Squamous Cell Carcinoma of the Skin

Background

This is the second most common form of skin cancer in Caucasians. Like basal cell carcinomas, there is a propensity for the cancer to occur on sun-exposed surfaces on fair skinned individuals. The head and neck are favored sites but it has occurred at nearly every site. Several skin diseases may predispose to the development of this carcinoma including dystrophic epidermolysis bullosa, porokeratosis, discoid lupus erythematosus, lichen sclerosis et atrophicus, balanitis xerotica obliterans, epidermodysplasia verruciformis, and acrodermatitis chronica atrophicans. Immunosuppression plays an important role and renal transplant patients are at 18 times increased risk. Many of these cancers are associated with Human Papilloma Virus (HPV) types 5 and 8. HPV, you may recall, is the etiologic agent for condyloma (venereal warts).

The cancers are shallow ulcers with a crust and are frequently elevated. Like basal cell carcinomas, these cancers can be locally aggressive with high rates of recurrence. Higher recurrence is usually seen with poorly differentiated tumors, perineural invasion, and acantholytic features. There is at least a double local recurrence rate as compared to basal cell carcinomas. Unlike basal cell carcinomas, these cancers do have a small but definite risk of metastasis. It varies depending upon the site and histologic type of cancer-see table. Metastasis may involve the regional lymph nodes and rarely the lungs and skin.

Like basal cell carcinomas, there are several histologic variants that are important to identify because of their more aggressive behavior. Spindle cell or sarcomatoid carcinomas have a predominately spindle cell appearance with minimal keratinization. Adenoid squamous or acantholytic cell carcinomas have discohesive features between squamous cells. Pseudovascular or pseudoangiosarcomatous carcinomas are composed of cells which mimic vascular structures, raising the differential diagnosis of an angiosarcoma. All of these variants are locally aggressive with increased risk for recurrence and high mortality.

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS SCC
Epidermoid carcinoma of the skin

INCIDENCE
20% of all dermatologic malignancies, second only to basal cell carcinomas

600,000 new cases of both SCC and BCC/year/United States

Arsenic exposure

Acts as a promoter causing mutations in the p53 tumor suppressor gene found in 90% of cancers

Cutaneous radiation

Human Papilloma virus 5 and 16

Polycyclic aromatic hydrocarbons

Psoralen plus UVA (PUVA) 30x more likely to develop SCC

Ultraviolet light exposure Dermatol Surg 1996;22:243-254
For every 8-10 degree decrease in latitude, there is a doubling in the incidence

DISEASE ASSOCIATIONS CHARACTERIZATION

ALBINISM Oculocutaneous albinism

BENIGN LYMPHOEPITHELIAL LESION

Benign lymphoepithelial lesion associated with squamous cell carcinoma of the skin: an immunohistochemical and molecular genetic study

Clelia Miracco
Karin Schürfeld
Concetta Cardone
Nazzareno Palummo
Luigi Pirtoli
Pietro Rubegni

J Cutan Pathol 2002;29:33 Abstract quote

Benign lymphoepithelial lesion associated with squamous cell carcinoma of the skin: an immunohistochemical and molecular genetic study
Clelia Miracco1, Karin Schürfeld1, Concetta Cardone1, Nazzareno Palummo1, Luigi Pirtoli2 and Pietro Rubegni3
Background: Benign lymphoepithelial lesions (BLEL) are usually found in salivary glands in autoimmune disorders. Some LEL are recognized to already be, or may progress to become, lymphomas. Skin lesions similar to LEL have been described in lymphomas, and are caused by neoplastic lymphocytes which infiltrate adnexal structures. To date, BLEL have not widely been recognized in the skin.
Methods: We describe skin lesions similar to BLELs, at the periphery of squamous cell carcinomas (SCC) in 8 healthy patients, in one of whom the lesion recurred. Immunocharacterization of both epithelial and lymphocytic components and molecular genetic investigation was performed. Polymerase chain reaction (PCR) analysis was done to detect IgH chain gene, and T-cell receptor and gene rearrangements. Association with Epstein-Barr virus (EBV) was also tested by in situ hybridization (ISH) for EBV-encoded RNAs (EBERs).

Results: Epithelial cells showed the immunophenotype of eccrine sweat gland ducts. Infiltrating lymphocytes expressed overwhelming B antigens and CD5. Neither clonal B and/or T proliferations nor EBERs signals were demonstrable.

Conclusions: We observed skin lesions similar to BLELs, showing modifications of sweat gland duct and CD5+, B lymphocytic expansion. In our cases there were no associated autoimmune disorders; the local immunoresponse to SCC might have caused BLEL.

RHEUMATOID ARTHRITIS

Rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis after starting tumor necrosis factor receptor IgG1-Fc fusion complex therapy

Kathleen J. Smith, MD
Henry G. Skelton, MD

Bethesda, Maryland, and Herndon, Virginia

J Am Acad Dermatol 2001;45:953-6. Abstract quote

Tumor necrosis factor (TNF-) is now believed to be a major contributor to the pathogenesis of the synovitis and joint destruction in rheumatoid arthritis. Etanercept is a recombinant human TNF- receptor Fc fusion protein consisting of a dimer of the extracellular portion of two p75 TNF- receptors fused to the Fc portion of human IgG1. Etanercept produces significant dose-dependent improvements in disease activity.

We describe 7 patients who experienced 1 or more squamous cell carcinomas that showed rapid growth and arose over a 2- to 4-month period of etanercept therapy.

Soluble TNF- receptor therapy through inhibition of a TH1 cytokine pattern and inhibition of the direct and indirect cytotoxic effects of TNF- may initially decrease mechanisms for controlling subclinical tumors and may contribute to the histologic features seen within these tumors. However, prolonged TNF- inhibition may have some antitumor effects.

VITILIGO

Squamous cell carcinoma in a patient with generalized vitiligo

Seung-Lee Seo, MD
Il-Hwan Kim, MD,PhD

Seoul, Korea

J Am Acad Dermatol 2001;45:S227-9 Abstract quote

Association of vitiligo and skin cancer has been a subject of controversy. Occurrence of skin cancer in long-lasting vitiligo is rare, and PUVA therapy-associated squamous cell carcinomas are not reported until recent years.

We report a case of squamous cell carcinoma and actinic keratosis in long-lasting vitiliginous patches in a patient with generalized vitiligo who did not receive PUVA therapy.

XERODERMA PIGMENTOSUM

PATHOGENESIS CHARACTERIZATION

ACTINIC KERATOSIS

Actinic keratosis as a precursor lesion
Lancet 1988;1:795-797
Arch Dermatol 1991;127:1029-1031

The rate of transformation has been debated

One study found a range of 0.075% to 0.096% per lesion/per year

This translates for an individual with 7.7 AKs, the rate of development over a decade is 10.2%

Others have estimated the risk of transformation at 13-20% over a ten year period

Semin Cutan Med Surg 1999;18:3-14
Some have suggested a reclassificationn of AK and SCC as keratinocytic intraepithelial neoplasia (KIN)

APOPTOSIS

Expression of CD95 (Fas) in sun-exposed human skin and cutaneous carcinomas.

Filipowicz E, Adegboyega P, Sanchez RL, Gatalica Z.

Division of Surgical Pathology, Department of Pathology, University of Texas Medical Branch, Galveston, Texas.
Cancer 2002 Feb 1;94(3):814-9 Abstract quote
BACKGROUND: Carcinomas of the skin are by far the most common human malignancies. Continuous exposure to ultraviolet (UV) light facilitates the development of precancerous lesions (actinic keratosis [AK]) that may progress to invasive squamous carcinomas. Apoptosis, triggered by the activation of CD95 (Fas), is one of the most important defense mechanisms against UV light-induced carcinogenesis in experimental models, but the dynamics of CD95 expression in patients with sun-induced lesions are largely unknown.

METHODS: The authors studied the expression of CD95 (Fas) in biopsy samples of normal skin (not exposed to sun) and compared it with chronically sun-exposed skin (as evidenced by solar elastosis), AK, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), and keratoacanthomas (KA).

RESULTS: Normal skin keratinocytes expressed CD95 in cytoplasmic membranes and intercellular bridges in the basal layer. In chronically sun-exposed keratinocytes (solar elastosis, no evidence of dysplasia), CD95 expression was up-regulated and was observed throughout the entire thickness of the epidermis. However, in actinic keratosis there was a complete absence of Fas in approximately two-thirds of the cases (8 of 12). In invasive SCC, CD95 was expressed focally and weakly only at the sites of contact with stromal lymphocytes. Keratoacanthomas consistently expressed CD95 at the interface with the inflammatory cells. No staining was observed in BCC.

