Secondary Logo

Clinicopathologic Variants of Cutaneous Squamous Cell Carcinoma

Lohmann, Christina M.; Solomon, Alvin R.

Advances in Anatomic Pathology: January 2001 - Volume 8 - Issue 1 - p 27-36
Review Articles And Mini Reviews
Free

Cutaneous squamous cell carcinomas (SCC) are one of the most common malignancies, which, with early recognition, may be curable. These tumors represent a broad spectrum of disorders with many significant clinical, morphologic, and etiologic distinctions. The objective of this article is to review the important clinicopathologic features of SCC with particular emphasis on important recent developments, practical application, and their relevance to the practice of pathology. The most pertinent literature of the last 5 years was reviewed and capsulized. Appropriate histologic interpretation and clinical management of patients with cutaneous SCC requires a comprehensive understanding of the latest advances in the broad field of dermatopathology. Squamous cell carcinoma of the skin represents a complex group of disease subtypes, each with its own characteristics, which may influence morphologic diagnosis as well as treatment and clinical management.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, U.S.A.

Address correspondence and reprint requests to Alvin R. Solomon, M.D., Department of Pathology and Laboratory Medicine, Room H172, Emory University Hospital, 1364 Clifton Rd. NE, Atlanta, GA 30322. E-mail: christinalohmann@hotmail.com.

Back to Top | Article Outline

INCIDENCE OF SQUAMOUS CELL CARCINOMA (SCC)

Nonmelanoma skin cancer (NMSC) is more common than any other cancer of the human body (1) with an estimated 2.75 million cases occurring annually worldwide (2). Second only to basal cell carcinomas (BCC), which are approximately five times more common, squamous cell carcinomas (SCC) account for 20% of all dermatologic malignancies (1,2). The incidence of SCC and BCC in the U.S. is estimated at 600,000 new cases annually. It is believed that this number dramatically underestimates the true number of cases since many lesions are untreated and others have not undergone histopathologic examination. Over the last decade the number of NMSC diagnoses has dramatically increased by 65%. Studies show a range of 65%–350% in women and 235% in men (3). Both BCC and SCC are capable of causing extensive tissue destruction with subsequent loss of function and disfigurement, thus making these tumors accountable for significant morbidity and health care expenditure in the U.S. (2). Although BCC is more common, the increased propensity for SCCs to metastasize makes them responsible for the majority of the estimated 1200 deaths from NMSC in the U.S. each year (3). With early detection, treatment is nearly always curable for these cancers.

Back to Top | Article Outline

CLINICOPATHOLOGIC FEATURES OF SCC

The pathogenesis of SCC is multifactorial. Squamous cell carcinoma can have many etiologies—extrinsic, intrinsic, or both. Ultraviolet sunlight exposure is unquestionably one of the most important. There is a linear correlation between SCC incidence and solar ultraviolet irradiation exposure (UVR). For every 8–10° decrease in latitude, there is a doubling in the incidence of SCC (1). Recent years have brought a greater understanding of UVR-induced carcinogenesis on a molecular basis. It is well established that UVR induces the formation of pyrimidine dimers resulting in DNA point mutations. Ultraviolet irradiation exposure can also act as a tumor promoter (4) apparently causing mutations in the p53 tumor suppressor gene found in 90% of SCCs (5). It has been postulated that early sunlight exposure may be the inciting event of carcinogenesis with subsequent exposures, later in life promoting tumor development and altering host immunity. Other extrinsic factors also play a role in SCC development. Cutaneous radiation is a well-known carcinogen. Patients treated with psoralen plus ultraviolet A (PUVA) are 30 times more likely to develop SCC than the general population (6–9). Exposure to chemicals such as arsenic (10), polycyclic aromatic hydrocarbons, or those found in tobacco products, is also strongly linked to tumor development. Infectious agents are also culpable. Human papillomavirus type-16 is consistently present in SCCs of the genital and periungual areas, as well as Bowen's disease lesions (11–13).

