with a central keratin pearl is seen separate from the overlying atypical squamous epithelium containing cytological atypia and mitotic activity. A subtle possible stromal desmoplastic response and a mild chronic inflammatory infiltrate are seen in the intervening tissue between the overlying epithelium and the abnormal squamous nest suspicious for invasion
Several histologic findings can aid in establishing evidence of invasion (Table 10.6, Fig. 10.10). Identification of epithelium with eosinophilic cytoplasm and atypical nuclei characterized by prominent nucleoli, so-called paradoxical maturation, is identified within well-differentiated squamous cell carcinoma. Furthermore, the presence of dyskeratosis and keratin pearls should increase suspicion for invasive squamous cell carcinoma. Evaluation of squamous nests within the dermis is also helpful. Small irregularly shaped nests with disordered orientation within the dermis point toward an invasive squamous cell carcinoma. The presence of single atypical malignant cells can occasionally be identified (Fig. 10.4). Finally, the presence of a desmoplastic stromal response, a loose and gray-blue stroma often with an associated inflammatory reaction, can also be useful. In difficult cases, these morphologic features may not be readily identified. Evaluation of additional histologic step sections can be beneficial to distinguish between VIN and invasive squamous cell carcinoma. Occasionally, rare cases may require a descriptive diagnosis stating that the possibility of a superficially invasive squamous cell carcinoma cannot be excluded (Fig. 10.9). In such cases, a description of the microscopic findings including maximal depth of possible invasive focus should be clearly stated within the diagnostic report. See also Vignette 3 at the end of this chapter.
Histologic features of invasive squamous cell carcinoma
Paradoxical squamous maturation
Dyskeratosis and keratin pearls
Irregularly shaped squamous nests within the dermis
Desmoplastic stromal reaction
This invasive squamous cell carcinoma displays all of the morphologic features of invasion. The tumor is composed of irregularly shaped anastomosing nests within the dermis that are surrounded by a pale stroma, indicative of stromal desmoplastic response. A single keratin pearl is observed. Within the invasive nests, the more centrally located malignant cells have minimal cytologic atypia and abundant brightly eosinophilic cytoplasm, so-called paradoxical maturation
Malignant melanoma comprises approximately 10 % of malignant vulvar tumors and is the second most common malignant tumor of the vulva . Postmenopausal Caucasian women are most frequently affected and present with an ulcer, nodule, or abnormal pigmented lesion. Melanomas have varied histological appearances. In this case, a sheet of tumor cells invades the underlying dermis (Fig. 10.11). The tumor cells are epithelioid with clear cytoplasm. There is no evidence of maturation. Pigment-laden macrophages are observed in the background. Malignant melanoma can, however, closely mimic squamous cell carcinoma, especially in amelanotic melanoma  or in melanomas with an intraepithelial component mimicking VIN. Careful scrutiny may reveal focal evidence of squamous differentiation, even in poorly differentiated squamous cell carcinomas, to exclude the possibility of melanoma. Occasionally a panel of immunoperoxidase stains will be necessary to exclude malignant melanoma. Squamous cell carcinomas are reactive with epithelial antibodies, such as high molecular weight cytokeratins (CK903 and CK5/6) and p63, and are nonreactive with S-100, HMB-45, and Mart-1. Occasionally melanoma reacts with epithelial antibodies; however, its characteristic reactivity with S-100, HMB-45, and melan-A will confirm the melanocytic origin of the tumor.
Malignant melanoma is infamously known as the great mimicker and can have varied histologic appearances. This example is characterized by sheets of epithelioid cells with clear cytoplasm and high nuclear/cytoplasmic ratio. There is no evidence of maturation. Pigment-laden macrophages are identified in the background, providing a useful clue
Distinguishing metastatic squamous cell carcinoma from primary vulvar squamous cell carcinoma can be difficult. Currently available immunoperoxidase stains cannot be used to localize squamous cell carcinomas to a primary site of origin. Therefore, a careful review of clinical history is critical and may provide useful clues for the site of origin. In addition to clinical history, identification of nearby VIN supports a primary carcinoma, whereas absence of VIN and the presence of an invasive carcinoma in the deep soft tissues without connection to the surface epidermis suggest a metastasis (with the caveat that squamous cell carcinoma arising in Bartholin’s glands can mimic this appearance).
Keratoacanthoma-like squamous cell carcinoma (KA) is a rapidly growing crater-like lesion that only rarely occurs on the vulva. Microscopically, this tumor is composed of a well-circumscribed squamous proliferation with a characteristic keratin-filled center (Figs. 10.15 and 10.16). The proliferating squamous cells have bland nuclei and have characteristic eosinophilic cytoplasm with a pushing border. Differentiating a KA from an invasive squamous cell carcinoma can be difficult, especially in the absence of pertinent clinical history, but the absence of VIN in the adjacent epithelium [71, 72] and absence of HPV DNA  favors a diagnosis of KA.
Keratinizing squamous cell carcinoma should also be distinguished from its benign mimics including pseudoepitheliomatous hyperplasia (PEH) and warty dyskeratoma. PEH is a benign, reactive proliferation of the epithelium seen in a variety of clinical conditions, including vulvar Enterobius vermicularis (pinworm) infection  and lichen sclerosus , and can easily mimic vSCC . PEH is also identified in the setting of hypertrophic herpes infections, a rare manifestation of herpes simplex virus (HSV) that clinically mimics vSCC in immunocompromised patients [76–79]. Irregular nests of squamous epithelium extend into the dermis. Cytologic atypia is usually minimal. Rare mitotic figures can be identified. Warty dyskeratoma is a benign keratotic nodule usually confined to the head and neck but has been rarely described on the vulva . It is characterized by suprabasal epidermal acantholysis with a keratotic plug overlying an epidermal invagination with a dermal villous-like architectural pattern.