CONCLUSIONS: CD95 (Fas) up-regulation in chronically sun-exposed keratinocytes indicates an important role in the control of sun-induced damage. Further sun exposure results, however, in significant down-regulation of this defense mechanism, proportional to the degree of dysplasia.

MISMATCH REPAIR GENES

Reduced human mismatch repair protein expression in the development of precancerous skin lesions to squamous cell carcinoma.

Liang SB, Furihata M, Takeuchi T, Sonobe H, Ohtsuki Y.

Department of Pathology II, Kochi Medical School, Japan.

Virchows Arch 2001 Nov;439(5):622-7 Abstract quote
Loss of human mismatch repair (hMSH2) gene function has been linked to hereditary non-polyposis colorectal cancer (HNPCC), Muir-Torre syndrome (MTS), and sporadic cancers, excluding skin cancers unrelated to MTS.

We immunohistochemically examined 125 squamous cell carcinomas (SCCs) using a monoclonal antibody to the hMSH2 protein and compared the results with those for 106 precursor lesions of SCC, consisting of actinic keratosis (AK), Bowenoid type of actinic keratosis (BAK), and Bowen's disease (BOD). In contrast to the homogeneous immunoreactivity of proliferating cells composed of AK, BAK, and BOD, heterogeneous and diminished immunostaining to hMSH2 was observed in tumor cells of SCCs examined. In addition, two SCCs (2 of 125; 1.6%) at multiple loci exhibited a complete lack of immunoreaction to hMSH2. Immunohistochemical staining of hMSH2 was semiquantitatively scored as 0 (0% of total cells examined), 1 (less than 10%), 2 (10-50%), or 3 (more than 50%). Percentage preservation of and average score for hMSH2 expression in normal, AK, BAK, BOD, and SCC were 56% and 2.06, 100% and 2.80, 94% and 2.88, 83% and 2.78, 63% and 2.36, respectively. The percentage preservation of and average scores for hMSH2 in AK, BAK, and BOD were significantly higher than those in presumably normal skin (P<0.01). There were no significant differences in the percentage preservation of and average scores for hMSH2 between presumably normal skin and SCC. The score for hMSH2 expression was significantly correlated with score for sun exposure in presumably normal skin of each lesion (R=0.70).

These findings for hMSH2 expression in precursor lesions and SCC suggest that promotion or activation of hMSH2 expression may be induced by the increased DNA damage caused by sun exposure and that diminished expression of it might occur according to the transformation from precancerous lesions to SCC.

SYNDECAN-1

Syndecan-1 is preferentially reduced compared to E-cadherin in acantholytic squamous cell carcinoma
J Cutan Pathol 2001;28:83-89

Both molecules may act in concert to stabilize the epithelium

Loss or decreased expression of both of these adhesion molecules is associated with malignant transformation

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION

General

VARIANTS

Tumors arising from non-sun exposed areas Trunk, genitalia, and soles

Human papillomavirus in cutaneous squamous cell carcinoma and cervix of a patient with psoriasis and extensive ultraviolet radiation exposure

Adelheid Rust, etal.

J Am Acad Dermatol 2001;44:681-6 Abstract quote

�High-risk� human papillomaviruses (HPVs) are associated with intraepithelial neoplasia and cancer of the uterine cervix. HPV has also been found in nonmelanoma skin cancer (NMSC), especially in squamous cell carcinomas (SCCs) of immunosuppressed patients. Recently, lesions of psoriasis have been shown to harbor HPV, and patients with psoriasis often have a history of extensive therapy with ultraviolet radiation (UVR). UVR is the major known risk factor in the occurrence of NMSC, in which HPV may be a cofactor for SCC.

We report an otherwise healthy, nonimmunosuppressed patient with psoriasis who had a history of extensive exposure to UVR and experienced multiple SCCs on UV-exposed body sites.

By the polymerase chain reaction method, we detected HPV in 5 of 9 SCCs. Automated sequencing showed HPV types 12 and 17. Only 1 of 3 normal skin specimens was HPV positive (HPV type 17). This positive specimen was from UV-exposed skin; one of the two HPV-negative, normal skin specimens was located on a body site not exposed to sun. In addition, HPV type 62 was found in a brush specimen of the uterine cervix.

This case report suggests an association between psoriasis, HPV infection, and UVR exposure, in onset of SCC.

Zosteriform and Epidermotropic Metastatic Primary Cutaneous Squamous Cell Carcinoma

Naoko Kato, M.D., Ph.D.; Satoru Aoyagi, M.D.; Hiroshi Sugawara, M.D.; Mariko Mayuzumi, M.D.

From the Department of Dermatology and Clinical Research Institute, National Sapporo Hospital, Sapporo, Japan.

Am J Dermatopathol 2001;23:216-220 Abstract quote

The first case of primary cutaneous squamous cell carcinoma (SCC) to cause zosteriform and epidermotropic metastasis to skin is reported.

The patient is a 72-year-old Japanese woman. A cutaneous SCC appeared on the lateral side of her right knee and was removed. After dissection of the right inguinal lymph nodes, which revealed metastases, and irradiation of the right inguinal region, the patient presented with slightly pruritic and painful erythematous papules on the right hip and small brownish papules and vesicles with crusts on the anterior side of the right thigh. The eruptions were in a zosteriform distribution along the right L1 to L3 dermatomes.

Histologically neoplastic squamous cell nests were observed in the epidermis, below the epidermal-dermal junction, and within lymphatic vessels in the deeper reticular dermis.

We postulate that neoplastic cells with the ability to fuse with adjacent squamous epithelium may have been carried beneath the basal lamina or to the epidermis via dermal lymphatic backflow, resulting in epidermotropic metastasis.

HISTOLOGICAL TYPES CHARACTERIZATION

General
Under the microscope, the tumor is composed of nests of squamous cells, arising from the epidermis and extending into the dermis. The cells usually have abundant eosinophilic cytoplasm and keratinization. They form squamous pearls and may show intercellular bridges

Tumors are usually graded by the degree of differentiation based upon how closely the tumor resembles normal squamous epithelium (well, moderately, poorly). The most poorly differentiated tumors show minimal keratinization and lack squamous pearls.

Microinvasive SCC
Controversial term but has been defined as:
Downward proliferation of lobules or cords of atypical keratinocytes in continuity with the overlying epidermis

OR it may consist of thick plaques of atypical keratinocytes that frequently have a bowenoid pattern of proliferation

VARIANTS

ACANTHOLYTIC
J Cutan Pathol 1989;16:114-121
Pseudoglandular acantholytic changes
Usually present as ulcer on the head and neck of men in 5-6th decade
Has been associated with recurrences following radiation therapy

ADENOSQUAMOUS

Primary cutaneous adenosquamous carcinoma: a case report and review of the literature

Daniel Azor�n1, Fernando L�pez-R�os1, Claudio Ballest�n1, Nuria Barrientos2 and Jos� Luis Rodr�guez-Peralto1

Departments of 1 Pathology and 2 Dermatology, �12 de Octubre� University Hospital, Madrid, Spain

Journal of Cutaneous Pathology 2001;28 (10), 542-545 Abstract quote

Background: Adenosquamous carcinoma (ASC) of skin is a rare but distinctive neoplasm that usually exhibits an aggressive course. To date, 13 well-documented and undisputed cases of primary cutaneous ASC have been reported. This term has been used for tumors with better prognosis, such as mucoepidermoid carcinomas and acantolytic squamous cell carcinomas, originating confusion. We report a primary cutaneous ASC and review the literature.

Methods: In this report a woman with primary ASC of the skin was studied. Histopathological examination and inmunohistochemical stains were performed.

Results: The tumor had two components: conventional squamous cell carcinoma merging with adenocarcinoma. After a local recurrence and lymph node metastases, the patient has no evidence of disease 8 months later.

Conclusions: Pathologists should reserve the term ASC for tumors exhibiting the above mentioned appearance. In such circumstances, a metastatic origin must always be excluded.

ADNEXAL DUCT CYSTS

Squamous Cell Carcinomas Arising From Adnexal Ductal Cysts

Henry G. Skelton, MD, Steven Flax, MD, Lawrence Chang, MD, and Kathleen J. Smith, MD

From the Departments of Dermatology and Pathology, University of Alabama, Birmingham (Drs Skelton and Smith); Dermatology Associates, Winchester, Va (Dr Flax); Newark, Del (Dr Chang).

Arch Pathol Lab Med 2002;Vol. 126, No. 1, pp. 76�78. Abstract quote

Malignant tumors arising from adnexal cysts are rare.

We report 2 cases of squamous cell carcinomas that developed within cystic structures arising from adnexal ducts. An in situ hybridization technique for human papillomaviruses (HPV)-6/11, -16, -18, and -31, and immunohistochemical staining for p53 were performed. Both tumors showed focal expression of HPV-16 within areas showing squamoid changes and diffuse expression of p53 within the areas of invasive squamous cell carcinoma.