Intrinsic factors in the evolution of SCC include skin pigmentation, age, and many primary dermatoses associated with photosensitivity or scarring. Two hereditary conditions associated with a high incidence of SCC include xeroderma pigmentosa and oculocutaneous albinism. Xeroderma pigmentosa is an autosomal recessive condition characterized by defects in the nucleotide excision repair pathway, which is responsible for the inability to repair UVR-induced DNA damage. They suffer from extreme photosensitivity and a 2000-fold increased risk for skin cancer. Patients with oculocutaneous albinism lack sufficient melanin production to protect themselves from harmful UVR damage. With the ever-growing number of organ transplant recipients and AIDS patients, the importance of immune status in the evolution of SCC has become increasingly recognized. Not only is there an increased incidence of SCC in these patients but their tumors also behave more aggressively.

Back to Top | Article Outline

SCC IN SUN-EXPOSED SKIN: PRECURSOR LESION

Squamous cell carcinomas arising in actinically damaged, sun-exposed skin are usually found in the head and neck region, upper extremities, trunk and, particularly in women, the lower extremities. Those tumors originating in nonsun-exposed areas are most frequently found in the trunk, genitalia, and soles. Historically, actinic keratosis (AK), also known as solar keratosis, has been thought of as precancerous. When confined to the epidermis, these lesions do not demonstrate metastatic potential. However, if left untreated, these lesions have the potential to invade the dermis and, subsequently, metastasize (14,15). For these reasons actinic keratosis and SCCs have been viewed as different points along the same spectrum (16). Currently, there is substantial disagreement over the rate of transformation of AK to SCC. There are few controlled studies accurately evaluating the progression of AK to SCC and most are confounded by numerous other variables. One study declared the likelihood of a fully developed SCC evolving from a given actinic keratosis to have a reported range of 0.075%–0.096% per lesion per year (17). Thus, for an individual with 7.7 AKs, the average number for an affected person, the rate of SCC development over a decade would be 10.2% (18). The actual risk of an individual AK may be low, but because most people have developed many, their overall risk for progression to SCC is relatively high. Others have estimated the rate of transformation to be 13–20% over a 10-year period (19). These rates are similar to those of intraepithelial neoplasia at other sites. For example, 15% of untreated low-grade cervical intraepithelial lesions (CIN I and CIN II) will evolve into squamous cell carcinoma in situ (20). Similar findings have been found in vulvar and vaginal intraepithelial neoplasia. In fact, a reclassification of AK and SCC, using the terminology keratinocytic intraepithelial neoplasia (KIN), has been proposed (21).

Back to Top | Article Outline

HISTOLOGIC SUBTYPES

There are several histologic subtypes of SCC with the generic or conventional (simplex) subtype being the most common (Table 1). There is some prognostic significance to the various subtypes with the generic type carrying the greatest risk of metastasis followed by lobular/acantholytic, bowenoid, and spindle/pleomorphic which all carry a similar risk (22,23). The most favorable prognosis is found with verrucous carcinomas (1).

TABLE 1

TABLE 1

Back to Top | Article Outline

Generic/Simplex

Most squamous cell carcinomas fall under the heading of generic, simplex, or conventional SCCs. Atypical keratinocytes develop within the epidermis and, subsequently, invade into the dermis (Fig. 1). Tumor cells show enlarged, hyperchromatic, variably pleomorphic nuclei with often prominent mitotic activity. Atypical mitoses are present. Many produce large amounts of keratin resulting in frequent keratin-pearl formation. Intercellular bridges are usually easily seen. An essential feature for the diagnosis is the presence of invasion. This can be difficult to clearly identify in early lesions. Fortunately, however, the treatment and prognosis for borderline invasive lesions is the same. Immunohistochemically, these tumors demonstrate positive antibody staining for high and occasionally even low molecular weight cytokeratins (24). Vimentin antibody immunoreactivity may be present in poorly differentiated tumors (25).