Non-keratinizing Squamous Cell Carcinoma
Non-keratinizing squamous cell carcinoma (Fig. 10.12) is a squamous cell carcinoma also identified in postmenopausal women with a long-standing history of LS. It can also, however, be identified in the setting of HPV infection. It is defined by an absence of keratin production. Individual dyskeratotic cells may be seen. Keratin pearls are, however, by definition not identified within non-keratinizing squamous cell carcinoma.
Non-keratinizing squamous cell carcinoma does not produce keratin pearls although individual dyskeratotic cells may be identified within the tumor. This tumor is composed of invasive nests of malignant squamous cells nuclear enlargement, hyperchromasia, increased nuclear/cytoplasmic ratio, and stromal desmoplastic response. An absence of keratin production is noted
Rarely, spindle cell morphology resembling a sarcomatoid carcinoma can be identified, and the tumor can be either monophasic or biphasic. Sarcomatoid carcinomas are exquisitely rare in the female genital tract and are usually clinically aggressive tumors . Very few cases have been described in the vulva [81–85], the majority of which show biphasic tumor morphology composed of areas of conventional squamous cell carcinoma as well as sarcomatoid carcinoma; rare tumors show heterologous differentiation including osteosarcoma and chondrosarcoma [82, 86].
Non-keratinizing vSCC should be distinguished from epithelioid sarcoma, an uncommon malignant soft tissue tumor that occurs in the distal extremities of young adults. Proximal/axial variants portend a worse prognosis and most commonly occur in the deep soft tissues or superficial inguinal soft tissues and rarely in the vulva . Microscopically, proximal epithelioid sarcomas are composed of acidophilic epithelioid tumor cells that may mimic invasive squamous cell carcinoma (Fig. 10.13) and contain cells with intracytoplasmic hyaline inclusions, resembling rhabdoid cells (Fig. 10.14). Large areas of necrosis are commonly identified. Both squamous cell carcinoma and epithelioid sarcoma express epithelial markers (keratin, EMA). Epithelioid sarcoma can be differentiated from squamous cell carcinoma based on its positive reaction with vimentin and variable expression of CD34, desmin, and smooth muscle actin (SMA).
Epithelioid sarcoma is a rare sarcoma that may have areas resembling a squamous cell carcinoma, especially sarcomatoid carcinomas
Epithelioid sarcoma, unlike squamous cell carcinoma, contains malignant cells with eosinophilic cytoplasmic inclusions, resembling rhabdomyoblasts
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Basaloid Squamous Cell Carcinoma
Basaloid squamous cell carcinoma is a non-keratinizing squamous cell carcinoma seen in association with HPV . The tumor is characterized by irregular nests of immature tumor cells resembling the basal-type cells identified within normal squamous epithelium (Fig. 10.15). The tumor cells are small with minimal cytoplasm and have a high N/C ratio. The chromatin is coarse but evenly distributed within the nucleus. These tumors typically fail to show evidence of squamous maturation. Rarely, squamous maturation and even keratinization can be identified within the center of tumor nests. Koilocytes are usually not identified.
Basaloid squamous cell carcinoma is HPV related and is composed of small basaloid-type squamous cells, which are cells that resemble the basal/parabasal cells of normal squamous epithelium. The cells are small and have a high nuclear/cytoplasmic ratio. Evidence of keratin production is usually not identified. Koilocyte-like cells are generally absent
Basaloid squamous cell carcinoma must be distinguished from basal cell carcinoma, metastatic small cell carcinoma, and Merkel cell carcinoma.
Basal cell carcinoma (BCC) is a common skin cancer identified on sun-exposed areas but is rarely seen on the vulva, comprising approximately 5 % of vulvar malignancies (Fig. 10.16) . The tumors have invasive nests of basaloid-type cells with characteristic peripheral palisading. Stromal desmoplasia and retraction artifact are also typically identified. Compared with basaloid squamous cell carcinoma, BCC is more circumscribed and is usually not associated with VIN. BCC is immunoreactive with BerEP4 (Table 10.7). Basaloid squamous cell carcinoma can also be BerEP4 reactive . One recent study found, however, that basaloid vSCC is BerEP4 negative . p16 is frequently reactive in both BCC and basaloid squamous cell carcinoma [91, 92]. BCC has patchy p16 expression with fewer than 30 % of tumor cells showing reactivity, which is in sharp contrast with the strong, diffuse p16 reaction observed in HPV-related basaloid vSCC . BerEP4 and p16 may not always be helpful in differentiating BCC and basaloid vSCC. In difficult cases, HPV in situ hybridization may be helpful, as BCC is HPV negative while basaloid vSCC is HPV positive . BCC is an indolent tumor that is locally invasive and is treated with complete surgical excision. See also Vignette 2 at the end of this chapter.
Basal cell carcinoma is characterized by invasive nests of basaloid cells that have peripheral nuclear palisading. Retraction artifact surrounding the invasive tumor nests is frequently identified. The stroma has a gray-blue characteristic
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