Although nuclear staining for HPV has been identified in tumors of adnexal origin, to our knowledge these are the first cases in which a highly oncogenic HPV subtype, HPV-16, has been identified within squamous cell carcinomas arising from adnexal ductal structures. These cases may help explain primary cutaneous squamous cell carcinomas with no epidermal origin.

BOWENOID

Clin Dermatol 1993;11:43-46
HPV 2 associated in extragenital lesions
HPV 16 most common in genital lesions

In situ carcinoma
If the neoplastic keratinocytes invade the dermis, the term bowenoid squamous cell carcinoma is used

ERYTHROPLASIA OF QUEYRAT

JAMA 1992;267:3305-3310

Squamous cell carcinoma in situ of mucous membranes
Probably traumatic in origin, secondary to poor hygiene, infection, or irritation

30% invade the dermis and 20% metastasize

PIGMENTED

Pigmented squamous cell carcinoma

M. ShaneChapman1, Mark J.Quitadamo1 and Ann E.Perry1,2

1Section of Dermatology, Department of Medicine, and 2Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA

J Cutan Pathol 2000;27 (2), 93-95 Abstract quote

Pigmented squamous cell carcinomas have been reported in the oral and ocular mucosae, but rarely in the skin.

We present a case of pigmented squamous cell carcinoma of the forehead and review the current English literature. Pigmented squamous cell carcinoma can be confused with pigmented basal cell carcinomas and melanoma, especially those melanomas associated with pseudoepitheliomatous hyperplasia and should be included in the differential diagnosis of atypical pigmented lesions.

Pigmented squamous cell carcinoma of the skin: morphologic and immunohistochemical study of five cases.

Morgan MB, Lima-Maribona J, Miller RA, Kilpatrick T, Tannenbaum M.

James Haley and Bay Pines Veteran's Administration Hospital and University of South Florida College of Medicine, St. Petersburg, USA.

J Cutan Pathol 2000 Sep;27(8):381-6 Abstract quote

Invasive pigmented squamous cell carcinoma (PSCC) of the skin is reportedly rare. Herein, we evaluate an additional five cases and compare their relative frequency with non-pigmented squamous cell carcinoma (SCC). Of 46,791 archived cases of SCC, a total of five cases of PSCC were discovered for a relative frequency of approximately 0.01%.

Grossly, each tumor presented as a rapidly growing crusted papule on actinic damaged skin of the face. Microscopically, all were composed of a mixture of keratininized squamous cells and melanin-producing dendritic melanocytes. The squamous cells stained for epithelial membrane antigen, and both low and high molecular keratins. The melanocytes stained for S-100 and HMB-45. A matched series of 31 SCCs were subjected to an identical immunohistochemical battery of stains to determine if a histologically subtle and unsuspected number of intratumoral melanocytes existed in SCC. Each of the cases failed to show intratumoral melanocytes.

The differential diagnosis and possible histogenesis of PSCC is discussed and the importance of extensive pathologic examination to prevent misdiagnosis is emphasized. Despite the histologic dissimilarity, the long-term prognosis of the reported cases was similar to conventional SCC.

SMALL CELL

May be associated with overlying SCC in situ
Nuclear molding is absent

Cytokeratin 20 negative, unlike Merkel cell carcinomas

SPINDLE CELL
Association with previous trauma or radiotherapy common
Usually on the face of the elderly with extensive sun damage
May stain positive for vimentin

VERRUCOUS
Exo or endophytic tumors often growing at sites of chronic irritation
Classified based upon location:
Oral
Plantar
Buschke-Lowenstein tumors

SPECIAL STAINS/IMMUNOPEROXIDASE/OTHER CHARACTERIZATION

Special stains

Immunoperoxidase
Positive for high molecular weight cytokeratin and sometimes low molecular weight cytokeratin

Vimentin may be positive in poorly differentiated tumors

RCAS1 antigen is highly expressed in extramammary Paget's disease and in advanced stage squamous cell carcinoma of the skin.

Takahashi H, Iizuka H, Nakashima M, Wada T, Asano K, Ishida-Yamamoto A, Watanabe T.

Department of Dermatology, Asahikawa Medical College, 2-1-1-1 Midorigaokahigashi,0788510, Asahikawa, Japan.

J Dermatol Sci 2001 Jun;26(2):140-4 Abstract quote

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1), which is a type II membrane protein expressed on cervical carcinoma cells, induces apoptosis in RCAS1 receptor expressing cells. RCAS1 is thus presumed to protect tumor cells from immune surveillance by infiltrating RCAS1 receptor-positive immunocytes (Sonoda et al. Int J Oncol 1995; 6: 1899-1904; Nakashima et al. Nature Med 1999; 5: 938-942).

We performed immunohistochemical analysis of RCAS1 expression in various skin tumors. RCAS1 was not detected in normal human epidermis.

One of 21 seborrheic keratosis (4.8%), one of 12 actinic keratosis (8.3%), two of 16 keratoacanthomas (12.5%), and two of 14 basal cell carcinomas (14.2%) expressed RCAS1. RCAS1 was not detected in Bowen's disease (0/17). RCAS1 was positive in 45 of 61 (73.8%) squamous cell carcinomas. Interestingly, the expression of RCAS1 was mostly correlated with clinical stages of squamous cell carcinoma. It was found that 46.1% of stage I, 61.1% of stage II, 85.7% of stage III, and 83.3% of stage IV squamous cell carcinomas were RCAS1-positive. In addition, RCAS1 was found to be highly expressed in extramammary Paget's disease. Fifty nine of 63 extramammary Paget's disease samples (93.7%) were positive for RCAS1. Fifty eight (92%) showed co-expression of RCAS1 and carcinoembryonic antigen (CEA). While two of 24 cases of melanoma (8.3%) expressed RCAS1 antigen, none of 20 cases of nevus pigmentosus showed positive staining.

These results indicate that RCAS1 is a highly sensitive marker for extramammary Paget's disease. RCAS1 is also expressed in various skin tumors including squamous cell carcinoma, where positive correlation with clinical staging was documented.

The utility of cytokeratin 5/6 in the recognition of cutaneous spindle cell squamous cell carcinoma

Jessica E. Sigel1, Marek Skacel1, Wilma F. Bergfeld1, Nancy S. House2, Michael S. Rabkin2 and John R. Goldblum1 1

The Cleveland Clinic Foundation, Cleveland, Ohio, USA, 2 Rabkin Dermatopathology Laboratory P.C., Pittsburgh, Pennsylvania, USA

Journal of Cutaneous Pathology 2001;28 (10), 520-524 Abstract quote

Background: Cutaneous spindle cell squamous cell carcinoma (SSCC) is a challenging diagnosis since it may be difficult to distinguish from spindle cell melanoma, leiomyosarcoma and atypical fibroxanthoma. Furthermore, it may be difficult to demonstrate epithelial differentiation by a traditional immunohistochemical panel. We performed an expanded immunohistochemical evaluation of ultrastructurally documented SSCC to assess its utility in diagnosing this entity.

Methods: We identified 16 cases of SSCC that were composed predominantly of spindle-shaped cells and with ultrastructural evidence of epithelial differentiation (i.e. at least rudimentary cell junctions). Immunohistochemical analysis using antibodies to a variety of cytokeratins (AE1/3, K903, CK5/6) and S-100 protein was performed. The extent of immunostaining was graded on a scale of 0 to 4+ (0: no staining; 1+: �25%; 2+: 26�50%; 3+: 51�75%; 4+: >75%).

Results: Of the 16 cases, 6 expressed AE1/3 (38%), 8 expressed K903 (50%) and 11 (69%) expressed CK5/6. Six cases were positive for all three CK markers and two cases were positive for both K903 and CK5/6 but negative for AE1/3. Three cases (19%) stained for CK5/6 without any staining for AE1/3 or K903. Five cases (31%) were negative for all epithelial markers. The extent of CK5/6 staining was either similar to or greater than K903 staining in 7 of 8 cases that stained with both markers. All 16 cases were negative for S-100 protein.

Conclusions: Including CK5/6 in the initial battery of immunostains performed on a cutaneous spindle cell neoplasm can help demonstrate epithelial differentiation in SSCC, even in the absence of AE1/3 or K903 staining. However, some cases of cutaneous SSCC can only be confirmed ultrastructurally, as up to one-third may not show evidence of epithelial differentiation using an expanded immunohistochemical panel.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

BOWENOID PAPULOSIS
May appear histologically identical to Bowen's disease with a gently mamillated low power configuration

Associated with multiple brown papules usually on the penile shaft

Some view this as a benign condition

PAGETOID DYSKERATOSIS

Pagetoid Dyskeratosis of the Lips M.

