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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.


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Epidermoid carcinoma of the skin

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

Time trends and familial risks in squamous cell carcinoma of the skin.

Hemminki K, Zhang H, Czene K.

Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.

Arch Dermatol. 2003 Jul;139(7):885-9. Abstract quote

OBJECTIVES: To study time trends and familial clustering of invasive and in situ squamous cell skin cancers (SCC), with particular reference to sun-exposed and covered sites of the body.

DESIGN: Epidemiologic follow-up study of the whole population.

SETTING: The Swedish Family-Cancer Database from the year 2000, to cover individuals born after 1931 with their biological parents, totaling 10.2 million persons.

PATIENTS: Cancer data were obtained from the Swedish Cancer Registry from 1961 through 1998 and included 1907 invasive SCCs in offspring and 12,702 and 7167 in fathers and mothers, respectively. The numbers of patients affected by in situ SCC were 2666, 13,739, and 13,321, respectively.

MAIN OUTCOME MEASURES: Standardized incidence ratios and 95% confidence intervals were calculated for SCC in offspring when parents had SCC. Incidence rates were calculated for the population in the Database.

RESULTS: Incidence trends showed a large increase in reported cases of SCC and particularly of in situ SCC. Among invasive cases, the increase was largest among covered sites. A clear cohort effect was observed particularly for SCC on covered sites. Familial standardized incidence ratios for offspring combining invasive and in situ SCC were 2.25 (95% confidence interval, 1.93-2.59) for concordant exposed sites and 2.60 (95% confidence interval, 1.38-4.20) for concordant covered sites, suggesting no difference between the body parts within the present statistical power.

CONCLUSIONS: The higher increase in incidence on covered sites and the strong cohort effect suggest a contribution by intentional tanning. The observed equal increase in the familial effect on exposed and covered sites suggests that familial risk increases proportionately to the background rate.


Squamous cell carcinoma of the legs in African Americans.

McCall CO, Chen SC.

Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

J Am Acad Dermatol 2002 Oct;47(4):524-9 Abstract quote

BACKGROUND: Squamous cell carcinoma (SCC) is the most common skin cancer in African Americans, but its incidence is low. Although incompletely described in the literature, an increased incidence of SCC in sun-protected areas in black patients has been reported.

OBJECTIVE: This study was conducted to better define the incidence, characteristics, and cutaneous markers of SCC occurring on the legs in African Americans.

METHODS: We did a 5-year retrospective chart review of patients diagnosed with SCC in the dermatology clinic of an inner city hospital in the southern United States.

RESULTS: A total of 35 African Americans had biopsy-proven SCC during the study period. Sixteen patients had lesions on the legs; all of them were elderly African-American women, and most showed atypical lesional and perilesional features.

CONCLUSION: SCC is not rare on the legs of elderly African-American women. It can present with atypical features, and physicians must be alert to this possibility. Accompanying cutaneous changes may assist in its diagnosis.

Cancer of the skin in blacks. I. A review of 163 black patients with cutaneous squamous cell carcinoma.

Mora RG, Perniciaro C.

J Am Acad Dermatol 1981 Nov;5(5):535-43 Abstract quote

Cancer of the skin, in general, is believed to be rather uncommon in black persons. Information from the Tumor Registry of Charity Hospital of Louisiana in New Orleans was reviewed in reference to black patients who were diagnosed as having squamous cell carcinoma (SCC) of the skin between 1948 and 1979.

During this period, 163 black patients had a total of 176 SCCs of the skin. The lesions were about 20% more common than basal cell carcinomas (BCCs) in blacks of the same patient population. A mortality of 18.4% was a significant finding.

The most common sites of involvement were the face and the lower extremity. Collectively, involvement of the non-sun-exposed areas was more common. The most common predisposing conditions were scarring processes.


ALBINISM Oculocutaneous albinism

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.


Aggressive squamous cell carcinomas in persons infected with the human immunodeficiency virus.

Nguyen P, Vin-Christian K, Ming ME, Berger T.

Department of Dermatology, University of California, San Francisco, 1701 Divisadero St, Third Floor, San Francisco, CA 94143.

Arch Dermatol 2002 Jun;138(6):758-63 Abstract quote

OBJECTIVES: To illustrate the potential for aggressive growth of cutaneous squamous cell carcinomas (SCCs) in patients infected with the human immunodeficiency virus (HIV) and to determine the factors associated with increased morbidity and mortality from aggressive SCCs in HIV-infected patients.

DESIGN: Retrospective nonrandomized case series. SETTING: University-based dermatologic referral center.

PATIENTS: A consecutive sample of 10 patients infected with HIV who had "aggressive" SCC based on the following criteria: diameter larger than 1.5 cm, rapid growth rate, local recurrence, and/or evidence of metastasis.

MAIN OUTCOME MEASURES: Morbidity and mortality.

RESULTS: Five patients died of metastatic SCC within 7 years of their initial diagnosis despite treatment. Human immunodeficiency virus stage and the degree of immunosuppression were not associated with increased morbidity and mortality. Patients initially undergoing combination surgery and radiation therapy or radical neck dissection had the best outcomes.

CONCLUSIONS: Patients infected with HIV can develop rapidly growing cutaneous SCCs at a young age, with a high risk of local recurrence and metastasis. High-risk SCCs should be managed aggressively and not palliatively in patients infected with HIV.

Scalp paraffinoma underlying squamous cell carcinoma.

Ko CJ, Sarantopoulos GP, Bhuta S, Binder SW.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles 90095, USA
Arch Pathol Lab Med. 2004 Oct;128(10):1171-2. Abstract quote  

We report the case of an 84-year-old man with multiple squamous cell carcinomas located on his bald scalp, arising in association with underlying paraffinoma. Histologically, poorly differentiated, acantholytic squamous cell carcinomas were located above characteristic pseudocystic spaces.

Carcinomas have been reported in association with penile and breast paraffinomas, but we are unaware of any reports of squamous cell carcinoma arising over a scalp paraffinoma.

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.

The higher incidence of squamous cell carcinoma in renal transplant recipients is associated with increased telomere lengths.

Molecular Oncology Laboratory, Department of Pathology, The Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.

Hum Pathol. 2007 Feb;38(2):351-8. Epub 2006 Nov 28. Abstract quote

The incidence and aggressiveness of nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma (SCC), in immunocompromised renal transplant recipients (RTRs) is dramatically higher (up to 100-fold) compared with the normal population. SCC lesions are also predominant in RTRs, in contrast to the normal population where basal cell carcinoma is more common.

The mechanisms underlying this phenomenon are unknown, but effective treatments for these skin tumors would have a significant impact upon morbidity in this group of patients. The fundamental role of telomeres and telomerase in the development of most human cancers, including melanoma, is well established, but very few reports have assessed their function during the onset of nonmelanoma skin cancer.

To assess whether telomere maintenance plays any role in the increased incidence of SCC in renal transplant patients, we analyzed both the telomere lengths and telomerase expression levels in 44 SCCs and 22 Bowen's disease (BD) samples (carcinoma in situ) from RTRs and nontransplant patients. Our findings provide statistically significant evidence that the telomeres are consistently longer in both BD RTR and SCC RTR lesions compared with their nontransplant counterparts. We also show by immunohistochemistry that there is a trend toward higher telomerase levels in both the BD RTR and SCC RTR lesions, although this was not statistically significant.

Our data thus suggest that telomere lengthening may possibly be an early event in the development of SCC in renal transplant patients and demonstrate that telomere maintenance mechanisms should be further evaluated with respect to developing a future therapeutic strategy for these cancers.
Cutaneous squamous cell carcinoma in organ transplant recipients: a study of the Swedish cohort with regard to tumor site.

Lindelof B, Dal H, Wolk K, Malmborg N.

Unit of Dermatology and Venereology, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden.
Arch Dermatol. 2005 Apr;141(4):447-51. Abstract quote  

OBJECTIVE: To establish the anatomical site distribution of cutaneous squamous cell carcinoma (SCC) in organ transplant recipients (OTRs) with regard to age and sex.

DESIGN: Retrospective population-based cohort study of OTRs.

SETTING: Patients who underwent organ transplantation in Sweden from January 1, 1970, to December 31, 1997, registered in the Swedish In-patient Registry and national Swedish Cancer Registry.

PATIENTS: From the cohort of 5931 OTRs, we could include 179 patients with 475 cutaneous SCCs. Information on the sites was received from the cancer registry and from the histopathological reports.

RESULTS: The site of each SCC was registered in a computer program displaying the results on a 3-dimensional human figure. The head and neck were the predominant sites in male patients, and the trunk was the predominant site in female patients. The most common site in younger patients (born in 1940 or after) was the chest; and in older patients, the face. The ear was a common site in male patients, but, in contrast, no tumors were located there in female patients. Overall, the OTRs were younger compared with the overall Swedish population with cutaneous SCC.

CONCLUSIONS: There are differences in the anatomical site distribution of cutaneous SCCs in OTRs with regard to sex and age, and with regard to the general distribution in Swedish patients. The level of sun exposure is considered the most important factor in explaining those differences, and highlights the importance of sun avoidance in this group of patients.

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.



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)

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.

Molecular genetic analysis of the BRCA2 tumor suppressor gene region in cutaneous squamous cell carcinomas.