FIG. 1

FIG. 1

Back to Top | Article Outline

Adenoid/Acantholytic

Adenoid, lobular, or acantholytic SCCs form a pseudoglandular, acantholytic, microscopic appearance (Fig. 2). Tumor cells are arranged in cords and nests with clefts produced by acantholysis of cells leaving spaces that superficially resemble glands. Enlarged free floating dysplastic keratinocytes may be found within the lumina. Clinically, these lesions typically present as an ulcer or crusted nodule on the head and neck of men in their fifth to sixth decade (1,26). These tumors have also been associated with recurrences following radiation therapy. The biologic behavior of adenoid SCC is somewhat controversial. There are studies showing that they behave more aggressively than conventional SCC (22) and other studies that claim the tendency to metastasize is less than that of de novo SCC (26).

FIG. 2

FIG. 2

Back to Top | Article Outline

Bowenoid

Originally described in 1912 by John T. Bowen, Bowen's disease is considered by most dermatopathologists to be squamous cell carcinoma in situ. The most common site is the head and neck, followed by the lower limbs, upper limbs, and trunk. Although men and women are affected equally, one recent study demonstrated that 72% of lower limb lesions were from women, whereas 79% of scalp and ear specimens were from men (27). The locations of these lesions are supportive of the role of ultraviolet radiation in their etiology. Other etiologic factors include radiation therapy, arsenic exposure, and the human papillomavirus. HPV 2 has been identified in extragenital lesions and type-16 has been associated with genital disease (28,29). Most affected individuals are in their sixth to eight decade (28). It had been previously hypothesized that Bowen's disease was related to other malignancies, especially internal cancers (30). Many recent studies, however, have been unable to substantiate this (31,32,33,34). Clinically, the classic presentation is that of a well-demarcated, slow-growing, erythematous, scaly patch measuring a few millimeters to centimeters in diameter. Morphologically, the epidermis displays hyperkeratosis and acanthosis with mild to moderate psoriasiform hyperplasia (Fig. 3)(28). The atypia is full thickness with a loss of polarity reflecting a cessation of maturation (28,34). Dyskeratotic cells and atypical mitoses are numerous. Adnexal structures are frequently involved (28). When the neoplastic keratinocytes invade the dermis, the term bowenoid squamous cell carcinoma is used for this subtype of SCC.

FIG. 3

FIG. 3

Back to Top | Article Outline

Erythroplasia of Queyrat

Erythroplasia of Queyrat (EoQ) represents SCC in situ presenting on the mucous membranes of the glans penis, vulva, and oral mucosa, Although many have considered EoQ to be identical to Bowen's disease, a few pertinent differences exist (35,36). Erythroplasia of Queyrat is believed to have its origin in trauma, poor hygiene, smegma irritation, friction, syphilis, and other inflammatory situations. Bowenoid atypia occurring in these sites is more aggressive than similar appearing lesions in other anatomic sites. Most importantly, 30% invade the dermis and approximately 20% metastasize (37). Patients are typically uncircumcised men in their 30's to 60's. These red, well-demarcated, velvety plaques are usually asymptomatic but minor itching and bleeding may occur (35,36,38,39,40). Histologically, these lesions are identical to the bowenoid pattern of squamous cell carcinoma in situ.

An important diagnostic consideration in the differential diagnosis of Bowen's disease and EoQ is bowenoid papulosis. These entities can appear histologically identical; however, their clinical characteristics and behavior differ dramatically. Bowenoid papulosis is a purportedly benign condition in contrast to the malignant behavior of Bowen's disease and EoQ. Their macroscopic appearances also differ—bowenoid papulosis forms multiple, small brown papules usually on the penile shaft, whereas Bowen's disease and EoQ present as well-defined erythematous plaques in a variety of sites. Bowenoid papulosis and EoQ are seen primarily in men; Bowen's disease occurs equally in men and women.