Francisca Garijo, M.D., Ph.D.; Daniel Val, M.D.; J. Fernando Val-Bernal, M.D., Ph.D.

Department of Anatomical Pathology, Marqu�s de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain.

Am J Dermatopathol 2001;23:329-333 Abstract quote

Pagetoid dyskeratosis is an incidental finding in a variety of lesions of the skin and squamous mucosa. The lesion is considered a selective keratinocytic response in which a small part of the normal population of keratinocytes is induced to proliferate in response to friction. As far as we know, pagetoid dyskeratosis has not been reported in the lips.

In this article, we describe the location of the lesion in the lips and its incidence in a group of 90 unselected patients who underwent biopsy or were surgically treated for diverse labial lesions. Histochemical staining and immunohistochemical studies were performed in selected cases. Pagetoid dyskeratosis was found in 38 cases (42.2%) but only in 6 cases (6.7%) the lesion was conspicuous. There was no significant difference between the upper and the lower lip in terms of incidence of the lesion. Labial pagetoid dyskeratosis was more frequent in younger patients (46.7 � 25.0 versus 58.5 � 20.5; p < 0.05) and in women ( 2 = 3.89; p < 0.05). Pagetoid cells were more common in suprabasal location and in the labial mucosa. These cells showed positivity for high-molecular weight cytokeratin and negative reaction for low-molecular weight cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, and human papilloma virus. The immunohistochemical profile is different from the surrounding keratinocytes, indicating premature keratinization. The main differential diagnoses include white sponge nevus, leukoedema, oral koilocytoses, hairy leukoplakia, pagetoid squamous cell carcinoma in situ, and extramammary Paget's disease of the oral mucosa.

The morphologic features of dyskeratotic pagetoid cells are distinctive and easily recognized as an incidental finding, thus preventing confusion with other important entities including an intraepidermal tumor.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSIS

Immune status

Arch Dermatol 1986;122:1288-1293
Organ transplant patients are 18-36x more prevalent than in general population

These patients are also at higher risk for lymph node metastasis

Risk is related to degree of immunosuppression

Survival
Int J Cancer 1999;81:555-59
An estimated 1200 deaths a year occur from basal cell and squamous cell carcinomas, with the majority occurring with Squamous cell carcinomas

J Eur Acad Dermatol Venereol 1998;11:37-44
3 YRS was 98% if tumor <3.5 mm in depth
84% >3.5 mm in depth

Recurrence
J Am Acad Dermatol 1992;26:976-990
<10% for lesions <2 cm
30% for lesions>2 cm

Tumor grade
Cancer 1983;51:1537
Poorly differentiated tumors have 3x recurrence rate of well-differentiated tumors

Microscopic growth pattern
Small nests, infiltrative pattern, diffuse haphazard growth, isolated strands, and clusters of cells or single cells are at higher risk

Perineural invasion
J Dermatol Surg Oncol 1982;8:589-600
Present in 2.4-14% of tumors
More frequent in recurrences
One study indicated a a 2 year cure rate of only 2% if perineural invasion was found

METASTASIS
Tumors with rapid growth rate
Closer to a mucosal surface

>2 cm doubles the recurrence rate and triples the metastatic rate to 30%

Tumor thickness

Surg Oncol Clin N Am 1997;6:625-638

Tumors >Clark's level IV or V or >4 mm had metastatic rate of 45.7%

Previous treatment
Clin Plast Surg 1980;7:361-368
Increased metastatic potential

Risk Factors for Metastasis
J Am Acad Dermatol 1992;26:976-990

% Risk

Acantholytic histology
2-19%

Arising in Bowen's disease
2-5%

Non-sun exposed skin
2-3%

Lip
2-16%

Arising in Marjolin's ulcer
10-30%

Perineum and penis
30-80%

TREATMENT

MOHS SURGERY

Squamous cell carcinoma of the lip treated with Mohs micrographic surgery: outcome at 5 years.

Holmkvist KA, Roenigk RK.

Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.

J Am Acad Dermatol 1998 Jun;38(6 Pt 1):960-6 Abstract quote

BACKGROUND: Mohs micrographic surgery (MMS) is believed to be a highly effective treatment of squamous cell carcinoma (SCC) of the lip.

OBJECTIVE: The goals of our study were to determine the long-term (5-year) outcome of patients treated with MMS for SCC of the lip and to identify factors associated with tumor recurrence.

METHODS: Clinical and histopathologic data from 50 consecutive cases of SCC of the lip treated with MMS were retrospectively reviewed.

RESULTS: There were no tumor-related deaths or metastases. Forty-six patients (92%) remained free of disease. Four patients (8%) were diagnosed with SCC at the surgical site after MMS. Recurrent lesions tended to be superficial and occurred in the setting of severe actinic cheilitis. The average time to diagnosis after MMS was 2.5 years. All patients with recurrent disease were treated with further MMS and had successful results. No recurrences were seen among patients who received adjuvant treatment for actinic cheilitis with the carbon dioxide (CO2) laser, had clinical lesions 1 cm or less in diameter, or had post-MMS defects 2 cm or less in diameter.

CONCLUSION: MMS is highly effective for treating both primary and recurrent SCC of the lip. Treatment of coexisting actinic cheilitis may lower the risk for local recurrence after MMS.

A retrospective study of outcome of Mohs' micrographic surgery for cutaneous squamous cell carcinoma using formalin fixed sections.

Turner RJ, Leonard N, Malcolm AJ, Lawrence CM, Dahl MG.

Department of Dermatology and Pathology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

Br J Dermatol 2000 Apr;142(4):752-7 Abstract quote

The surgical management of recurrent or large squamous cell carcinoma (SCC) can be challenging as tumours often extend beyond visible margins. Micrographic surgery is a potentially effective method of ensuring complete clearance of tumour.

A retrospective study of all cases of SCC treated by micrographic surgery in this department between 1986 and 1996 has been done. Sixty-one patients were treated using a formalin-fixed paraffin-embedded tissue technique with a median follow-up of 4 years. In two cases there was local recurrence and in three others metastasis to local lymph nodes. The overall cure rate was 92% (56 of 61), which compares favourably with published series using chemosurgery and frozen tissue techniques.

The results show that this technique of micrographic surgery is a satisfactory and cost-effective alternative to conventional frozen section techniques in the treatment of SCC. The formalin-fixed tissue method has the advantage of providing high-quality permanent histological sections using existing conventional pathology services.

RADIATION

Adjuvant radiotherapy after excision of cutaneous squamous cell carcinoma.

Geohas J, Roholt NS, Robinson JK.

Department of Dermatology, Northwestern University Medical School, Chicago, Illinois.

J Am Acad Dermatol 1994 Apr;30(4):633-6 Abstract quote

Most cutaneous squamous cell carcinomas (SCCs) of the trunk and extremities are small enough to be cured by simple surgical excision. Because the risk of metastasis of SCCs of the head and neck arising from mucosal surfaces is higher than the risk of metastasis of SCCs arising from cutaneous surfaces, it may be more appropriate to review case reports of the trunk and extremities separately from those of the head and neck when seeking prognostic indicators. A small group of advanced lesions, however, is more difficult to treat and has an increased risk of local recurrence or metastasis and a poorer prognosis.

We describe a patient with high-risk cutaneous SCC who is disease-free 1 year after adjuvant radiotherapy subsequent to excision by Mohs micrographic surgery. This report discusses prognostic indicators of cutaneous SCC and suggests adjuvant modalities for the treatment of high-risk disease after surgical excision.

Radiotherapy is a rational choice as adjuvant therapy for the treatment of high-risk cutaneous SCC after excision.

SENTINEL LYMPH NODE DISSECTION

Combined sentinel lymphadenectomy and mohs micrographic surgery for high-risk cutaneous squamous cell carcinoma.

Weisberg NK, Bertagnolli MM, Becker DS.

Departments of Dermatology and Surgery, Weill Cornell Medical School, New York, NY 10021, USA.

J Am Acad Dermatol 2000 Sep;43(3):483-8 Abstract quote

BACKGROUND: There are subgroups of cutaneous squamous cell carcinoma (SCC) that have a higher risk for both regional and distant metastasis. When cutaneous SCC does metastasize, it typically spreads first to local nodal groups. Sentinel lymph node (SLN) localization has been successfully used to evaluate nodal metastasis in breast carcinoma, melanoma, and other select tumors. It may also be useful in certain high-risk cutaneous SCCs. Currently, Mohs micrographic surgery is the treatment of choice for these tumors.

METHODS: A patient presented with a high-risk recurrent SCC on the forehead. The regional nodal groups were clinically negative and radiographically negative by computed tomographic scan. Sentinel lymphadenectomy was performed by means of technetium 99m-radiolabeled sulfur colloid. The main tumor was resected with Mohs micrographic surgery.