Molecular Oncology Laboratory, Pathology Department, Royal College of Surgeons in Ireland and Beaumont Hospital, Dublin, Ireland.


J Cutan Pathol. 2008 Jan;35(1):1-9. Abstract quote

Background: Germ line mutations of the BRCA2 tumor suppressor gene with subsequent loss of the remaining wild-type BRCA2 allele have been identified in up to 35% of familial breast cancer cases. A high frequency of allelic loss at the BRCA2 gene locus has also been reported in a variety of sporadic epithelial tumors including oesophageal squamous cell carcinomas (SCC), and sporadic head and neck SCC.

Aim: The present study aimed to examine the integrity of the BRCA2 gene in cutaneous SCC.

Materials and methods: Allelic imbalance/loss of heterozygosity (AI/LOH) was examined in 22 histologically confirmed cutaneous SCC at two microsatellite markers, D13S260 (centromeric to the BRCA2 gene) and D13S267 (telomeric to the BRCA2 gene). Immunohistochemical analysis of BRCA2 protein expression was also examined in the cutaneous SCC.

Results: AI/LOH at the D13S260 locus was found in eight of the 19 informative SCC, and AI/LOH at the D13S267 locus was found in 12 of the 18 informative SCC. Seven SCC showed allelic loss at both markers, and six SCC showed retention of heterozygosity at both markers. Expression of BRCA2 protein was only detected in six of the normal epidermises and three of the 21 SCC examined.

Conclusion: AI/LOH of the BRCA2 gene region was found to be common in the cutaneous SCC.
Expression of E-Cadherin and Beta-Catenin in Cutaneous Squamous Cell Carcinoma and its Precursors.

Lyakhovitsky A, Barzilai A, Fogel M, Trau H, Huszar M.

*Department of Dermatology, Sheba Medical Center, Tel-Hahomer and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Hashomer, Israel; and daggerDepartment of Pathology, Kaplan Medical Center, Rehovot, and Faculty of Medicine, The Hebrew University, Jerusalem, Israel.

Am J Dermatopathol. 2004 Oct;26(5):372-378. Abstract quote  

The E-cadherin-beta-catenin complex regulates the architectural integrity of epithelia by mediating intercellular adhesion. Down-regulation of its expression may contribute to invasion and metastatic behavior of carcinoma cells. Several studies demonstrated an abnormal expression of E-cadherin, beta-catenin, or both in various carcinomas, including non-melanoma skin cancer.

The aim of the present study was to investigate the involvement of E-cadherin-catenin adhesion system in the progression of human cutaneous squamous cell carcinoma (SCC). For that purpose, sections from normal skin, skin showing solar elastosis (SE), solar keratosis (SK), and SCC were stained with monoclonal antibodies against E-cadherin and beta-catenin. Evaluation of the staining results was performed using a semi-quantitative method in which pattern and intensity of staining, percentage of positive cells, and cytoplasmic staining were evaluated. Normal skin and skin showing mild and moderate solar elastosis strongly expressed membranous E-cadherin and beta-catenin. E-cadherin expression was progressively reduced in the epidermis of skin with severe solar elastosis through solar keratosis to SCC. The same phenomenon was observed for beta-catenin starting from solar keratosis. In some cases of SCC, additional cytoplasmic staining was observed.

We found no correlation between E-cadherin and beta-catenin expression and tumor differentiation or between SCC from sun-exposed and sun-protected skin. Statistical analysis revealed correlation between expression of both E-cadherin and beta-catenin and the morphology of the lesion.

These results support a gradual evolution from severely sun-damaged skin to SCC, not only on a morphologic level, but also at the molecular level.

Chromosomal aberrations in squamous cell carcinoma and solar keratoses revealed by comparative genomic hybridization.

Ashton KJ, Weinstein SR, Maguire DJ, Griffiths LR.

Genomics Research Centre, Griffith University-Gold Coast, Bundall, Queensland, Australia.

Arch Dermatol. 2003 Jul;139(7):876-82. Abstract quote

OBJECTIVE: To identify chromosomal copy numbers of frequent genetic aberrations within squamous cell carcinomas (SCCs) and solar keratoses (SKs), and provide further evidence to support or challenge current dogma concerning the relationship between these lesions.

DESIGN: Retrospective analysis of genetic aberrations in DNA from SK and SCC biopsy specimens by comparative genomic hybridization.

SETTING: University-based research laboratory in Queensland, Australia.

PATIENTS: Twenty-two biopsy specimens from patients with diagnosed SKs (n = 7), cutaneous SCCs (n = 10), or adjoining lesions (n = 5).

MAIN OUTCOME MEASURES:Identification of frequent genetic aberrations both specific to SK and SCC and shared by these lesions to investigate their clonal relationship.

RESULTS: Shared genomic imbalances were identified in SK and SCC. Frequent gains were located at chromosome arms 3q, 17q, 4p, 14q, Xq, 5p, 9q, 8q, 17p, and 20q, whereas shared regional losses were observed at 9p, 3p, 13q, 17p, 11p, 8q, and 18p. Significant loss of 18q was observed only in SCC lesions.

CONCLUSIONS: Our results demonstrate that numerous chromosomal aberrations are shared by the 2 lesions, suggesting a clonal relationship between SK and SCC. Additionally, the genomic loss of 18q may be a significant event in SK progression to SCC. Finally, the type and frequency of aberrations suggests a common mode of tumorigenesis in SCC-derived tumors.


Expression of desmosomal proteins in squamous cell carcinomas of the skin

Hjalmar Kurzen, Ivonne Münzing and Wolfgang Hartschuh

J Cutan Pathol 2003;30:621-630 Abstract quote

Background: Desmosomal proteins are well established markers of epithelial differentiation. Down-regulation of desmosomal proteins has been suggested to be a sign of reduced adhesiveness in metastasizing cells.

Methods: We examined actinic keratoses, Bowen's disease, and squamous cell carcinoma (SCC) of the skin for the expression of desmosomal proteins using isoform-specific antibodies on paraffin-embedded sections. Evaluation was performed qualitatively in comparison to the epidermis and semiquantitatively using an area-intensity-score.

Results: We found no qualitative correlation of desmoplakin or plakoglobin expression with risk of metastasis. Plakophilin 1, desmoglein 1, and the desmocollins 1-3 were found to be heterogeneously expressed in all neoplasms without significant correlation to aggressive tumor behavior. Plakophilin 2 was not expressed in any of the neoplasms examined. As most striking finding, desmoglein 2 was up-regulated qualitatively in half of all neoplasms examined and showed a significant higher proportion of positive cells in high-risk SCC than in low-risk SCC.

Conclusions: Desmosomal proteins are highly regulated in cutaneous SCC. Only desmoglein 2 expression correlates with risk of metastasis. Desmosomes may still be functional in metastasizing tumor cells.


Evidence for the association of human papillomavirus infection and cutaneous squamous cell carcinoma in immunocompetent individuals.

Masini C, Fuchs PG, Gabrielli F, Stark S, Sera F, Ploner M, Melchi CF, Primavera G, Pirchio G, Picconi O, Petasecca P, Cattaruzza MS, Pfister HJ, Abeni D.

Clinical Epidemiology Unit, Istituto Dermopatico dell'Immacolata Rome, Italy.

Arch Dermatol. 2003 Jul;139(7):890-4. Abstract quote

OBJECTIVE: The aim of our study was to evaluate human papillomavirus (HPV) infection as a risk factor for cutaneous squamous cell carcinoma (SCC) in immunocompetent individuals.

DESIGN: Hospital-based case-control study.

SETTING: Referral center for dermatologic diseases for central and southern Italy.

PARTICIPANTS: Consecutive patients with histologically confirmed cutaneous SCC (n = 46) and control subjects (n = 84) chosen by frequency matching (age and sex) among patients admitted with unrelated diseases.

MAIN OUTCOME MEASURE: Infection with epidermodysplasia verruciformis-related HPV types, blindly assessed by serologic testing (viruslike particle enzyme-linked immunosorbent assay). Information was obtained on known potentially confounding risk factors (family history, history and signs of sun exposure, and pigmentary traits) and on history of HPV-related lesions and diseases, assessed by interview and examination by a dermatologist.

RESULTS: Positive serologic findings for HPV type 8 were associated with SCC (odds ratio, 3.2; 95% confidence interval, 1.3-7.9) independently of other risk factors, whereas positive serologic findings for HPV type 15 were negatively associated with SCC (odds ratio, 0.4; 95% confidence interval, 0.2-0.9). Other variables significantly associated with the tumor were family history of skin cancer, professional or recreational sun exposure, light eye color, high number of solar keratoses and seborrheic keratoses on the body surface, and residency in radon-emitting buildings.

CONCLUSIONS: Positive serologic findings for HPV type 8 are associated with SCC occurrence in immunocompetent individuals. Viral infection could act as a cofactor in the tumor development, along with genetic predisposition, solar radiation, and other environmental exposures. If confirmed, these findings could open new perspectives for treatment and prevention of SCC.


Inflammation is associated with progression of actinic keratoses to squamous cell carcinomas in humans.

Berhane T, Halliday GM, Cooke B, Barnetson RS.