Back to Top | Article Outline

Spindle/Pleomorphic/Sarcomatoid

Another type of squamous cell carcinoma is the rare spindle-cell/pleomorphic variant. An association with previous trauma or radiotherapy has been occasionally noted. Most commonly found on the face and other sun-exposed areas of the elderly, these tumors are often diagnostically challenging. Ulceration is common, although they may present as an exophytic mass. Microscopically, whorls of atypical squamous cells comingle with collagen fibers (Fig. 4)(41). Intertwining fascicles and bundles of atypical keratinocytes are surrounded by a myxoid and often storiform stroma (1). Pleomorphic giant cells may be present (1). The neoplastic keratinocytes have hyperchromatic eosinophilic cytoplasm, elongated, pleomorphic, and vesicular nuclei with multiple nucleoli (42). Numerous mitotic figures are present with occasional atypical forms seen (42). Immunohistochemistry may be useful in characterizing these neoplasms. Spindle-cell SCC stains positively with antibodies to cytokeratins, epithelial membrane antigen, and vimentin (Fig. 5)(42). Awareness of the potential for vimentin-positivity is critical to avoid erroneous interpretation of spindle/pleomorphic SCC as a sarcoma, such as atypical fibrous xanthoma or a malignant fibrous histiocytoma.

FIG. 4

FIG. 4

FIG. 5

FIG. 5

Back to Top | Article Outline

Verrucous

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.

FIG. 6

FIG. 6

Back to Top | Article Outline

Small Cell

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.

FIG. 7

FIG. 7

Back to Top | Article Outline

Actinic Keratosis, SCC In-Situ, and Microinvasive SCC

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).

FIG. 8

FIG. 8

Back to Top | Article Outline

RISK FACTORS FOR METASTASIS AND RECURRENCES

Anatomic Considerations

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.

Back to Top | Article Outline

Histopathologic Parameters

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).

FIG. 9

FIG. 9

Back to Top | Article Outline

Immune Status

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).

Back to Top | Article Outline

CONCLUSION

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.