RESULTS: A left preauricular SLN was localized by lymphoscintigraphy. The SLN was located intraoperatively by means of a gamma probe and excised. Subsequent pathologic evaluation of the SLN was negative for evidence of metastatic SCC by light microscopy with hematoxylin and eosin, and with immunohistochemical stains for cytokeratins AE1 and AE3. The day after SLN excision, the tumor was removed via Mohs micrographic surgery with clear surgical margins after a total of 8 stages. Aggressive subclinical spread by both subcutaneous "skating" and perineural invasion was noted.

CONCLUSION: The combination of Mohs micrographic surgery and sentinel lymphadenectomy is feasible and has theoretical utility in the management of a subset of cutaneous SCCs at high risk for metastasis. The ability of sentinel lymphadenectomy to identify regionally metastatic cutaneous SCC as well as the additive benefit of SLN and Mohs micrographic extirpation in the treatment of high-risk cutaneous SCC remain to be further clarified.

Adv Anat Pathol 2001;8:27-36.

Commonly Used Terms

Marjolin's ulcer-Aggressive form of squamous cell carcinoma that arises from sites of chronic injury, scars, burns, or irradiation sites.

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HISTOLOGICAL TYPES	CHARACTERIZATION
General	Under the microscope, the tumor is composed of nests of squamous cells, arising from the epidermis and extending into the dermis. The cells usually have abundant eosinophilic cytoplasm and keratinization. They form squamous pearls and may show intercellular bridges Tumors are usually graded by the degree of differentiation based upon how closely the tumor resembles normal squamous epithelium (well, moderately, poorly). The most poorly differentiated tumors show minimal keratinization and lack squamous pearls.
Microinvasive SCC	Controversial term but has been defined as: Downward proliferation of lobules or cords of atypical keratinocytes in continuity with the overlying epidermis OR it may consist of thick plaques of atypical keratinocytes that frequently have a bowenoid pattern of proliferation
VARIANTS
ACANTHOLYTIC	J Cutan Pathol 1989;16:114-121 Pseudoglandular acantholytic changes Usually present as ulcer on the head and neck of men in 5-6th decade Has been associated with recurrences following radiation therapy
ADENOSQUAMOUS
Primary cutaneous adenosquamous carcinoma: a case report and review of the literature Daniel Azor�n1, Fernando L�pez-R�os1, Claudio Ballest�n1, Nuria Barrientos2 and Jos� Luis Rodr�guez-Peralto1 Departments of 1 Pathology and 2 Dermatology, �12 de Octubre� University Hospital, Madrid, Spain	Journal of Cutaneous Pathology 2001;28 (10), 542-545 Abstract quote Background: Adenosquamous carcinoma (ASC) of skin is a rare but distinctive neoplasm that usually exhibits an aggressive course. To date, 13 well-documented and undisputed cases of primary cutaneous ASC have been reported. This term has been used for tumors with better prognosis, such as mucoepidermoid carcinomas and acantolytic squamous cell carcinomas, originating confusion. We report a primary cutaneous ASC and review the literature. Methods: In this report a woman with primary ASC of the skin was studied. Histopathological examination and inmunohistochemical stains were performed. Results: The tumor had two components: conventional squamous cell carcinoma merging with adenocarcinoma. After a local recurrence and lymph node metastases, the patient has no evidence of disease 8 months later. Conclusions: Pathologists should reserve the term ASC for tumors exhibiting the above mentioned appearance. In such circumstances, a metastatic origin must always be excluded.
ADNEXAL DUCT CYSTS
Squamous Cell Carcinomas Arising From Adnexal Ductal Cysts Henry G. Skelton, MD, Steven Flax, MD, Lawrence Chang, MD, and Kathleen J. Smith, MD From the Departments of Dermatology and Pathology, University of Alabama, Birmingham (Drs Skelton and Smith); Dermatology Associates, Winchester, Va (Dr Flax); Newark, Del (Dr Chang).	Arch Pathol Lab Med 2002;Vol. 126, No. 1, pp. 76�78. Abstract quote Malignant tumors arising from adnexal cysts are rare. We report 2 cases of squamous cell carcinomas that developed within cystic structures arising from adnexal ducts. An in situ hybridization technique for human papillomaviruses (HPV)-6/11, -16, -18, and -31, and immunohistochemical staining for p53 were performed. Both tumors showed focal expression of HPV-16 within areas showing squamoid changes and diffuse expression of p53 within the areas of invasive squamous cell carcinoma. Although nuclear staining for HPV has been identified in tumors of adnexal origin, to our knowledge these are the first cases in which a highly oncogenic HPV subtype, HPV-16, has been identified within squamous cell carcinomas arising from adnexal ductal structures. These cases may help explain primary cutaneous squamous cell carcinomas with no epidermal origin.
BOWENOID	Clin Dermatol 1993;11:43-46 HPV 2 associated in extragenital lesions HPV 16 most common in genital lesions In situ carcinoma If the neoplastic keratinocytes invade the dermis, the term bowenoid squamous cell carcinoma is used
ERYTHROPLASIA OF QUEYRAT	JAMA 1992;267:3305-3310 Squamous cell carcinoma in situ of mucous membranes Probably traumatic in origin, secondary to poor hygiene, infection, or irritation 30% invade the dermis and 20% metastasize
PIGMENTED
Pigmented squamous cell carcinoma M. ShaneChapman1, Mark J.Quitadamo1 and Ann E.Perry1,2 1Section of Dermatology, Department of Medicine, and 2Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA	J Cutan Pathol 2000;27 (2), 93-95 Abstract quote Pigmented squamous cell carcinomas have been reported in the oral and ocular mucosae, but rarely in the skin. We present a case of pigmented squamous cell carcinoma of the forehead and review the current English literature. Pigmented squamous cell carcinoma can be confused with pigmented basal cell carcinomas and melanoma, especially those melanomas associated with pseudoepitheliomatous hyperplasia and should be included in the differential diagnosis of atypical pigmented lesions.
Pigmented squamous cell carcinoma of the skin: morphologic and immunohistochemical study of five cases. Morgan MB, Lima-Maribona J, Miller RA, Kilpatrick T, Tannenbaum M. James Haley and Bay Pines Veteran's Administration Hospital and University of South Florida College of Medicine, St. Petersburg, USA.	J Cutan Pathol 2000 Sep;27(8):381-6 Abstract quote Invasive pigmented squamous cell carcinoma (PSCC) of the skin is reportedly rare. Herein, we evaluate an additional five cases and compare their relative frequency with non-pigmented squamous cell carcinoma (SCC). Of 46,791 archived cases of SCC, a total of five cases of PSCC were discovered for a relative frequency of approximately 0.01%. Grossly, each tumor presented as a rapidly growing crusted papule on actinic damaged skin of the face. Microscopically, all were composed of a mixture of keratininized squamous cells and melanin-producing dendritic melanocytes. The squamous cells stained for epithelial membrane antigen, and both low and high molecular keratins. The melanocytes stained for S-100 and HMB-45. A matched series of 31 SCCs were subjected to an identical immunohistochemical battery of stains to determine if a histologically subtle and unsuspected number of intratumoral melanocytes existed in SCC. Each of the cases failed to show intratumoral melanocytes. The differential diagnosis and possible histogenesis of PSCC is discussed and the importance of extensive pathologic examination to prevent misdiagnosis is emphasized. Despite the histologic dissimilarity, the long-term prognosis of the reported cases was similar to conventional SCC.
SMALL CELL	May be associated with overlying SCC in situ Nuclear molding is absent Cytokeratin 20 negative, unlike Merkel cell carcinomas
SPINDLE CELL	Association with previous trauma or radiotherapy common Usually on the face of the elderly with extensive sun damage May stain positive for vimentin
VERRUCOUS	Exo or endophytic tumors often growing at sites of chronic irritation Classified based upon location: Oral Plantar Buschke-Lowenstein tumors