Department of Medicine (Dermatology), Melanoma and Skin Cancer Research Institute, University of Sydney at Royal Prince Alfred Hospital, Sydney, Camperdown, NSW 2050, Australia.

Br J Dermatol 2002 May;146(5):810-5 Abstract quote

BACKGROUND: Squamous cell carcinoma (SCC) is a common skin tumour that may metastasize and lead to death. We have observed that before actinic keratoses (AK) progress to SCCs they may become tender and inflamed. In some of these, histological examination shows that they are, in fact, SCCs.

OBJECTIVES: To study the progression of AK to SCCs.

METHODS: We studied skin tumours from 50 patients with either asymptomatic AK, inflamed AK or SCCs, using immunocytochemistry. The diagnosis of each tumour was confirmed by histological examination.

RESULTS: Studies of differentiation using heat shock protein 27 showed a stepwise loss of differentiation as the tumours progressed from asymptomatic AK, through inflamed AK to SCCs. During the inflamed AK phase, there was a marked increase in T lymphocytes and Langerhans cells: the number of infiltrating cells diminished as progression to SCC occurred. There was an increase in immunoreactive p53 and the apoptosis inhibitor bcl-2 as tumours progressed from AK to SCCs, and a decrease in Fas and Fas ligand.

CONCLUSIONS: These studies have shown that progression from benign to malignant tumours may be associated with an inflammatory response, which appears to drive malignant conversion, but subsides rapidly following this conversion.


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.

Photoexposition discriminates Notch 1 expression in human cutaneous squamous cell carcinoma.

1Department of Pathology, University of Ioannina Medical School, Ioannina, Greece.


Mod Pathol. 2008 Mar;21(3):316-25. Abstract quote

The Notch signaling pathway may play opposing roles in cancer. It can be oncosuppressive or protumoral, depending on the cellular and tissue context. In skin cancer, Notch 1 expression is downregulated, thus supporting the hypothesis of an oncosuppressive role in cutaneous carcinomas. However, as members of the Notch family undergo downregulation upon exposure to UV irradiation, we wondered whether Notch 1 expression in skin carcinomas may be governed by additional factors, including UV exposure.

We investigated the expression of Notch 1 and its ligands, Jagged 1, Jagged 2 and Delta-like 1, by immunohistochemistry in a series of premalignant and invasive cutaneous carcinomas, including 4 solar keratoses, 5 Bowen's disease, 5 squamous cell carcinomas on sun-exposed skin, 6 squamous cell carcinomas on sun-protected genital skin and 14 basal cell carcinomas of different histotypes (nodular, superficial type, sclerodermiform/infiltrating and baso-squamous). Expression of Notch 1 was decreased in solar keratoses and invasive squamous cell carcinomas localized on sun-exposed skin. In contrast, marked Notch 1 staining was observed in extragenital Bowen's disease as well as in genital (penile) human papilloma virus-related in situ and invasive squamous cell carcinomas. A diffuse Notch 1 staining was detected in nodular and superficial basal cell carcinomas while sclerodermiform/infiltrating and baso-squamous basal cell carcinomas showed a low to absent Notch 1 expression. Jagged 1, Jagged 2 and Delta-like 1 proteins were expressed in all tissues examined. Present findings show divergent expression of Notch 1 in skin cancer, depending on anatomical site and tumor histotype.

Thus, whereas in UV-related squamous cell photocarcinogenesis Notch 1 downregulation could mirror a tumor suppressor function of the receptor, in sun-protected squamous cell carcinomas Notch 1 was upregulated. Furthermore, Notch 1 expression was minimal in basal cell carcinoma subtypes correlated with risk of recurrence (sclerodermiform/infiltrating and baso-squamous) in comparison with nodular and superficial types.

Peroxisome proliferator-activated receptors in squamous cell carcinoma and its precursors.

Nijsten T, Geluyckens E, Colpaert C, Lambert J.

Department of Dermatology, University Hospital Antwerp, Antwerp, Belgium.
J Cutan Pathol. 2005 May;32(5):340-7. Abstract quote  

Background: Peroxisome proliferator-activated receptors (PPARs) mediate several functions that are of interest in carcinogenesis. Although PPARalpha, PPARbeta, and PPARgamma are expressed in multiple human, their expression has not been investigated in non-melanoma skin cancer.

Methods: We performed a retrospective paired immunohistochemical analysis of normal skin, actinic keratosis (AK), and squamous cell carcinoma (SCC) among 35 individuals. Specimens were considered PPAR immunoreactive when 1% or more of the tumor cells showed clear evidence of immunostaining. Cyclooxygenase-2 (COX-2) expression, the fraction of proliferating endothelial cells, and microvessel density were also evaluated in these samples.

Results: PPARalpha immunoreactivity was significantly less likely to occur in SCC and AK than in normal skin of each individual. In contrast to PPARalpha, PPARbeta appeared to be upregulated in (pre)malignant skin lesions. For each individual, the likelihood that normal skin, AK, or SCC was immunoreactive against PPARgamma was comparable. COX-2 immunopositivity was significantly associated with PPARbeta and PPARgamma immunoreactivity. No statistical differences were noted for the angiogenesis parameters and PPARalpha, PPARbeta, or PPARgamma expression, except that the microvessel density was significantly higher among PPARbeta-immunoreactive SCCs compared to that among immunonegative SCCs.

Conclusion: Although further research is warranted, these results suggest that PPAR ligands such as fibrates and thiazolidinediones may have chemoprophylactic properties in skin carcinogenesis.
Retinoblastoma protein function and p16(INK4a) expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16(INK4a) expression and infiltrative behavior.

Nilsson K, Svensson S, Landberg G.

1Department of Laboratory Medicine, Division of Pathology, Lund University, Malmo University Hospital, Malmo, Sweden.
Mod Pathol. 2004 Dec;17(12):1464-74. Abstract quote  

p16(INK4a) is involved in many important regulatory events in the cell and the expression and function is closely associated with the retinoblastoma protein (Rb). Earlier, we have in colorectal cancer and in basal cell carcinoma showed that p16(INK4a) is upregulated at the invasive front causing cell cycle arrest in infiltrative tumor cells via a functional Rb. This role for p16(INK4a) as a regulator of proliferation when tumor cells infiltrate might besides a general cyclin-dependent kinase (cdk) inhibitory effect explain why p16(INK4a) is deregulated in many tumor forms. The expression pattern of p16(INK4a) in relation to Rb-function in squamous cancer and precancerous forms of the skin has not been fully detailed.

We therefore characterized the expression of p16(INK4a), Rb-phosphorylation and proliferation in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma with special reference to infiltrative behavior. The expression of p16(INK4a) varied between the lesions, with weak and cytoplasmic p16(INK4a) expression and functional Rb in actinic keratosis. Strong nuclear and cytoplasmic p16(INK4a) expression was observed in all carcinomas in situ in parallel with lack of Rb-phosphorylation but high proliferation indicating a nonfunctional Rb. Invasive squamous carcinoma showed a mixed p16(INK4a) expression pattern where some tumors had strong cytoplasmic p16(INK4a) expression, large fraction of Rb-phosphorylated cells and high proliferation. Interestingly, despite this disability of p16(INK4a) to inhibit proliferation there was an upregulation of cytoplasmic p16(INK4a) in infiltrative cells compared to tumor cells towards the tumor center. A similar scenario but strong and combined nuclear and cytoplasmic p16(INK4a) expression in infiltrative cells, was observed in other invasive squamous cancers.

This suggests that the p16(INK4a) upregulation in infiltrative cells is governed independently of the subcellular localization or of the potential to affect proliferation via Rb, and suggests a potentially proliferation independent function for p16(INK4a) in infiltrative behavior.

Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin.

Hodges A, Smoller BR.

Departments of Pathology (AH, BRS) and Dermatology (BRS), University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Mod Pathol 2002 Nov;15(11):1121-5 Abstract quote

There are approximately 200,000 new cases of cutaneous squamous cell carcinoma diagnosed each year in the United States, with between 1300 and 2300 deaths per year from metastatic disease. The tumor suppressor p16, encoded by the CDKN2/INK4a locus, has been reported mutated in >/=24% of squamous cell carcinomas. Mutations of the p16 gene have also been found in actinic keratoses, the first identifiable lesion in the continuum from normal skin to squamous cell carcinoma. We hypothesized that there may be an appreciable difference in expression of p16 between normal skin, actinic keratoses, squamous cell carcinoma in situ, and invasive squamous cell carcinoma.

Ten actinic keratoses, 10 in situ squamous cell carcinomas, and 10 invasive squamous cell carcinomas were examined using the immunoperoxidase method with antigen retrieval for anti-p16(INK4a) antibody. All 10 actinic keratoses were positive for weak to moderate p16 staining in the lower third to lower half of the epidermis (especially the basal keratinocytes). This staining was significant when compared with the lack of staining seen in normal skin controls. Twenty percent of in situ squamous cell carcinomas had moderate to strong staining in only the lower half to lower two thirds of the epidermis, whereas 70% of the in situ squamous cell carcinomas exhibited full-thickness p16 staining, with no staining in the dermis. Thirty percent of invasive squamous cell carcinomas had full-thickness staining of the in situ component of the lesion, and 100% of invasive squamous cell carcinomas exhibited moderate to strong staining of the invasive component of the lesion.