Back to Top | Article Outline

REFERENCES

1. Bernstein SC, Lim KK, Brodland DG, et al. The many faces of squamous cell carcinoma. Dermatol Surg 1996; 22:243–54.
2. Strom SS, Yamamura Y. Epidemiology of nonmelanoma skin cancer. Clin Plast Surg 1997; 24:627–36.
3. Karagas MR, Greenberg ER, Spencer SK, et al. Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA. New Hampshire Skin Cancer Study Group. Int J Cancer 1999; 81:555–9.
4. Rundel RD. Promotional effects of ultraviolet radiation on human basal and squamous cell carcinoma. Photochem Photobiol 1983; 38:569–75.
5. Ziegler A, Jonason A, Simon J, et al. Tumor suppressor gene mutations and photocarcinogenesis. Photochem Photobiol 1996; 63:432–5.
6. Stern RS, Laird N, Melski J, et al. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med 1984; 310:1156–61.
7. Forman AB, Roenigk Jr, HH Caro WA, et al. Long-term follow-up of skin cancer in the PUVA-48 cooperative study. Arch Dermatol 1989; 125:515–9.
8. Stern RS, Laird N, Melski J, et al. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med 1984; 310:1156–61.
9. Stern RS, Lange R. Non-melanoma skin cancer occurring in patients treated with PUVA five to ten years after first treatment [published erratum appears in J Invest Dermatol 1989 Feb;92(2): 300]. J Invest Dermatol 1988; 91:120–4.
10. Wong SS, Tan KC, Goh CL. Cutaneous manifestations of chronic arsenicism: review of seventeen cases. J Am Acad Dermatol 1998; 38:179–85.
11. Crum CP, Ikenberg H, Richart RM, et al. Human papillomavirus type 16 and early cervical neoplasia. N Engl J Med 1984; 310:880–3.
12. Moy R, Eliezri YD. Significance of human papillomavirus-induced squamous cell carcinoma to dermatologists [editorial] [see comments]. Arch Dermatol 1994; 130:235–8.
13. Moy RL, Eliezri YD, Nuovo GJ, et al. Human papillomavirus type 16 DNA in periungual squamous cell carcinomas [see comments]. JAMA 1989; 261:2669–73.
14. Dinehart SM, Nelson-Adesokan P, Cockerell C, et al. Metastatic cutaneous squamous cell carcinoma derived from actinic keratosis. Cancer 1997; 79:920–3.
15. Fukamizu H, Inoue K, Matsumoto K, et al. Metastatic squamous-cell carcinomas derived from solar keratosis. J Dermatol Surg Oncol 1985; 11:518–22.
16. Freeman RG. History of the American Society of Dermatopathology. Am J Dermatopathol 1984; 6:25–33.
17. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1988; 1:795–7.
18. Dodson JM, DeSpain J, Hewett JE et al. Malignant potential of actinic keratoses and the controversy over treatment: a patient-oriented perspective. Arch Dermatol 1991; 127:1029–31.
19. Montgomery H, Dorfell J. Verruca senilis and keratoma senile. Arch f Dermat u Syphil 1939; 39:387–408.
20. Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol 1993; 12:186–92.
21. Yantsos VA, Conrad N, Zabawski E, et al. Incipient intraepidermal cutaneous squamous cell carcinoma: a proposal for reclassifying and grading solar (actinic) keratoses. Semin Cutan Med Surg 1999; 18:3–14.
22. Nappi O, Pettinato G, Wick MR. Adenoid (acantholytic) squamous cell carcinoma of the skin. J Cutan Pathol 1989; 16:114–21.
23. Goepfert H, Dichtel WJ, Medina JE, et al. Perineural invasion in squamous cell skin carcinoma of the head and neck. Am J Surg 1984; 148:542–7.
24. Iyer PV, Leong ASY. Poorly differentiated squamous cell carcinomas of the skin can express vimentin. J Cutan Pathol 1992; 19:34–3.
25. Smith KJ, Skelton HG, Morgan AM, et al. Spindle cell neoplasms coexpressing cytokeratin and vimentin (metaplastic squamous cell carcinoma). J Cutan Pathol 1992; 19:286–93.
26. Johnson WC, Helwig EB. Adenoid squamous cell carcinoma (adenoacanthoma): a clinicopathologic study of 155 patients. Cancer 1966; 19:1639–50.
27. Kossard S, Rosen R. Cutaneous Bowen's disease: an analysis of 1001 cases according to age, sex, and site. J Am Acad Dermatol 1992; 27:406–10.
