Verrucous carcinomas are exophytic or endophytic masses which often grow at sites of chronic irritation, slowly invading into soft tissues or underlying bone when left untreated. Morphologically, they appear well differentiated with little atypia. Their behavior is indolent with local destruction but little to no propensity for metastasis. There are three distinct clinicopathologic types of verrucous carcinoma based primarily on location: oral, plantar, and the Buschke–Loewenstein tumors.
Oral verrucous carcinoma has been reported in the literature under a variety of names, including oral florid verrucosis, florid papillomatosis, and verruca acuminata. Originally described by Lauren Ackerman in 1948, this tumor represents 4.5%–9% of all oral cavity tumors (43). Tobacco chewing, snuff dipping, and betel leaf/nut and lime use, have shown a particularly strong association with this tumor (44). Human papillomavirus DNA has been identified in up to 85% of patients with laryngeal verrucous carcinoma (45). Poor oral hygiene and denture use have also been implicated (44). Clinically, these tumors presented as slow-growing white/gray warty growths on the buccal mucosa of elderly Caucasian men (1,46). Other common locations include gingivae, alveolar ridge, floor of the mouth, tongue, tonsils, and the retromolar areas. Patients may be asymptomatic, but pain, soreness, and difficulty chewing have been described (1). Lesions begin as white translucent patches on an erythematous base and progress to larger, cauliflower-like papillomas, which may extend over large areas of oral mucosa (1). Histologically, the epithelium resembles that of a well-differentiated SCC with a papillomatous growth pattern. Hyperkeratosis with orthokeratosis overlies numerous undulating, broad, bulbous-rete pegs that “bulldoze rather than stab” surrounding tissues (47). Cells are large and mitotic figures are easily identified.
Plantar carcinoma is also known as epithelioma cuniculatum, papillomatosis cutis, or carcinoma cuniculatum. Cuniculatum means “rabbit burrow” or “rabbit warren” and relates to the many crypt openings of this tumor to the skin surface. A relationship between this tumor and HPV has not been established; however, studies of proliferating cell nuclear antigens have suggested a link to large warts or condylomata (48,49). Possible etiologies for this tumor include low dose radiotherapy, chronic infection, or inflammation (50). Most cases occur in older men with a mean age of 60 years (1). Clinically, these are slowly enlarging, fleshy pink, well-circumscribed, exophytic masses that most commonly involve the skin overlying the first metatarsal head. They may also occur on the toes, heel, midplantar region, and even leg, knee, wrist, finger, hand, abdominal wall, buttocks, nose, or scalp (48). Deep sinus tracts draining foul-smelling keratinaceous material may cause bleeding and pain upon ambulation. Morphologically, this tumor demonstrates a verrucous hyper/parakeratotic exophytic component, as well as an endophytic component composed of epithelial-lined crypts filled with keratinaceous debris. Few mitotic figures are identified.
The anogenital type of verrucous carcinoma was first described by Buschke and Loewenstein in 1925 and subsequently named after them. Other terms also used include giant malignant condyloma, or carcinoma-like condyloma. These tumors constitute 5%–24% of all penile cancers and occur most commonly in uncircumcised men under the age of 50 (51). HPV types 6 and 11 have been detected in these lesions (52). They present as cauliflower-like excrescences most commonly on the glans penis, although the prepuce, coronal sulcus, and perianal mucosa may also be involved. Ulceration and fistulas are common. A foul smell may be noticed. Compression or involvement of the urethra, genitalia, and perineum may ultimately cause functional impairment (52). Microscopically, Buschke–Loewenstein tumors are characterized by extensive verrucous acanthosis with subtle-to-prominent extension into the dermis and subcutis (Fig. 6). Keratinocyte atypia is minimal. Hypergranulosis and crypt/sinus tract formation are evident. Koilocytic changes may be seen.