These findings indicate correlation between the increased expression of p16 during the progression of skin from actinic keratosis to in situ squamous cell carcinoma to invasive squamous cell carcinoma. These data may lend further support to the view of the actinic keratosis as a precursor lesion to squamous cell carcinoma.

Analysis of p53 and bcl-2 protein expression in the non-tumorigenic, pretumorigenic, and tumorigenic keratinocytic hyperproliferative lesions.

Hussein MR, Al-Badaiwy ZH, Guirguis MN.

Department of Pathology, Faculties of Medicine, Assuit and South Valley Universities, Assuit, Egypt.
J Cutan Pathol. 2004 Nov;31(10):643-51. Abstract quote  

Background: The hyperproliferative keratinocytic lesions encompass a wide range of non-tumorigenic, pretumorigenic, and tumorigenic conditions. The aim of this work was to examine the expression patterns of apoptosis-linked molecules (bcl-2 and p53) in these lesions.

Methods: Immunoperoxidase staining methods were applied to analyze p53 and bcl-2 protein expression in a total of 66 cases, including 12 squamous cell carcinomas (both in situ and invasive SCC), 11 actinic keratoses (AK), 13 psoriasis vulgaris (PV), eight verruca vulgaris (VV), six chronic dermatitis (CD), five seborrheic keratosis (SK), four lichen planus (LP), three epidermodysplasia verruciformis (EDV), two condyloma acuminata (CA), two lichen simplex chronicus (LSC), and 10 specimens from normal skin.

Results: As compared to normal skin (0.70 +/- 0.26), the bcl-2 average weighted scores in the non-tumorigenic (0.76 +/- 0.16), pretumorigenic (1.45 +/- 0.28), and tumorigenic lesions (2.83 +/- 0.50 and 2.92 +/- 0.50 for in situ and invasive SCC, respectively) showed significant up-regulation (p = 0.001). In the non-tumorigenic lesions, the bcl-2 expression values decreased in the following order: SK > EDV > CD > LP > CA > PV > VV (1.40 +/- 0.24 > 1.33 +/- 0.67 > 0.83 +/- 0.40 > 0.67 +/- 0.21 > 0.50 +/- 0.20 > 0.46 +/- 0.22 > 0.13 +/- 0.01, respectively). As compared to normal skin (1.10 +/- 0.23), the p53 average weighted scores in the non-tumorigenic (1.86 +/- 0.18), pretumorigenic (3.64 +/- 0.53), and tumorigenic lesions (5.00 +/- 1.00 and 5.08 +/- 0.86 for in situ and invasive SCC, respectively) showed significant up-regulation (p = 0.021). In the non-tumorigenic lesions, p53 average weighted scores decreased in the following order: SK > PV > CA > LP > CD > VV > EDV (3.20 +/- 0.49 > 2.38 +/- 0.27 > 2.0 +/- 0.0 > 1.83 +/- 0.48 > 1.0 +/- 0.37 > 1.0 +/- 0.33 > 1.0 +/- 0.0, respectively). There was a positive correlation between bcl-2 and p53 protein expression in normal skin (r = 0.966, p = 0.0001), non-tumorigenic (r = 0.775, p = 0.0001), pretumorigenic (r = 0.830, p = 0.001), and tumorigenic lesions (r = 0.757, p = 0.003).

Conclusions: Bcl-2 and p53 proteins are altered in the keratinocytic hyperproliferative lesions. Determination of whether these alterations reflect underlying gene mutations will require further investigations.
p63 is a useful marker for cutaneous spindle cell squamous cell carcinoma.

Dotto JE, Glusac EJ.

Department of Pathology, Dermatopathology, Yale University School of Medicine, New Haven, CT, USA.

J Cutan Pathol. 2006 Jun;33(6):413-7 Abstract quote.  

Background: Cutaneous spindle cell squamous cell carcinoma (SCSCC) is a rare variant of SCC. This lesion is sometimes difficult to diagnose based purely on morphologic features. p63 is a member of the p53 gene family that can be identified in epithelial malignancies.

Methods: Thirteen cases of spindle SCC were stained with p63, CK34betaE12, MNF116, vimentin, and S100. Control cases included desmoplastic melanoma (eight cases), atypical fibroxanthoma (AFX) (10 cases), dermatofibrosarcoma protuberans (eight cases), and cutaneous leiomyosarcoma (LMS) (four cases).

Results: p63 was expressed diffusely in the nuclei of 100% (13/13) of SCSCCs. Of controls, p63 showed focal labeling of two LMS and two AFX. MNF116 and CK34betaE12 were positive in 13/13 SCSCCs. Of controls, one LMS was focally positive for MNF116. All SCSCCs and all control cases were positive for vimentin.

Conclusions: In the given differential diagnosis, p63 appears relatively specific to SCSCC and adds a useful nuclear marker to the available repertoire. The findings also suggest that cytokeratins MNF116 and CK34betaE12 may be more useful than standard cytokeratins in labeling SCSCC.

p63 expression in normal skin and usual cutaneous carcinomas.

Reis-Filho JS, Torio B, Albergaria A, Schmitt FC.

IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, School of Health Sciences, University of Minho, Braga, Department of Pathology, Hospital Fernando da Fonseca, Amadora-Sintra, Lisbon, and Porto Medical Faculty, University of Porto, Porto, Portugal

J Cutan Pathol 2002 Oct;29(9):517-523 Abstract quote

BACKGROUND: p63 is a p53 homologue that is mapped to chromosome 3q27. This gene encodes six different isoforms, which have either transactivating or dominant negative effects on p53-reporter genes. It has been described that in contrast to p53, p63 seems not to be associated with tumor predisposition, as neither p63 knockout mouse models nor germline p63 mutations are related to an increased risk of tumorigenesis. It has been demonstrated that p63 is a reliable keratinocyte stem cell marker and that it is involved in the maintenance of the stem cell population. Scant data on p63 expression in normal skin, basal cell carcinomas (BCCs), keratoacanthomas and squamous cell carcinomas (SCCs) have been reported. We herein evaluated p63 expression in 16 BCCs, one keratoacanthoma and 13 SCCs.

METHODS: Immunohistochemistry according to the streptavidin-biotin-peroxidase technique, using the antibody 4A4 raised against all p63 isoforms, was performed. p63 expression was evaluated in epidermal cells and skin appendages. Semi-quantitative evaluation (-, +, ++, +++) of p63 expression in BCCs, keratoacanthoma and SCCs was carried out. Only nuclear expression was considered as specific.

RESULTS: p63 was expressed in the nuclei of epidermal basal and suprabasal cells, in the cells of the germinative hair matrix and the external root sheath of hair follicles, in the basal cells of the sebaceous gland and in the myoepithelial/basal cells of the sweat glands. All terminally differentiated cells were negative for p63. All BCCs showed ++ to +++ immunoreactivity. At variance, keratoacanthomas and grade I and II SCCs showed variable p63 reactivity in a basal layer-like distribution, whereas undifferentiated cells of grade III SCCs showed ++ to +++ positivity. A grade IV spindle SCC showed + immunoreactivity. The SCCs in situ showed remarkable expression of p63 in all cell layers. Terminally differentiated squamous cells were either negative or showed only focal immunoreactivity in the carcinomas.

CONCLUSIONS: p63 is consistently expressed in the basal cells of epidermis and cutaneous appendages, including the basal/myoepithelial cells of sweat glands. Based on our findings, the balance of probabilities favors that p63 might play a role in the pattern of differentiation and in the oncogenesis of usual carcinomas of the skin.

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


Reduction of expression of tuberin, the tuberous-sclerosis-complex-gene-2 product in tuberous sclerosis complex associated connective tissue nevi and sporadic squamous and basal cell carcinomas.

Wienecke R, Klemm E, Karparti S, Swanson NA, Green AJ, DeClue JE.

Department of Dermatology and Allergology, Ludwig-Maximilians-University Munich, Munich, Germany, National Institutes of Health, National Cancer Institute, Laboratory of Cellular Oncology, Bethesda, Maryland, USA, Department of Dermatology, Semmelweis University, Budapest, Hungary, Oregon Health Sciences University, Department of Dermatology, Portland, Oregon, USA, Department of Medical Genetics and Conway Institute, University College Dublin, Ireland

J Cutan Pathol 2002 May;29(5):287-290 Abstract quote

Background: Patients affected with tuberous sclerosis complex (TSC) are prone to the development of multiple benign tumors of the skin and other organs. Tuberin, the protein product of the tuberous-sclerosis-complex-2 tumor suppressor gene (TSC2) has been shown to inhibit cell proliferation. In TSC associated kidney tumors and sporadic brain tumors the loss/reduction of tuberin has been shown.

Methods: Specimens of nine squamous cell carcinomas (SCC) and five basal cell carcinomas (BCC) from patients without TSC and six biopsies of connective tissue nevi (CTN) of patients with TSC were obtained. Specimens were analyzed by immunoblotting for the expression of tuberin. Results: Absent or reduced levels of tuberin were detected in the dermal parts of three of six shagreen patches, two of five BCC, and four of nine SCC.