SPECIAL STAINS/IMMUNOPEROXIDASE/OTHER	CHARACTERIZATION
Special stains
Immunoperoxidase	Positive for high molecular weight cytokeratin and sometimes low molecular weight cytokeratin Vimentin may be positive in poorly differentiated tumors
RCAS1 antigen is highly expressed in extramammary Paget's disease and in advanced stage squamous cell carcinoma of the skin. Takahashi H, Iizuka H, Nakashima M, Wada T, Asano K, Ishida-Yamamoto A, Watanabe T. Department of Dermatology, Asahikawa Medical College, 2-1-1-1 Midorigaokahigashi,0788510, Asahikawa, Japan.	J Dermatol Sci 2001 Jun;26(2):140-4 Abstract quote Receptor-binding cancer antigen expressed on SiSo cells (RCAS1), which is a type II membrane protein expressed on cervical carcinoma cells, induces apoptosis in RCAS1 receptor expressing cells. RCAS1 is thus presumed to protect tumor cells from immune surveillance by infiltrating RCAS1 receptor-positive immunocytes (Sonoda et al. Int J Oncol 1995; 6: 1899-1904; Nakashima et al. Nature Med 1999; 5: 938-942). We performed immunohistochemical analysis of RCAS1 expression in various skin tumors. RCAS1 was not detected in normal human epidermis. One of 21 seborrheic keratosis (4.8%), one of 12 actinic keratosis (8.3%), two of 16 keratoacanthomas (12.5%), and two of 14 basal cell carcinomas (14.2%) expressed RCAS1. RCAS1 was not detected in Bowen's disease (0/17). RCAS1 was positive in 45 of 61 (73.8%) squamous cell carcinomas. Interestingly, the expression of RCAS1 was mostly correlated with clinical stages of squamous cell carcinoma. It was found that 46.1% of stage I, 61.1% of stage II, 85.7% of stage III, and 83.3% of stage IV squamous cell carcinomas were RCAS1-positive. In addition, RCAS1 was found to be highly expressed in extramammary Paget's disease. Fifty nine of 63 extramammary Paget's disease samples (93.7%) were positive for RCAS1. Fifty eight (92%) showed co-expression of RCAS1 and carcinoembryonic antigen (CEA). While two of 24 cases of melanoma (8.3%) expressed RCAS1 antigen, none of 20 cases of nevus pigmentosus showed positive staining. These results indicate that RCAS1 is a highly sensitive marker for extramammary Paget's disease. RCAS1 is also expressed in various skin tumors including squamous cell carcinoma, where positive correlation with clinical staging was documented.
The utility of cytokeratin 5/6 in the recognition of cutaneous spindle cell squamous cell carcinoma Jessica E. Sigel1, Marek Skacel1, Wilma F. Bergfeld1, Nancy S. House2, Michael S. Rabkin2 and John R. Goldblum1 1 The Cleveland Clinic Foundation, Cleveland, Ohio, USA, 2 Rabkin Dermatopathology Laboratory P.C., Pittsburgh, Pennsylvania, USA	Journal of Cutaneous Pathology 2001;28 (10), 520-524 Abstract quote Background: Cutaneous spindle cell squamous cell carcinoma (SSCC) is a challenging diagnosis since it may be difficult to distinguish from spindle cell melanoma, leiomyosarcoma and atypical fibroxanthoma. Furthermore, it may be difficult to demonstrate epithelial differentiation by a traditional immunohistochemical panel. We performed an expanded immunohistochemical evaluation of ultrastructurally documented SSCC to assess its utility in diagnosing this entity. Methods: We identified 16 cases of SSCC that were composed predominantly of spindle-shaped cells and with ultrastructural evidence of epithelial differentiation (i.e. at least rudimentary cell junctions). Immunohistochemical analysis using antibodies to a variety of cytokeratins (AE1/3, K903, CK5/6) and S-100 protein was performed. The extent of immunostaining was graded on a scale of 0 to 4+ (0: no staining; 1+: �25%; 2+: 26�50%; 3+: 51�75%; 4+: >75%). Results: Of the 16 cases, 6 expressed AE1/3 (38%), 8 expressed K903 (50%) and 11 (69%) expressed CK5/6. Six cases were positive for all three CK markers and two cases were positive for both K903 and CK5/6 but negative for AE1/3. Three cases (19%) stained for CK5/6 without any staining for AE1/3 or K903. Five cases (31%) were negative for all epithelial markers. The extent of CK5/6 staining was either similar to or greater than K903 staining in 7 of 8 cases that stained with both markers. All 16 cases were negative for S-100 protein. Conclusions: Including CK5/6 in the initial battery of immunostains performed on a cutaneous spindle cell neoplasm can help demonstrate epithelial differentiation in SSCC, even in the absence of AE1/3 or K903 staining. However, some cases of cutaneous SSCC can only be confirmed ultrastructurally, as up to one-third may not show evidence of epithelial differentiation using an expanded immunohistochemical panel.

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	SCC Epidermoid carcinoma of the skin
INCIDENCE	20% of all dermatologic malignancies, second only to basal cell carcinomas 600,000 new cases of both SCC and BCC/year/United States
Arsenic exposure
	Acts as a promoter causing mutations in the p53 tumor suppressor gene found in 90% of cancers
Cutaneous radiation
Human Papilloma virus 5 and 16
Polycyclic aromatic hydrocarbons
Psoralen plus UVA (PUVA)	30x more likely to develop SCC
Ultraviolet light exposure	Dermatol Surg 1996;22:243-254 For every 8-10 degree decrease in latitude, there is a doubling in the incidence

DISEASE ASSOCIATIONS	CHARACTERIZATION
ALBINISM	Oculocutaneous albinism
BENIGN LYMPHOEPITHELIAL LESION
Benign lymphoepithelial lesion associated with squamous cell carcinoma of the skin: an immunohistochemical and molecular genetic study Clelia Miracco Karin Schürfeld Concetta Cardone Nazzareno Palummo Luigi Pirtoli Pietro Rubegni	J Cutan Pathol 2002;29:33 Abstract quote Benign lymphoepithelial lesion associated with squamous cell carcinoma of the skin: an immunohistochemical and molecular genetic study Clelia Miracco1, Karin Schürfeld1, Concetta Cardone1, Nazzareno Palummo1, Luigi Pirtoli2 and Pietro Rubegni3 Background: Benign lymphoepithelial lesions (BLEL) are usually found in salivary glands in autoimmune disorders. Some LEL are recognized to already be, or may progress to become, lymphomas. Skin lesions similar to LEL have been described in lymphomas, and are caused by neoplastic lymphocytes which infiltrate adnexal structures. To date, BLEL have not widely been recognized in the skin. Methods: We describe skin lesions similar to BLELs, at the periphery of squamous cell carcinomas (SCC) in 8 healthy patients, in one of whom the lesion recurred. Immunocharacterization of both epithelial and lymphocytic components and molecular genetic investigation was performed. Polymerase chain reaction (PCR) analysis was done to detect IgH chain gene, and T-cell receptor and gene rearrangements. Association with Epstein-Barr virus (EBV) was also tested by in situ hybridization (ISH) for EBV-encoded RNAs (EBERs). Results: Epithelial cells showed the immunophenotype of eccrine sweat gland ducts. Infiltrating lymphocytes expressed overwhelming B antigens and CD5. Neither clonal B and/or T proliferations nor EBERs signals were demonstrable. Conclusions: We observed skin lesions similar to BLELs, showing modifications of sweat gland duct and CD5+, B lymphocytic expansion. In our cases there were no associated autoimmune disorders; the local immunoresponse to SCC might have caused BLEL.
RHEUMATOID ARTHRITIS
Rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis after starting tumor necrosis factor receptor IgG1-Fc fusion complex therapy Kathleen J. Smith, MD Henry G. Skelton, MD Bethesda, Maryland, and Herndon, Virginia	J Am Acad Dermatol 2001;45:953-6. Abstract quote Tumor necrosis factor (TNF-) is now believed to be a major contributor to the pathogenesis of the synovitis and joint destruction in rheumatoid arthritis. Etanercept is a recombinant human TNF- receptor Fc fusion protein consisting of a dimer of the extracellular portion of two p75 TNF- receptors fused to the Fc portion of human IgG1. Etanercept produces significant dose-dependent improvements in disease activity. We describe 7 patients who experienced 1 or more squamous cell carcinomas that showed rapid growth and arose over a 2- to 4-month period of etanercept therapy. Soluble TNF- receptor therapy through inhibition of a TH1 cytokine pattern and inhibition of the direct and indirect cytotoxic effects of TNF- may initially decrease mechanisms for controlling subclinical tumors and may contribute to the histologic features seen within these tumors. However, prolonged TNF- inhibition may have some antitumor effects.
VITILIGO
Squamous cell carcinoma in a patient with generalized vitiligo Seung-Lee Seo, MD Il-Hwan Kim, MD,PhD Seoul, Korea	J Am Acad Dermatol 2001;45:S227-9 Abstract quote Association of vitiligo and skin cancer has been a subject of controversy. Occurrence of skin cancer in long-lasting vitiligo is rare, and PUVA therapy-associated squamous cell carcinomas are not reported until recent years. We report a case of squamous cell carcinoma and actinic keratosis in long-lasting vitiliginous patches in a patient with generalized vitiligo who did not receive PUVA therapy.
XERODERMA PIGMENTOSUM