28. Lee MM, Wick MM. Bowen's disease. Clin Dermatol 1993; 11:43–6.
29. Ikenberg H, Gissmann L, Gross G, et al. Human papillomavirus type-16-related DNA in genital Bowen's disease and in bowenoid papulosis. Int J Cancer 1983; 32:563–5.
30. Graham JH, Helwig EB. Bowen's disease and its relationship to systemic cancer. Arch Dermatol 1959; 80:133–59.
31. Chute CG, Chuang TY, Bergstralh EJ, et al. The subsequent risk of internal cancer with Bowen's disease: a population-based study [see comments]. JAMA 1991; 266:816–9.
32. Chuang TY, Tse J, Reizner GT. Bowen's disease (squamous cell carcinoma in situ) as a skin marker for internal malignancy: a case-control study. Am J Prev Med 1990; 6:238–43.
33. Reymann F, Ravnborg L, Schou G, et al. Bowen's disease and internal malignant diseases: a study of 581 patients. Arch Dermatol 1988; 124:677–9.
34. Fitzpatrick JE. The histologic diagnosis of intraepithelial pagetoid neoplasms. Clin Dermatol 1991; 9:255–9.
35. Kaye V, Zhang G, Dehner LP, et al. Carcinoma in situ of penis. Is distinction between erythroplasia of Queyrat and Bowen's disease relevant? Urology 1990; 36:479–82.
36. Dixon RS, Mikhail GR. Erythroplasia (Queyrat) of conjunctiva. J Am Acad Dermatol 1981; 4:160–5.
37. Karagas MR, Stukel TA, Greenberg ER, et al. Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. Skin Cancer Prevention Study Group. JAMA 1992; 267:3305–10.
38. Bernstein G, Forgaard DM, Miller JE. Carcinoma in situ of the glans penis and distal urethra [published erratum appears in J Dermatol Surg Oncol 1987 Mar;13(3):following 226]. J Dermatol Surg Oncol 1986; 12:450–5.
39. Gerber GS. Carcinoma in situ of the penis. J Urol 1994; 151:829–33.
40. Schellhammer PF, Jordan GH, Robey EL, et al. Premalignant lesions and nonsquamous malignancy of the penis and carcinoma of the scrotum. Urol Clin North Am 1992; 19:131–42.
41. Marks R. Squamous cell carcinoma. Lancet 1996; 347:735–8.
42. Smith KJ, Skelton HGD, Morgan AM, et al. Spindle cell neoplasms coexpressing cytokeratin and vimentin (metaplastic squamous cell carcinoma). J Cutan Pathol 1992; 19:286–93.
43. Spiro RH. Verrucous carcinoma, then and now. Am J Surg 1998; 176:393–7.
44. Florin EH, Kolbusz RV, Goldberg LH. Verrucous carcinoma of the oral cavity. Int J Dermatol 1994; 33:618–22.
45. Kasperbauer JL, O'Halloran GL, Espy MJ, et al. Polymerase chain reaction (PCR) identification of human papillomavirus (HPV) DNA in verrucous carcinoma of the larynx. Laryngoscope 1993; 103:416–20.
46. Grinspan D, Abulafia J. Oral florid papillomatosis (verrucous carcinoma). Int J Dermatol 1979; 18:608–22.
47. Goldman GD. Squamous cell cancer: a practical approach. Semin Cutan Med Surg 1998; 17:80–95.
48. Coldiron BM, Brown FC, Freeman RG. Epithelioma cuniculatum (carcinoma cuniculatum) of the thumb: a case report and literature review. J Dermatol Surg Oncol 1986; 12:1150–5.
49. Noel JC, Heenen M, Peny MO, et al. Proliferating cell nuclear antigen distribution in verrucous carcinoma of the skin. Br J Dermatol 1995; 133:868–73.
50. McKee PH, Wilkinson JD, Black MM, et al. Carcinoma (epithelioma) cuniculatum: a clinico-pathological study of nineteen cases and review of the literature. Histopathology 1981; 5:425–36.
51. Schwartz RA, Nychay SG, Lyons M, et al. Buschke-Lowenstein tumor: verrucous carcinoma of the anogenitalia. Cutis 1991; 47:263–6.
52. Seixas AL, Ornellas AA, Marota A, et al. Verrucous carcinoma of the penis: retrospective analysis of 32 cases. J Urol 1994;152:1476–8; discussion 1478–9.
53. Sibley RK, Dehner LP, Rosai J. Primary neuroendocrine (Merkel cell?) carcinoma of the skin: I. A clinicopathologic and ultrastructural study of 43 cases. Am J Surg Pathol 1985; 9:95.
54. Visscher D, Cooper PH, Zarbo RJ, et al. Cutaneous neuroendocrine (Merkel cell) : an immunophenotypic, clinicopathologic and flow cytometric study. Mod Pathol 1989; 2:331.