Conclusions: In tumors/hamartomas of patients with TSC the complete loss of TSC2 and tuberin is a mechanism which could be shown for CTN, thereby excluding the possibility of haploinsufficiency of TSC2. In a substantial number of cutaneous BCC and SCC the loss or downregulation of tuberin seems to be epigenetic, as alterations of TSC2 are not known in these tumors. The absence or reduction of tuberin might contribute to their proliferation.


Expression of vascular endothelial growth factor in basal cell carcinoma and cutaneous squamous cell carcinoma of the head and neck.

Bowden J, Brennan PA, Umar T, Cronin A.

Department of Oral and Maxillofacial Surgery, Poole General Hospital, Poole, UK, Department of Pathology, Bournemouth General Hospital, Bournemouth, Dorset, UK and Department of Oral and Maxillofacial Surgery, Queen Alexandra Hospital, Cosham, Portsmouth, UK.

J Cutan Pathol 2002 Nov;29(10):585-589 Abstract quote

BACKGROUND: Basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) can both arise from any cutaneous epithelial surface. BCC are slow growing and rarely metastasise, whereas SCC are usually more aggressive. It is likely that the angiogenic process plays a key role in determining rate of growth and propensity for dissemination. Angiogenesis is a complex process requiring many factors and a pivotal group of proteins involved in this process is vascular endothelial growth factor (VEGF).

METHODS: Immunohistochemical expression of VEGF was assessed in 44 cases of BCC and 41 cases of cutaneous SCC from the head and neck region.

RESULTS: VEGF was expressed by blood vessel endothelial cells in both adjacent skin and tumour, and in the basal keratinocyte layer of epidermis. In BCC, VEGF was expressed by tumour epithelial cells, predominantly at the invasive tumour front, in 24/44 cases and its expression was significantly greater than in adjacent skin (p = 0.038). More widespread VEGF expression was found in 32/41 cases of SCC, and it was significantly associated with the degree of tumour differentiation (p < 0.001).

CONCLUSIONS: The patterns of VEGF expression in BCC and SCC may help to explain the different behaviour that is usually seen with these tumours.


Analysis of the vitamin D system in cutaneous squamous cell carcinomas

Jörg Reichrath, Leyla Rafi, Martin Rech, Tanja Mitschele, Viktor Meineke, Barbara C. Gärtner, Wolfgang Tilgen and Michael F. Holick

Journal of Cutaneous Pathology Volume 31 Issue 3 Page 224 - March 2004 Abstract quote

Background: Increasing evidence points at an important function of vitamin D metabolites for growth regulation in various tissues, and new vitamin D analogs are interesting candidates for the treatment of malignancies, including squamous cell carcinomas (SCC).

Methods: We have analyzed expression of vitamin D receptor (VDR), vitamin D-25-hydroxylase (25-OHase), 25-hydroxyvitamin D-1-hydroxylase (1-OHase), and 1,25-dihydroxyvitamin D-24-hydroxylase (24-OHase) in SCC.

Results: Intensity of VDR immunoreactivity was increased in SCCs as compared to normal human skin. VDR staining did not correlate with histological type or grading, nor with markers for proliferation, differentiation, or apoptotic cells. Incubation of SCC cell lines (SCL-1, SCL-2) with calcitriol resulted in a dose-dependent suppression of cell proliferation (approximately up to 30%) in vitro, as measured by a tetrazolium salt (WST-1)-based colorimetric assay. RNA levels for VDR, 25-OHase, 1-OHase, and 24-OHase were significantly elevated in SCCs as compared to HS, as measured by real-time polymerase chain reaction.

Conclusions: Our findings demonstrate that modulation of VDR expression and local synthesis or metabolism of vitamin D metabolites may be of importance for growth regulation of SCCs. Additionally, SCCs represent potential targets for therapy with new vitamin D analogs that exert little calcemic side effects or for pharmacological modulation of calcitriol synthesis/metabolism in these tumors.


Effects of biopsy-induced wound healing on residual basal cell and squamous cell carcinomas: rate of tumor regression in excisional specimens.

Swetter SM, Boldrick JC, Pierre P, Wong P, Egbert BM.

Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, and Department of Dermatology, Stanford University Medical Center, Stanford, CA, USA.


J Cutan Pathol 2003 Feb;30(2):139-46 Abstract quote

BACKGROUND: Wound healing following a partial biopsy of basal cell (BCC) and squamous cell carcinomas (SCC) may induce tumor regression.

METHODS: Nonmelanoma skin cancer (NMSC) biopsy and re-excision specimens from 1994 to 2001 were reviewed for histologic evidence of scar vs. presence of residual tumor in excision specimens. Regressed and non-regressed tumors were analyzed to assess the influence of anatomic location, biopsy technique (punch vs. shave), histologic subtype of BCC or SCC, time interval between biopsy and excision, and patient age.

RESULTS: Nine hundred and ten excisions were performed for transected BCC or SCC, 217 (24%) of which showed scar with no residual tumor. Logistic regression analysis revealed significant differences in the regressed vs. non-regressed subsets. SCCs were more likely to regress than BCCs (40% vs. 20%, respectively, p < 0.00001). Independent of the NMSC type, tumors regressed more often following shave rather than punch biopsy (34% vs. 15%, respectively, p < 0.00001), as did tumors on the trunk and extremities compared with head and neck cases (31% vs. 21%, respectively, p < 0.01).

CONCLUSIONS: In our series, 24% of NMSCs transected on the initial biopsy showed no residual tumor in the excision specimens, implying that some event in the interval between biopsy and excision may lead to the eradication of residual tumor. The exact mechanism is unclear, but wound healing likely plays an important role.



Human papillomavirus-associated digital squamous cell carcinoma: literature review and report of 21 new cases.

Alam M, Caldwell JB, Eliezri YD.

Division of Cutaneous and Aesthetic Surgery, Department of Dermatology, Feinberg School of Medicine, Northwestern University, USA

J Am Acad Dermatol 2003 Mar;48(3):385-93 Abstract quote

OBJECTIVE: Our aim was to review the clinical behavior of human papillomavirus (HPV)-associated digital squamous cell carcinoma (SCC). Specifically, we examined evidence for the tumor's (1) infectious origin and spread, (2) response to therapy, and (3) prognosis and metastatic risk.

DESIGN: We reviewed and performed data tabulation of all 51 reported cases in the English-language literature and a case series of 23 cases (21 of them not previously reported). We present 2 of the cases in depth.

SETTING: We used previously reported cases from MEDLINE and a case series from a single dermatologic operation practice from 1985 to 1999.

RESULTS: (1) Of all cases, 10% (7/72) had an antecedent genital dysplasia or carcinoma containing the same HPV subtype as the digital SCC. (2) The rate of recurrence after general surgical therapy was 43% (6/14). After Mohs micrographic surgery the recurrence rate was 13% (2/16) for the cases in the literature, and 26% (6/23) for our case series. (3) Of tumors, 3% (2/72) have been observed to metastasize.

CONCLUSIONS: (1) This suggests the possibility of genital-digital spread as a mechanism of tumor genesis. (2) HPV-associated digital SCC is more likely to recur after surgical treatment than previously reported. This rate of recurrence greatly exceeds that for cutaneous SCCs in general and may be caused by residual postsurgical HPV. (3) The rate of metastasis, however, appears to be low.


Factors associated with large cutaneous squamous cell carcinomas.

Renzi C, Mastroeni S, Passarelli F, Mannooranparampil TJ, Caggiati A, Potenza C, Pasquini P.

Clinical Epidemiology Unit, Istituto Dermopatico dell'Immacolata, Rome, Italy.

J Am Acad Dermatol. 2010 Sep;63(3):404-11. Epub 2010 Jul 2.
Abstract quote

BACKGROUND: Large cutaneous squamous cell carcinoma (SCC) is associated with a higher risk of disfigurement, local recurrence, and metastasis; however, little is known about factors associated with tumor size at diagnosis.

OBJECTIVES: We sought to evaluate factors associated with SCC size, including diagnostic/treatment delay and patient and tumor characteristics.

METHODS: We studied a stratified sample of 308 patients with SCC recently treated at a dermatologic referral center in Italy. Medical records were reviewed and telephone interviews conducted. Multiple logistic regression was used to examine factors associated with SCC size.

RESULTS: With univariate analyses, among both invasive and in situ cases, SCC greater than 2 cm was significantly associated with male gender, tumors arising in chronic lesions, and tumors located on not easily visible sites. Long delay before surgical removal was significantly associated with large SCC size only for invasive SCC (P < .001). Among patients with invasive SCC, when controlling for age and gender, multivariate analysis showed a significantly higher likelihood of SCC greater than 2 cm with a total delay longer than 18 months before surgical removal (odds ratio=4.18; 95% confidence interval 2.45-7.13) and for tumors arising in chronic lesions (odds ratio=6.42; 95% confidence interval 3.13-13.2).

LIMITATIONS: The study was cross-sectional and based on a single center.

CONCLUSIONS: Long total delay in removal significantly increased the likelihood of invasive SCC greater than 2 cm. Our findings highlight the importance of early detection and treatment to prevent large invasive SCCs, which are associated with a higher risk of disfigurement, recurrence, and metastasis. Particular attention should be paid to chronic skin lesions and not easily visible body sites during physician- and patient-performed examinations.

A Clinicopathological and Immunohistochemical Comparison of Squamous Cell Carcinoma Arising in Scars Versus Nonscar SCC in Japanese Patients.