PATHOGENESIS	CHARACTERIZATION
ACTINIC KERATOSIS
Actinic keratosis as a precursor lesion	Lancet 1988;1:795-797 Arch Dermatol 1991;127:1029-1031 The rate of transformation has been debated One study found a range of 0.075% to 0.096% per lesion/per year This translates for an individual with 7.7 AKs, the rate of development over a decade is 10.2%
	Others have estimated the risk of transformation at 13-20% over a ten year period
	Semin Cutan Med Surg 1999;18:3-14 Some have suggested a reclassificationn of AK and SCC as keratinocytic intraepithelial neoplasia (KIN)
APOPTOSIS
Expression of CD95 (Fas) in sun-exposed human skin and cutaneous carcinomas. Filipowicz E, Adegboyega P, Sanchez RL, Gatalica Z. Division of Surgical Pathology, Department of Pathology, University of Texas Medical Branch, Galveston, Texas.	Cancer 2002 Feb 1;94(3):814-9 Abstract quote BACKGROUND: Carcinomas of the skin are by far the most common human malignancies. Continuous exposure to ultraviolet (UV) light facilitates the development of precancerous lesions (actinic keratosis [AK]) that may progress to invasive squamous carcinomas. Apoptosis, triggered by the activation of CD95 (Fas), is one of the most important defense mechanisms against UV light-induced carcinogenesis in experimental models, but the dynamics of CD95 expression in patients with sun-induced lesions are largely unknown. METHODS: The authors studied the expression of CD95 (Fas) in biopsy samples of normal skin (not exposed to sun) and compared it with chronically sun-exposed skin (as evidenced by solar elastosis), AK, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), and keratoacanthomas (KA). RESULTS: Normal skin keratinocytes expressed CD95 in cytoplasmic membranes and intercellular bridges in the basal layer. In chronically sun-exposed keratinocytes (solar elastosis, no evidence of dysplasia), CD95 expression was up-regulated and was observed throughout the entire thickness of the epidermis. However, in actinic keratosis there was a complete absence of Fas in approximately two-thirds of the cases (8 of 12). In invasive SCC, CD95 was expressed focally and weakly only at the sites of contact with stromal lymphocytes. Keratoacanthomas consistently expressed CD95 at the interface with the inflammatory cells. No staining was observed in BCC. CONCLUSIONS: CD95 (Fas) up-regulation in chronically sun-exposed keratinocytes indicates an important role in the control of sun-induced damage. Further sun exposure results, however, in significant down-regulation of this defense mechanism, proportional to the degree of dysplasia.
MISMATCH REPAIR GENES
Reduced human mismatch repair protein expression in the development of precancerous skin lesions to squamous cell carcinoma. Liang SB, Furihata M, Takeuchi T, Sonobe H, Ohtsuki Y. Department of Pathology II, Kochi Medical School, Japan.	Virchows Arch 2001 Nov;439(5):622-7 Abstract quote Loss of human mismatch repair (hMSH2) gene function has been linked to hereditary non-polyposis colorectal cancer (HNPCC), Muir-Torre syndrome (MTS), and sporadic cancers, excluding skin cancers unrelated to MTS. We immunohistochemically examined 125 squamous cell carcinomas (SCCs) using a monoclonal antibody to the hMSH2 protein and compared the results with those for 106 precursor lesions of SCC, consisting of actinic keratosis (AK), Bowenoid type of actinic keratosis (BAK), and Bowen's disease (BOD). In contrast to the homogeneous immunoreactivity of proliferating cells composed of AK, BAK, and BOD, heterogeneous and diminished immunostaining to hMSH2 was observed in tumor cells of SCCs examined. In addition, two SCCs (2 of 125; 1.6%) at multiple loci exhibited a complete lack of immunoreaction to hMSH2. Immunohistochemical staining of hMSH2 was semiquantitatively scored as 0 (0% of total cells examined), 1 (less than 10%), 2 (10-50%), or 3 (more than 50%). Percentage preservation of and average score for hMSH2 expression in normal, AK, BAK, BOD, and SCC were 56% and 2.06, 100% and 2.80, 94% and 2.88, 83% and 2.78, 63% and 2.36, respectively. The percentage preservation of and average scores for hMSH2 in AK, BAK, and BOD were significantly higher than those in presumably normal skin (P<0.01). There were no significant differences in the percentage preservation of and average scores for hMSH2 between presumably normal skin and SCC. The score for hMSH2 expression was significantly correlated with score for sun exposure in presumably normal skin of each lesion (R=0.70). These findings for hMSH2 expression in precursor lesions and SCC suggest that promotion or activation of hMSH2 expression may be induced by the increased DNA damage caused by sun exposure and that diminished expression of it might occur according to the transformation from precancerous lesions to SCC.
SYNDECAN-1
Syndecan-1 is preferentially reduced compared to E-cadherin in acantholytic squamous cell carcinoma	J Cutan Pathol 2001;28:83-89 Both molecules may act in concert to stabilize the epithelium Loss or decreased expression of both of these adhesion molecules is associated with malignant transformation