The small cell nonkeratinizing variant of SCC may closely resemble metastatic small cell neuroendocrine carcinoma or cutaneous Merkel cell carcinoma. Small cell SCC can usually be differentiated from small cell neuroendocrine carcinoma at the light microscopic level. Small cell SCC may be associated with overlying in situ SCC and invades in cohesive nests with an adjacent intense inflammatory and desmoplastic host response. While nuclear molding is prominent in the small cells of neuroendocrine carcinoma, this finding is typically absent in small cell SCC (Fig. 7). Immunohistochemistry can help to differentiate the two, but there is some overlap in immunophenotype. Squamous cell carcinomas typically demonstrate diffuse cytoplasmic positivity for cytokeratins, but may also react with neuroendocrine markers, particularly neuron-specific enolase (NSE). Merkel cell carcinomas also demonstrate immunopositivity with antibodies to cytokeratins with a perinuclear globular or “dot-like” pattern (53,54,55). Cytokeratin 20 can also be useful in distinguishing Merkel cell carcinoma from SCC, since this marker is limited to the former. Merkel cell carcinomas may also show positive antibody staining with antibodies to chromogranin A, synaptophysin, epithelial membrane antigen, NSE, calcitonin, and vasoactive intestinal peptide.
Actinic keratosis (AK) is generally considered to be a precursor lesion of SCC—malignant transformation is estimated at 0.1% per lesion per year (56). There is little debate that multiple AKs indicate an increased risk for cutaneous SCC. Less certain, however, is the ability of dermatopathologists to reproducibly differentiate between AK and SCC in-situ (SCCIS). Full thickness keratinocyte atypia is frequently proposed as a prerequisite for the histopathologic diagnosis of SCCIS (57). However, since the areas of full thickness atypia are usually multifocal, there is considerable overlap in the microscopic appearance of AK and SCCIS, so that some authors have proposed the more descriptive term “keratinocyte intraepidermal neoplasm” to encompass the entire range of noninvasive keratinocytic neoplasia (21). Although this is a reasonable concept, we prefer to use the traditional clinicopathologic terms AK and SCCIS, while fully realizing the subjectivity of these terms. The reason for this preference is that dermatologists may desire to treat lesions at the SCCIS end of the spectrum more aggressively than those at the AK end, i.e., electrodesiccation and curettage versus cryotherapy.
Recognition of the breakpoint between hypertrophic AK, SCCIS, and SCC with thin dermal invasion is also subjective. The requirement of recognizable disruption of the basement membrane zone as applied to other organs, such as SCC of the uterine cervix, is clearly not a reasonable criterion for invasion in cutaneous SCC. This requirement would lead to the untenable position of a diagnosis of in-situ SCC for those SCCs with lobules of atypical keratinocytes in the deep dermis or even subcutis that are in continuity with the epidermal surface such as verrucous SCC.
In order to avoid this problem and call attention to early invasive SCC, we employ the term microinvasive SCC (MISCC). Differentiating these neoplasms from hypertrophic AKs and thick SCC in-situ is subjective, but is again potentially useful since it alerts the dermatologist to neoplasms presumed to be at a greater risk, although minimally, for more aggressive clinical behavior. Microinvasive SCC is usually characterized by downward proliferation of lobules or cords of atypical keratinocytes in continuity with the overlying epidermis (Fig. 8). A second pattern of MISCC consists of thick plaques of atypical keratinocytes that frequently have a bowenoid pattern of proliferation. Microinvasive SCC may be in continuity with a deep invasive SCC. Consequently, proper biopsy selection, an adequate specimen, and the judicious use of step sections as discussed by Carag et al. are essential for proper evaluation of these neoplasms (58).