From the *First Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan; and daggerDepartment of Laboratory, Kanto Rosai Hospital, Kanagawa, Japan.


Am J Dermatopathol. 2006 Dec;28(6):472-477. Abstract quote

Squamous cell carcinoma (SCC) of the skin shows an indolent prognosis in general. However, the prognosis of SCC arising in a scar (scar carcinoma) is considered to be worse than that of SCC without any clinical history of injury (nonscar SCC).

The aim of this study was to compare several indices, p53, Ki-67, E-cadherin, and beta-catenin, which are related to tumor behavior, between scar carcinoma and nonscar SCC clinicopathologically and immunohistochemically. The materials were from 10 cases of scar carcinoma and 10 cases of nonscar SCC.

Clinicopathologically, the mean ages at diagnosis of scar carcinoma and nonscar SCC were 59.2 and 71.2, respectively. The most frequent anatomic site of scar carcinoma was the limbs. The most common cause of scars in our study was burns. The mean duration from the initial injury to the diagnosis of carcinoma was 30.5 years.

Immunohistochemically, the mean labeling index (calculated as the percentage of positive cells) of p53 was 16.5 and 58.6 in scar carcinoma and nonscar SCC, respectively (P < 0.01, Welch test). The LI of Ki-67 was 19.1 in scar carcinoma and 52.1 in nonscar SCC (P < 0.01, Welch test). The rates of positivity of the other proteins, such as E-cadherin and beta-catenin, were similar between scar carcinoma and nonscar SCC.

In this study, the follow-up time was short and the number of patients was small, and for these reasons it might not have been possible to obtain evidence that scar carcinoma is aggressive.
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.



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.

Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification. Part one.

Cassarino DS, Derienzo DP, Barr RJ.

Department of Pathology, Stanford University, Palo Alto, CA 94305, USA.
J Cutan Pathol. 2006 Mar;33(3):191-206. Abstract quote  

Cutaneous squamous cell carcinoma (SCC) includes many subtypes with widely varying clinical behaviors, ranging from indolent to aggressive tumors with significant metastatic potential. However, the tendency for pathologists and clinicians alike is to refer to all squamoid neoplasms as generic SCC. No definitive, comprehensive clinicopathological system dividing cutaneous SCCs into categories based upon their aggressiveness has yet been promulgated.

Therefore, we have proposed the following based upon the malignant potential of SCC variants, separating them into categories of low (< or = 2% metastatic rate), intermediate (3-10%), high (greater than 10%), and indeterminate behavior. Low-risk SCCs include SCC arising in actinic keratosis, HPV-associated SCC, tricholemmal carcinoma, and spindle cell SCC (unassociated with radiation). Intermediate-risk SCCs include adenoid (acantholytic) SCC, intraepidermal epithelioma with invasion, and lymphoepithelioma-like carcinoma of the skin. High-risk subtypes include de novo SCC, SCC arising in association with predisposing factors (radiation, burn scars, and immunosuppression), invasive Bowen's disease, adenosquamous carcinoma, and malignant proliferating pilar tumors. The indeterminate category includes signet ring cell SCC, follicular SCC, papillary SCC, SCC arising in adnexal cysts, squamoid eccrine ductal carcinoma, and clear-cell SCC.

Subclassification of SCC into these risk-based categories, along with enumeration of other factors including tumor size, differentiation, depth of invasion, and perineural invasion will provide prognostically relevant information and facilitate the most optimal treatment for patients.

The diagnostic concordance of actinic keratosis and squamous cell carcinoma.

Davis DA, Donahue JP, Bost JE, Horn TD.

Departments of Dermatology and Pathology, University of Arkansas for Medical Sciences, Central Arkansas Healthcare System, Little Rock, AR, USA.
J Cutan Pathol. 2005 Sep;32(8):546-51. Abstract quote  

Diagnostic concordance of intraepithelial malignancy is generally only fair. Because the diagnosis of actinic keratosis (AK) and squamous cell carcinoma (SCC) is not uniform and because such terms are not consonant with the nomenclature of other human epithelial malignancies, nomenclature revisions have been attempted.

One hundred dermatopathologists were solicited to review 15 tissue sections representing a spectrum of varying thickness epidermal malignancy and to choose either AK or SCC as the diagnosis. Among the 77 participating dermatopathologists, intraclass correlation was high for what was perceived as AK, SCC, and their differentiation.

Development of a two-tiered diagnostic system that retains our present diagnostic capabilities, but better fits the pathobiology of superficial epidermal malignancy is suggested.

Histopathologic evaluation of cutaneous squamous cell carcinoma: Results of a survey among dermatopathologists.

Khanna M, Fortier-Riberdy G, Dinehart SM, Smoller B.

Departments of Dermatology and Pathology, University of Arkansas for Medical Sciences.

J Am Acad Dermatol 2003 May;48(5):721-6 Abstract quote

BACKGROUND: There are numerous histopathologic features related to prognosis in cutaneous squamous cell carcinoma (CSCC). We hypothesize that there is no uniform approach toward the reporting of these features. This may be related to differing opinions on their prognostic use.

METHODS: A written survey concerning the microscopic evaluation of CSCC was sent to 120 dermatopathologists in the United States and Canada. Respondents were asked whether they comment on specific microscopic features of CSCC, and whether they believe that each specific feature can predict prognosis.

RESULTS: The response rate was 78%. Histologic type, and the presence of perineural or vascular/lymphatic invasion, is reported by most dermatopathologists (90%, 96%, and 95%, respectively). These features are also thought to predict prognosis by the majority of respondents. Only 54% report histologic grade, and 49% think grade predicts prognosis. Depth is reported anatomically by 63%, but by only 8% in actual millimeters of invasion. However, 55% think tumor depth predicts prognosis. A total of 43% report the presence of an associated actinic keratosis, although very few (16%) think it predicts prognosis. Very few comment on the presence of inflammation.

CONCLUSIONS: Histopathologic reporting of CSCC is not uniform among dermatopathologists. Also, there appears to be differing opinions on the use of certain histopathologic features for predicting prognosis.

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

Pseudovascular adenoid squamous cell carcinoma of the skin. A neoplasm that may be mistaken for angiosarcoma.

Nappi O, Wick MR, Pettinato G, Ghiselli RW, Swanson PE.

Department of Pathology, Benevento General City Hospital, Italy.

Am J Surg Pathol 1992 May;16(5):429-38 Abstract quote

The adenoid variant of squamous cell carcinoma has been well-documented in several anatomic sites, including the skin. This tumor is characterized by acantholytic arrays of neoplastic keratinocytes that form pseudoglandular profiles. Although it is typically confused with adenocarcinomas, adenoid squamous cell carcinoma also may be mistaken for malignant vascular proliferations.

This report concerns six acantholytic cutaneous squamous cell carcinomas that closely simulated angiosarcomas on conventional histologic examination. They arose in sun-exposed skin areas in middle-aged or elderly patients (mean age, 60 years), five of whom were men. In contrast to the typical clinical appearance of angiosarcoma, pseudovascular adenoid squamous cell carcinoma presented itself as a discrete cutaneous ulcer or crusted tanpink nodule. Microscopically, this lesion was characterized by interanastomosing cordlike arrays of polygonal or flattened tumor cells, with internal pseudolumina that contained detached tumor cells. A connection between the dermal neoplasm and the epidermis was apparent in three cases, but it was focal. Erythrocytes were seen in pseudovascular spaces in five tumors.

Immunohistochemically, all examples of pseudovascular adenoid squamous carcinoma were reactive with antibodies to cytokeratin and epithelial membrane antigen (EMA). In addition, three expressed vimentin, two exhibited blood group antigen-positivity, and two bound Ulex europaeus I agglutinin. None of them was immunoreactive for Factor VIII-related antigen, and two of three studied for CD34-reactivity were likewise negative. A control group of six cutaneous angiosarcomas was uniformly nonreactive for cytokeratin and EMA, but they showed positivity for vimentin, Ulex binding, and CD34 positivity in all instances. Pseudovascular adenoid squamous cell carcinoma may be distinguished effectively from angiosarcoma of the skin by attention to its clinical features and by appropriate immunohistochemical studies.

These two tumors differ in biologic behavior; three patients with pseudovascular adenoid squamous cell carcinoma died of their tumors, whereas all angiosarcomas in this series proved fatal.


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

Daniel Azorín1, Fernando López-Ríos1, Claudio Ballestín1, Nuria Barrientos2 and José Luis Rodríguez-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.


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.


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


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


Follicular squamous cell carcinoma of the skin: a poorly recognized neoplasm arising from the wall of hair follicles.

Diaz-Cascajo C, Borghi S, Weyers W, Bastida-Inarrea J.

Center for Dermatopathology, Freiburg, Germany, and Department of Dermatology, University Hospital Doctor Negrin, Las Palmas, Spain.
J Cutan Pathol. 2004 Jan;31(1):19-25 Abstract quote.

BACKGROUND: In the last decades, a number of clinicopathologic subtypes of squamous cell carcinoma (SCC) of the skin, ranging from highly aggressive tumors with a tendency to recur and metastasize to neoplasms with a favorable prognosis, have been described. SCCs arising from the wall of hair follicles have been briefly mentioned by some authors but never reported in a series.