GROSS APPEARANCE/CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
Tumors arising from non-sun exposed areas	Trunk, genitalia, and soles
Human papillomavirus in cutaneous squamous cell carcinoma and cervix of a patient with psoriasis and extensive ultraviolet radiation exposure Adelheid Rust, etal.	J Am Acad Dermatol 2001;44:681-6 Abstract quote �High-risk� human papillomaviruses (HPVs) are associated with intraepithelial neoplasia and cancer of the uterine cervix. HPV has also been found in nonmelanoma skin cancer (NMSC), especially in squamous cell carcinomas (SCCs) of immunosuppressed patients. Recently, lesions of psoriasis have been shown to harbor HPV, and patients with psoriasis often have a history of extensive therapy with ultraviolet radiation (UVR). UVR is the major known risk factor in the occurrence of NMSC, in which HPV may be a cofactor for SCC. We report an otherwise healthy, nonimmunosuppressed patient with psoriasis who had a history of extensive exposure to UVR and experienced multiple SCCs on UV-exposed body sites. By the polymerase chain reaction method, we detected HPV in 5 of 9 SCCs. Automated sequencing showed HPV types 12 and 17. Only 1 of 3 normal skin specimens was HPV positive (HPV type 17). This positive specimen was from UV-exposed skin; one of the two HPV-negative, normal skin specimens was located on a body site not exposed to sun. In addition, HPV type 62 was found in a brush specimen of the uterine cervix. This case report suggests an association between psoriasis, HPV infection, and UVR exposure, in onset of SCC.
Zosteriform and Epidermotropic Metastatic Primary Cutaneous Squamous Cell Carcinoma Naoko Kato, M.D., Ph.D.; Satoru Aoyagi, M.D.; Hiroshi Sugawara, M.D.; Mariko Mayuzumi, M.D. From the Department of Dermatology and Clinical Research Institute, National Sapporo Hospital, Sapporo, Japan.	Am J Dermatopathol 2001;23:216-220 Abstract quote The first case of primary cutaneous squamous cell carcinoma (SCC) to cause zosteriform and epidermotropic metastasis to skin is reported. The patient is a 72-year-old Japanese woman. A cutaneous SCC appeared on the lateral side of her right knee and was removed. After dissection of the right inguinal lymph nodes, which revealed metastases, and irradiation of the right inguinal region, the patient presented with slightly pruritic and painful erythematous papules on the right hip and small brownish papules and vesicles with crusts on the anterior side of the right thigh. The eruptions were in a zosteriform distribution along the right L1 to L3 dermatomes. Histologically neoplastic squamous cell nests were observed in the epidermis, below the epidermal-dermal junction, and within lymphatic vessels in the deeper reticular dermis. We postulate that neoplastic cells with the ability to fuse with adjacent squamous epithelium may have been carried beneath the basal lamina or to the epidermis via dermal lymphatic backflow, resulting in epidermotropic metastasis.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
BOWENOID PAPULOSIS	May appear histologically identical to Bowen's disease with a gently mamillated low power configuration Associated with multiple brown papules usually on the penile shaft Some view this as a benign condition
PAGETOID DYSKERATOSIS
Pagetoid Dyskeratosis of the Lips M. Francisca Garijo, M.D., Ph.D.; Daniel Val, M.D.; J. Fernando Val-Bernal, M.D., Ph.D. Department of Anatomical Pathology, Marqu�s de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain.	Am J Dermatopathol 2001;23:329-333 Abstract quote Pagetoid dyskeratosis is an incidental finding in a variety of lesions of the skin and squamous mucosa. The lesion is considered a selective keratinocytic response in which a small part of the normal population of keratinocytes is induced to proliferate in response to friction. As far as we know, pagetoid dyskeratosis has not been reported in the lips. In this article, we describe the location of the lesion in the lips and its incidence in a group of 90 unselected patients who underwent biopsy or were surgically treated for diverse labial lesions. Histochemical staining and immunohistochemical studies were performed in selected cases. Pagetoid dyskeratosis was found in 38 cases (42.2%) but only in 6 cases (6.7%) the lesion was conspicuous. There was no significant difference between the upper and the lower lip in terms of incidence of the lesion. Labial pagetoid dyskeratosis was more frequent in younger patients (46.7 � 25.0 versus 58.5 � 20.5; p < 0.05) and in women ( 2 = 3.89; p < 0.05). Pagetoid cells were more common in suprabasal location and in the labial mucosa. These cells showed positivity for high-molecular weight cytokeratin and negative reaction for low-molecular weight cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, and human papilloma virus. The immunohistochemical profile is different from the surrounding keratinocytes, indicating premature keratinization. The main differential diagnoses include white sponge nevus, leukoedema, oral koilocytoses, hairy leukoplakia, pagetoid squamous cell carcinoma in situ, and extramammary Paget's disease of the oral mucosa. The morphologic features of dyskeratotic pagetoid cells are distinctive and easily recognized as an incidental finding, thus preventing confusion with other important entities including an intraepidermal tumor.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Immune status	Arch Dermatol 1986;122:1288-1293 Organ transplant patients are 18-36x more prevalent than in general population These patients are also at higher risk for lymph node metastasis Risk is related to degree of immunosuppression
Survival	Int J Cancer 1999;81:555-59 An estimated 1200 deaths a year occur from basal cell and squamous cell carcinomas, with the majority occurring with Squamous cell carcinomas
	J Eur Acad Dermatol Venereol 1998;11:37-44 3 YRS was 98% if tumor <3.5 mm in depth 84% >3.5 mm in depth
Recurrence	J Am Acad Dermatol 1992;26:976-990 <10% for lesions <2 cm 30% for lesions>2 cm
Tumor grade	Cancer 1983;51:1537 Poorly differentiated tumors have 3x recurrence rate of well-differentiated tumors
Microscopic growth pattern	Small nests, infiltrative pattern, diffuse haphazard growth, isolated strands, and clusters of cells or single cells are at higher risk
Perineural invasion	J Dermatol Surg Oncol 1982;8:589-600 Present in 2.4-14% of tumors More frequent in recurrences One study indicated a a 2 year cure rate of only 2% if perineural invasion was found
METASTASIS	Tumors with rapid growth rate Closer to a mucosal surface >2 cm doubles the recurrence rate and triples the metastatic rate to 30%
Tumor thickness	Surg Oncol Clin N Am 1997;6:625-638 Tumors >Clark's level IV or V or >4 mm had metastatic rate of 45.7%
Previous treatment	Clin Plast Surg 1980;7:361-368 Increased metastatic potential
Risk Factors for Metastasis	J Am Acad Dermatol 1992;26:976-990
	% Risk
Acantholytic histology	2-19%
Arising in Bowen's disease	2-5%
Non-sun exposed skin	2-3%
Lip	2-16%
Arising in Marjolin's ulcer	10-30%
Perineum and penis	30-80%
TREATMENT
MOHS SURGERY
Squamous cell carcinoma of the lip treated with Mohs micrographic surgery: outcome at 5 years. Holmkvist KA, Roenigk RK. Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.	J Am Acad Dermatol 1998 Jun;38(6 Pt 1):960-6 Abstract quote BACKGROUND: Mohs micrographic surgery (MMS) is believed to be a highly effective treatment of squamous cell carcinoma (SCC) of the lip. OBJECTIVE: The goals of our study were to determine the long-term (5-year) outcome of patients treated with MMS for SCC of the lip and to identify factors associated with tumor recurrence. METHODS: Clinical and histopathologic data from 50 consecutive cases of SCC of the lip treated with MMS were retrospectively reviewed. RESULTS: There were no tumor-related deaths or metastases. Forty-six patients (92%) remained free of disease. Four patients (8%) were diagnosed with SCC at the surgical site after MMS. Recurrent lesions tended to be superficial and occurred in the setting of severe actinic cheilitis. The average time to diagnosis after MMS was 2.5 years. All patients with recurrent disease were treated with further MMS and had successful results. No recurrences were seen among patients who received adjuvant treatment for actinic cheilitis with the carbon dioxide (CO2) laser, had clinical lesions 1 cm or less in diameter, or had post-MMS defects 2 cm or less in diameter. CONCLUSION: MMS is highly effective for treating both primary and recurrent SCC of the lip. Treatment of coexisting actinic cheilitis may lower the risk for local recurrence after MMS.
A retrospective study of outcome of Mohs' micrographic surgery for cutaneous squamous cell carcinoma using formalin fixed sections. Turner RJ, Leonard N, Malcolm AJ, Lawrence CM, Dahl MG. Department of Dermatology and Pathology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.	Br J Dermatol 2000 Apr;142(4):752-7 Abstract quote The surgical management of recurrent or large squamous cell carcinoma (SCC) can be challenging as tumours often extend beyond visible margins. Micrographic surgery is a potentially effective method of ensuring complete clearance of tumour. A retrospective study of all cases of SCC treated by micrographic surgery in this department between 1986 and 1996 has been done. Sixty-one patients were treated using a formalin-fixed paraffin-embedded tissue technique with a median follow-up of 4 years. In two cases there was local recurrence and in three others metastasis to local lymph nodes. The overall cure rate was 92% (56 of 61), which compares favourably with published series using chemosurgery and frozen tissue techniques. The results show that this technique of micrographic surgery is a satisfactory and cost-effective alternative to conventional frozen section techniques in the treatment of SCC. The formalin-fixed tissue method has the advantage of providing high-quality permanent histological sections using existing conventional pathology services.
RADIATION
Adjuvant radiotherapy after excision of cutaneous squamous cell carcinoma. Geohas J, Roholt NS, Robinson JK. Department of Dermatology, Northwestern University Medical School, Chicago, Illinois.	J Am Acad Dermatol 1994 Apr;30(4):633-6 Abstract quote Most cutaneous squamous cell carcinomas (SCCs) of the trunk and extremities are small enough to be cured by simple surgical excision. Because the risk of metastasis of SCCs of the head and neck arising from mucosal surfaces is higher than the risk of metastasis of SCCs arising from cutaneous surfaces, it may be more appropriate to review case reports of the trunk and extremities separately from those of the head and neck when seeking prognostic indicators. A small group of advanced lesions, however, is more difficult to treat and has an increased risk of local recurrence or metastasis and a poorer prognosis. We describe a patient with high-risk cutaneous SCC who is disease-free 1 year after adjuvant radiotherapy subsequent to excision by Mohs micrographic surgery. This report discusses prognostic indicators of cutaneous SCC and suggests adjuvant modalities for the treatment of high-risk disease after surgical excision. Radiotherapy is a rational choice as adjuvant therapy for the treatment of high-risk cutaneous SCC after excision.
SENTINEL LYMPH NODE DISSECTION
Combined sentinel lymphadenectomy and mohs micrographic surgery for high-risk cutaneous squamous cell carcinoma. Weisberg NK, Bertagnolli MM, Becker DS. Departments of Dermatology and Surgery, Weill Cornell Medical School, New York, NY 10021, USA.	J Am Acad Dermatol 2000 Sep;43(3):483-8 Abstract quote BACKGROUND: There are subgroups of cutaneous squamous cell carcinoma (SCC) that have a higher risk for both regional and distant metastasis. When cutaneous SCC does metastasize, it typically spreads first to local nodal groups. Sentinel lymph node (SLN) localization has been successfully used to evaluate nodal metastasis in breast carcinoma, melanoma, and other select tumors. It may also be useful in certain high-risk cutaneous SCCs. Currently, Mohs micrographic surgery is the treatment of choice for these tumors. METHODS: A patient presented with a high-risk recurrent SCC on the forehead. The regional nodal groups were clinically negative and radiographically negative by computed tomographic scan. Sentinel lymphadenectomy was performed by means of technetium 99m-radiolabeled sulfur colloid. The main tumor was resected with Mohs micrographic surgery. RESULTS: A left preauricular SLN was localized by lymphoscintigraphy. The SLN was located intraoperatively by means of a gamma probe and excised. Subsequent pathologic evaluation of the SLN was negative for evidence of metastatic SCC by light microscopy with hematoxylin and eosin, and with immunohistochemical stains for cytokeratins AE1 and AE3. The day after SLN excision, the tumor was removed via Mohs micrographic surgery with clear surgical margins after a total of 8 stages. Aggressive subclinical spread by both subcutaneous "skating" and perineural invasion was noted. CONCLUSION: The combination of Mohs micrographic surgery and sentinel lymphadenectomy is feasible and has theoretical utility in the management of a subset of cutaneous SCCs at high risk for metastasis. The ability of sentinel lymphadenectomy to identify regionally metastatic cutaneous SCC as well as the additive benefit of SLN and Mohs micrographic extirpation in the treatment of high-risk cutaneous SCC remain to be further clarified.