55. LeBoit PE, Crutcher WA, Shapiro PE. Pagetoid intraepidermal spread in Merkel cell (primary neuroendocrine) carcinoma of the skin. Am J Surg Pathol 1992; 16:584.
56. Marks R, Rennie G, Selwood TS. The malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1988; 1:795–7.
57. Barnhill R, Textbook of dermatopathology; McGraw–Hill, 1998;507.
58. Carag HR, Prieto VG, Yballe LS, et al. Utility of step sections. Arch Dermatol 2000; 136:471–5.
59. Breuninger H, Black B, Rassner G. Microstaging of squamous cell carcinomas. Am J Clin Pathol 1990; 94:624–7.
60. Scotto J, Fears TR, Fraumen JF. Incidence of non-melanoma skin cancer in the United States. Publication No. 83-2433 Bethesda: NIH, 1983.
61. Rowe DE, Carroll RJ, Day Jr. CL Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip: implications for treatment modality selection [see comments]. J Am Acad Dermatol 1992; 26:976–90.
62. Lever LR, Farr PM. Skin cancers or premalignant lesions occur in half of high-dose PUVA patients. Br J Dermatol 1994; 131:215.
63. Ballantyne AJ, McCarten AB, Ibanez M. The extension of cancer of the head and neck through peripheral nerves. Am J Surg 1963; 106:651–67.
64. Barksdale SK, O'Connor N, Barnhill R. Prognostic factors for cutaneous squamous cell and basal cell carcinoma: determinants of risk of recurrence, metastasis, and development of subsequent skin cancers. Surg Oncol Clin N Am 1997; 6:625–38.
65. Frierson HF, Cooper PH. Prognostic factors in squamous cell carcinoma of the lower lip. Hum Pathol 1986; 17:346.
66. Petter G, Haustein UF. Squamous cell carcinoma of the skin: histopathological features and their significance for the clinical outcome. J Eur Acad Dermatol Venereol 1998; 11:37–44.
67. Immerman SC, Scanlon EF, Christ M. Recurrent squamous cell carcinoma of the skin. Cancer 1983; 51:1537.
68. Maize JE. Skin cancer in immunosuppressed patients. JAMA 1977; 237:1857–8.
69. Cottel WI. Perineural invasion by squamous-cell carcinoma. J Dermatol Surg Oncol 1982; 8:589–600.
70. Gupta AK, Cardella CJ, Haberman HF. Cutaneous malignant neoplasms in patients with renal transplants. Arch Dermatol 1986; 122:1288–93.
71. Penn I. Immunosuppression and skin cancer. Clin Plast Surg 1980; 7:361–8.
72. Hardie IR, Strong RW, Hartley LC, et al. Skin cancer in Caucasian renal allograft recipients living in a subtropical climate. Surgery 1980; 87:177–83.
73. Hartevelt MM, Bavinck JN, Kootte AM, et al. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 1990; 49:506–9.
74. Lampros TD, Cobanoglu A, Parker F, et al. Squamous and basal cell carcinoma in heart transplant recipients. J Heart Lung Transplant 1998; 17:586–91.
75. Penn I, Brunson ME. Cancers after cyclosporine therapy. Transplant Proc 1988; 20:885–92.
76. Penn I. Depressed immunity and the development of cancer. Clin Exp Immunol 1981; 146:459–74.
77. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999; 40:177–86.
78. McGregor JM, Proby CM. Skin cancer in transplant recipients [letter; comment]. Lancet 1995; 346:964–5.
79. Cohen E, Komorowski R, Clowry L. Cutaneous complications in renal transplant recipients. Am J Clin Pathol 1997; 88:32–7.
80. Dyall-Smith D, Trowell H, Dyall-Smith ML. Benign human papillomavirus infection in renal transplant recipients. Int J Dermatol 1991; 30:785–9.
81. Euvrard S, Chardonnet Y, Pouteil-Noble C, et al. Association of skin malignancies with various and multiple carcinogenic and noncarcinogenic human papillomaviruses in renal transplant recipients. Cancer 1993; 72:2198–206.
82. Cowen EW, Billingsley EM. Awareness of skin cancer by kidney transplant patients. J Am Acad Dermatol 1999; 40:697–701.
Keywords:

Squamous cell carcinoma (SCC); Skin tumor; Skin cancer; Cutaneous malignancy

© 2001 Lippincott Williams & Wilkins, Inc.