METHODS: Cases of SCC arising from the wall of hair follicles were collected from the files of two large German Centers for Dermatopathology and analyzed clinicopathologically and immunohistochemically.

RESULTS: Sixteen cases of SCC developing in hair follicles were found among more than 7000 cases of cutaneous SCC reviewed. In most cases, tumors arose on sun-damaged skin of the face of elderly persons. There was a male predominance (11/5). The most common clinical diagnosis was basal cell carcinoma (BCC). Microscopically, tumors developed in the upper part of hair follicles without or with focal involvement of the overlying epidermis at the border with the involved follicle. Immunohistochemically, tumors were positive for cytokeratin and negative for a battery of immunomarkers, including antibodies against the most common carcinogenic human papillomaviruses (HPV) of the skin. Most tumors were excised by simple excision. In two cases, a recurrence was noted after incomplete excision. No further recurrences or metastasis have been noted after a follow-up period ranging from 11 months to 12 years.

CONCLUSION: SCC of the hair follicle represents a poorly recognized but distinctive subset of SCC of the skin that should be considered in the differential diagnosis of other cutaneous epithelial tumors. The term follicular SCC (FSCC) is proposed for this neoplasm.
Keratoacanthoma and infundibulocystic squamous cell carcinoma.

Skin and Cancer Foundation Australia, Sydney, Australia.

Am J Dermatopathol. 2008 Apr;30(2):127-34. Abstract quote

One of the major controversies in dermatopathology is the relationship of keratoacanthoma to squamous cell carcinoma. Leaders in the field remain polarized in their views. Carcinomas with distinct follicular pattern of differentiation have been described in reference to the isthmus as trichilemmal carcinomas, to the follicular bulb as pilomatricomal carcinomas, and to the stem cell or rapidly amplifying cell compartment as basal cell carcinomas (trichoblastic carcinomas).

We have employed the term infundibulocystic or infundibular squamous cell carcinoma to identify a subset of squamous cell carcinomas that demonstrate this pattern of differentiation. The recognition of infundibular squamous cell carcinoma is important in that well-differentiated examples are likely to have been diagnosed as keratoacanthoma, whereas moderately or poorly differentiated tumors would be more often reported as squamous cell carcinomas, leading to underrecognition of these infundibular variants of squamous cell carcinoma.

The descriptive term infundibulocystic or infundibular squamous cell carcinoma may help to better define an alternative follicular-based pathway to squamous cell carcinoma distinct from the more common evolution from solar keratoses and also refine the classification of keratoacanthoma.

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

Poorly differentiated squamous cell carcinoma with osteoclastic giant-cell-like proliferation.

Department of Dermatopathology, Mount Sinai Medical Center, New York, USA.


J Cutan Pathol. 2007 Dec;34(12):930-3. Abstract quote

Although osteoclast giant-cell-like proliferations have been reported in a diverse range of human malignancies, to the best of our knowledge, they have never been described in cutaneous squamous cell carcinoma (SCC). Histologically, osteoclastic giant cell tumors within extraosseous malignancy resemble their bony and soft tissue counterparts, with round to spindle-shaped cells admixed with osteoclast-like multinucleate cells. These cells should be distinguished from sarcomatoid differentiation within a carcinoma; they have a benign morphology with a low nuclear to cytoplasmic ratio, minimal pleomorphism/mitoses and negative immunohistochemistry for cytokeratin.

The authors report the rare occurrence of osteoclast-like giant cells (OGCs) and accompanying epithelioid histiocytes lacking overtly malignant features in association with a poorly differentiated SCC occurring on sun-damaged skin. Immunohistochemically, the area rich in OGCs was strongly positive for CD68 and completely negative for cytokeratin, whereas the poorly differentiated infiltrative area had the reverse immunophenotype and nuclear positivity for p63.

The histological differential diagnosis and the origin of the proliferation are discussed in this article.


Cutaneous papillary squamous cell carcinoma. A report of two cases.

Landman G, Taylor RM, Friedman KJ.

Department of Dermatology, John Hopkins Hospital, Baltimore, MD.

J Cutan Pathol 1990 Apr;17(2):105-10 Abstract quote

Several histologic patterns of squamous cell carcinomas (SCC) have been described, including classical, adenoid, verrucous, and clear cell.

We report 2 cases of an unusual purely exophytic papillary growth pattern. Both tumors occurred on sun-exposed skin of elderly patients and exhibited rapid growth. The tumors were red-tan and fungating, raising the clinical differential diagnoses of pyogenic granuloma, SCC, metastatic carcinoma or amelanotic melanoma.

Histologically there was a prominent papillary growth pattern with several layers of notably atypical squamous epithelium overlying a fibro-vascular core in both cases. Mitoses were frequent. The tumors lacked deep invasion, although focal invasion of the stalk was present. These tumors were histologically distinct from verrucous carcinoma, verrucous Bowen's disease, and previously described adnexal carcinomas. The lack of deep invasion and the absence of local recurrence or metastatic disease after 18 months follow-up suggest that this histologic variant is a low-grade malignancy, although study of more cases and longer follow-up will be necessary to accurately assess the biology of this papillary variant of SCC.

We believe that this growth pattern has not yet been described and a pure papillary form must be included as one of the histological subtypes of cutaneous SCC.


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.

Pseudoangio-sarcomatous squamous cell carcinoma of skin arising adjacent to decubitus ulcers.

Conde-Taboada A, Florez A, De la Torre C, Feal C, Garcia-Doval I, Cruces M.

Servicio de Dermatologia, Complexo Hospitalario de Pontevedra, Pontevedra, Spain.
Am J Dermatopathol. 2005 Apr;27(2):142-4. Abstract quote  

Pseudoangiosarcomatous, or pseudovascular, squamous cell carcinoma of skin is an unusual form of acantholytic (adenoid, pseudoglandular) squamous cell carcinoma that mimics the histolopathologic appearance of angiosarcoma.

We report a case of pseudoangiosarcomatous squamous cell carcinoma arising adjacent to decubitus ulcers. The histopathologic examination of a wedge biopsy specimen revealed infiltrative cords of neoplastic cells that formed interanastomosing channels imitating angiosarcoma. Immunohistochemical staining was negative for the endothelial markers (CD31, CD34, and factor VIII-related antigen) and positive using cytokeratin antibodies (AE1/AE3 and 34 betaE12). Because of metastatic disease, palliative measures were undertaken and the patient died four months later.

To our knowledge, our patient is the first with pseudoangiosarcomatous squamous cell carcinoma of skin developing within decubitus ulcer.

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

Cytokeratin 20 negative, unlike Merkel cell carcinomas

Association with previous trauma or radiotherapy common
Usually on the face of the elderly with extensive sun damage
May stain positive for vimentin
Exo or endophytic tumors often growing at sites of chronic irritation
Classified based upon location:
Buschke-Lowenstein tumors
Fatal Genital Verrucous Carcinoma.

From the *Sapporo Institute for Dermatopathology, Sapporo, Japan; and daggerDepartment of Dermatology, Yamagata University School of Medicine, Yamagata, Japan.

Am J Dermatopathol. 2007 Feb;29(1):68-71. Abstract quote

A rare, fatal case of verrucous carcinoma on the labia majora of a 65-year-old woman is presented. Histopathologically, the neoplasm was repeatedly diagnosed as a verruca over the course of many years.

A diagnosis of verrucous carcinoma was rendered only after the documentation of lymph node metastasis. Although most cases of verrucous carcinoma have a favorable prognosis, this case illustrates that verrucous carcinoma can metastasize even when the neoplasm is superficially situated and the histopathologic findings are subtle.

Verrucous carcinoma of the axilla: case report and review.

Assaf C, Steinhoff M, Petrov I, Geilen CC, De Villiers EM, Schultz-Ehrenburg U, Orfanos CE.

Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Berlin, and Reference Center For Human Pathogenic Papillomavirus, Division of Tumor Virus Characterization, Deutsches Krebsforschungszentrum, Heidelberg, Germany.

J Cutan Pathol. 2004 Feb;31(2):199-204. Abstract quote  

BACKGROUND: Verrucous carcinoma, a variant of squamous cell carcinoma, is distinct from squamous cell carcinoma in morphology and behavior. It preferentially occurs on the oropharyngeal mucosa, the urogenital mucosa, and the soles. In contrast to its malignant clinical picture, the tumor grows locally invasive but is histologically benign and metastasizes rarely.

METHODS: We report the uncommon occurrence of a large verrucous carcinoma on apparently uninvolved skin in the right axilla in a 47-year-old male.

RESULTS: Histologic examination reveals a cauliflower-like tumor consisting of deep invaginated epidermal proliferation with rabbit burrow-like, keratin-filled sinus formations; the basement membrane, however, remains intact. Immunohistology showed positivity for pancytokeratin (KL-1) and cytokeratin (CK) 18 and negativity for CK7, and assessment of the proliferative activity of the tumor cells revealed low percentage of Ki-67 expression. Furthermore, there were only scattered cells expressing p53 or bcl-2. Polymerase chain reaction excluded the presence of human papillomavirus. After complete excision, no signs of recurrence occurred over a follow-up period of three years.