Many factors are thought to influence the biologic behavior of SCC. Several studies have demonstrated an association between the largest tumor diameter and prognosis (59,60). Size greater than 2 cm doubles the recurrence rate and triples the metastatic rate to 30%, as opposed to a recurrence rate of 10% for lesions <2cm (60). Squamous cell carcinomas with a rapid growth rate are at increased risk for metastatic spread. Location also plays a role. Cutaneous sun-exposed SCCs are less likely to recur (5%) or metastasize (0.05%) than nonsun-exposed/mucosal surface tumors (61,62). Scar carcinomas, in particular, are extremely aggressive with burn-scar carcinomas exhibiting a 30% metastatic rate. This may be due to the difficulty of detecting a tumor in a scarred area or to a poor immune response secondary to an inadequate local blood supply. Cancers of the lip (16%) and ear have a higher metastatic rate (10%) than those of other head and neck sites (63,64). This may be due to a paucity of subcutaneous fat, which allows easy access to the underlying lymphatics of the auricular perichondrium and labial musculature (65). In general, the closer to a mucosal orifice, the greater the potential for recurrence and/or metastasis in SCC. Tumor thickness, analogous to Breslow's micromeasurements in melanoma, correlates with survival (66). The cumulative metastasis/ recurrence-free survival at 3 years was 98% for tumors <3.5mm in depth and 84% for SCCs thicker than 3.5mm (66). Clark's levels of invasion, as employed in melanoma diagnoses, can also have prognostic implications in SCC. Tumors greater than a Clark's level IV or V or greater than 4mm in depth, had a metastatic rate of 45.7% (64,65,67). Previously treated SCCs are associated with greater metastatic potential (71). Twenty-five percent of recurrent cancers metastasize. If the primary tumor was located on the ear, the metastatic rate may actually be as high as 45%, or 32% for the lip.
Histopathologic parameters can also aid in predicting tumor behavior. Broder's classification stratifies tumors into four categories based on the degree of nuclear pleomorphism and cytoplasmic maturity. Tumors are assigned a grade I–IV representing, well-differentiated (<25% undifferentiated cells), moderately welldifferentiated (<50% undifferentiated), poorly differentiated (<75% undifferentiated), and anaplastic/pleomorphic (>75% undifferentiated). Poorly differentiated tumors have a recurrence rate approximately three times that of well-differentiated examples (67). Microscopic growth patterns can influence prognosis. Squamous cell carcinomas with a small nest, infiltrative pattern, diffuse haphazard growth, isolated strands, and clusters of cells or single cells are at a higher risk for recurrence and metastasis than those with broad, pushing borders. Perineural invasion, defined as contiguous tumor growth along the loose connective tissue of the perineurium, is found in 2.4%–14% of SCCs and is even more frequent in recurrences (22,67–69) (Fig. 9). Goepfert et al. reported a 2-year cure rate of only 2% after surgical excision for cutaneous SCC with perineural invasion (69). However, many studies on the significance of perineural invasion have been confounded by the presence of many other “high risk” factors. It is generally thought that the generic/simplex SCC histologic subtype has the greatest risk of metastasis. Studies concerning the prognostic implications of the adenoid or acantholytic pattern are controversial at best (22,26).
Many investigators have found an increased incidence of dermatologic malignancies in transplant patients (70–72). Squamous cell carcinoma is at least 18 to 36 times more prevalent in organ transplant recipients than in the general population (70–72). Also, the ratio of BCC to SCC is reversed, with SCCs occurring more frequently than BCC at a reported ratio of 3.6:1 (39,73). One study calculated the cumulative risk of SCC or BCC development in a heart transplant recipient to be 3% at 1 year, growing to 21% at 5 years and 35% at 10 years (74). In addition to the increased frequency of skin tumors in this population, the tumors appear to be biologically more aggressive (68,70,75,76). Transplant patients with SCC have a higher incidence of lymph node metastases and deaths secondary to skin cancer (76). The pathogenesis of SCC in this immunosuppressed population relates primarily to three factors: immunosuppressive drugs, ultraviolet irradiation, and viral infection. The risk of post-transplant SCC is related to the degree of immunosuppression. One study found that renal transplant recipients receiving cyclosporine, azathioprine, and prednisolone had a 2.8 times higher risk of developing a cutaneous SCC compared to those patients receiving only azathioprine and prednisolone (77). The etiologic role of sun exposure is highlighted by the finding that over 90% of tumors develop on sun-exposed areas of the body (73,78–80). HPV DNA has also been strongly associated with SCC occurrence in kidney transplant recipients (80,81). Unfortunately, a recent study demonstrated the need for increasing awareness of the risk for cutaneous malignancies in transplant recipients. Of 122 renal transplant recipients, only 41% were able to recall specific skin cancer education and only 14% were followed up regularly by a dermatologist (82).
Cutaneous squamous cell carcinomas are a heterogenous group of tumors with many distinctive characteristics that can affect diagnosis and appropriate patient management. Histologic parameters, etiologic considerations, clinical features, and treatment options must all be evaluated and understood in order to provide optimal patient care.
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