CONCLUSION: Verrucous carcinoma should be distinguished from typical squamous cell carcinoma. The clinicopathological features, differential diagnosis, and therapy are discussed here together with the molecular biologic aspects of the tumor.
Invasive Cutaneous Verruco-Cystic Squamous Cell Carcinoma
A Pattern Commonly Present in Transplant Recipients

Edward B. Stelow, MD,1 Robert Skeate, MD,1 Monika M. Wahi,3 Desire Langel, MD,2 and Jose Jessurun, MD

Am J Clin Pathol 2003;119:807-810 Abstract quote

To determine whether certain histologic features are more common in cutaneous squamous cell carcinomas (CSCCs) arising in transplant recipients than in others, we assessed several features of CSCCs from 23 patients who had not undergone transplantation and 25 transplant recipients (size, depth of invasion, sun damage, nuclear atypia, keratinization, epidermal inclusion cyst [EIC]-like features, verrucous features [VFs], shape, and mitoses per 10 high-power fields).

We analyzed relationships by using c2 and t tests and logistic regression analysis. Transplant recipients tended to be younger than control subjects (mean [SD] age, 56.2 [14.3]; 74.1 [10.6], respectively; P < .0001) and less likely to show severe sun damage (P = .0455; c2). CSCCs with VFs and EIC-like features were associated strongly with transplantation: odds ratio, 12.57 (95% confidence interval, 1.28-123.47; P = .0162). No other features were associated significantly with transplant status. Posttransplant tumors commonly showed verrucous and EIC-like features mimicking benign conditions.

The younger age of these patients, the frequent absence of solar elastosis, and the infrequent occurrence of well-differentiated verruco-cystic CSCC in the nontransplant population suggest a different pathogenesis in the development of these neoplasms. Pathologists should be aware of this pattern, especially when diagnosing small biopsy specimens from transplant recipients.


Special stains  

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

Vimentin may be positive in poorly differentiated tumors


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.


P27 and mib1 expression in actinic keratosis, Bowen disease, and squamous cell carcinoma.

Oh CW, Penneys N.

Department of Dermatology, College of Medicine, GyeongSang National University, Chinju, South Korea.

Am J Dermatopathol. 2004 Feb;26(1):22-6. Abstract quote  

The histologic boundary between actinic keratosis, Bowen disease, and invasive squamous cell carcinoma is not clear in many cases. We determined nuclear expression of p27 (a protein associated with cellular quiescence) and Ki-67 (a marker of proliferation) immunohistochemically in actinic keratosis, Bowen disease, and squamous cell carcinoma to see if differential patterns of expression for p27 exist and how these might correlate with Ki-67 expression.

We determined a labeling index for p27-stained nuclei and assessed the pattern of Ki-67 expression. The student's t test was used to evaluate the p27 labeling index. The p27 labeling index was decreased in invasive aggregates of squamous cell carcinoma (76.9+/- 1.1%) when compared with those of normal epidermis (97.2+/- 2.4%), actinic keratosis (95.3 +/- 1.4%), and Bowen disease (98.0+/- 0.5%). Ki-67 was expressed in a scattered to confluent linear pattern in the basal/parabasal cell layer of normal epidermis and actinic keratosis. Keratinocytes in squamous cell carcinoma exhibited Ki-67 in the peripheral layers of the neoplasm and frequently within the tumor aggregates. Ki-67 was observed in nuclei throughout the full thickness of the epidermis in Bowen disease.

The staining pattern of Ki-67 in Bowen disease separated this entity from others under study. The combination pattern of p27 and Ki-67 staining can be used to support differentiation of actinic keratosis, Bowen disease, and squamous cell carcinoma.
Utility of p63 in the differential diagnosis of atypical fibroxanthoma and spindle cell squamous cell carcinoma

Briana C. Gleason 1 , Kenneth B. Calder 2 , Thomas L. Cibull 1 , Antoinette B. Thomas 3 , Steven D. Billings 3 , Michael B. Morgan 2 , Kim M. Hiatt 1 and Bruce R. Smoller 1
  1 Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA,
 2Department of Pathology, University of South Florida College of Medicine, Tampa, FL, USA and
 3Department of Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA
J Cutan Pathol 2009;36:543-547 Abstract quote

Atypical fibroxanthoma (AFX), spindle cell squamous cell carcinoma (SCSCC) and spindle cell melanoma are the primary entities in the differential diagnosis of a cytologically atypical spindle cell tumor arising on sun-damaged skin. AFX is generally regarded as a diagnosis of exclusion in this context: in the absence of S100 or keratin reactivity, a diagnosis of AFX is favored. However, keratin reactivity may be focal or even absent in SCSCC, and although numerous positive markers of AFX have been proposed, none has shown sufficient sensitivity and specificity for routine diagnostic use.

We evaluated 20 AFX and 10 SCSCC with a panel of cytokeratins and p63 to assess the utility of the latter antibody in this differential diagnosis. All 10 SCSCC showed strong expression of p63, whereas all 20 AFX were p63 negative. Two additional cases (excluded from the study) were negative for keratins and S100 on initial shave biopsies, resulting in a favored diagnosis of AFX, but p63 stains performed retrospectively were positive. However, review of the excision specimens in both cases revealed deep subcutaneous extension, excluding AFX.

p63 reactivity argues against the diagnosis of AFX and is therefore a useful addition to the standard immunohistochemical panel for cutaneous spindle cell neoplasms.


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.


Adnexal clear cell carcinoma with comedonecrosis: clinicopathologic analysis of 12 cases.

Department of Pathology, Leeds General Infirmary, Leeds, United Kingdom.


Arch Pathol Lab Med. 2007 Nov;131(11):1655-64. Abstract quote

CONTEXT: Cutaneous clear cell tumors can pose a diagnostic challenge even to the experienced dermatopathologist; this is partly because of limitations of existing diagnostic categories.

OBJECTIVE: To describe a previously unrecognized, distinctive cutaneous adnexal carcinoma capable of an aggressive clinical course.

DESIGN: Clinicopathologic analysis of a series of 12 cases.

RESULTS: The patients were older individuals (median age, 71 years) with equal gender frequency. The lesions showed wide anatomic distribution with predilection for the head and neck area, especially the scalp. The lesions presented as rapidly growing, erythematous to flesh-colored, solitary papules/nodules that were capable of quickly reaching a size of several centimeters. Histologically, adnexal clear cell carcinoma with comedonecrosis was characterized by dermal proliferation of nests of epithelial cells showing distinctive zonal arrangement. The periphery of the tumor nests was formed by squamoid cells merging with centrally located clear cell areas containing foci of comedonecrosis. The lesions often showed multilobular or trabecular growth pattern and infiltrating border. Nuclear pleomorphism was variable; mitotic count ranged from 2 to 32/mm2 (median, 8/mm2). No ductal, cuticular, or apocrine differentiation was seen. All cases showed expression of epithelial membrane antigen and cytokeratin 17 in clear cells, with focal carcinoembryonic antigen expression in some cases. Follow-up (average, 37 months) revealed local recurrence (4 cases) and regional and distant metastases (2 cases).

CONCLUSIONS: Adnexal clear cell carcinoma with comedonecrosis appears to be a distinctive adnexal neoplasm that has to be distinguished from more indolent squamous cell and tricholemmal carcinomas.

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

Probably best thought of as a variant of Bowen's disease usually occurring on genital skin

Cutaneous lupus erythematosus simulating squamous neoplasia: the clinicopathologic conundrum and histopathologic pitfalls.

Department of Pathology, University of North Carolina Hospitals, Chapel Hill, North Carolina, USA.


J Am Acad Dermatol. 2007 Jun;56(6):1013-20. Abstract quote

BACKGROUND: The clinical distribution and character of cutaneous lupus erythematosus lesions can simulate squamous neoplasms, leading physicians to submit a shave biopsy specimen with a differential diagnosis of squamous neoplasm.

OBJECTIVE: Our aim was to describe histologic features of interface dermatitis that cause difficulty in distinguishing between cutaneous lupus erythematosus and squamous neoplasia in shave biopsy specimens and to identify distinguishing criteria.

METHODS: Twenty-six biopsy specimens from 10 patients initially diagnosed with squamous neoplasia that ultimately proved to be cutaneous lupus erythematosus were identified. Comparisons were made of these to 38 control biopsies of chronic cutaneous lupus erythematosus and 34 control biopsies of keratoses/carcinomas without lupus. All biopsies were scored (0 or 1: absent or present) with respect to 11 histologic criteria.

RESULTS: The criteria of perifollicular inflammation, follicular plugging, vacuolar interface change, compact orthokeratosis, and acrosyringeal inflammation were significantly more common in the lupus cases than in the keratoses/carcinomas controls. The mean lupus case score was 6.88, lupus control score 6.55, and keratoses/carcinomas control score 5.08.

LIMITATIONS: A limited number of patients were studied. Microscopic observations and assumptions with inherent subjectivity were used in establishing the histologic scores.

CONCLUSION: Use of the criteria presented, although not absolute, should alert one to the possibility of lupus in an atypical squamous proliferation, especially in suspected squamous neoplasms that worsen or recur after therapy.
Metaplastic breast carcinoma histologically mimicking cutaneous spindle cell squamous cell carcinoma.

Derienzo DP, Barr RJ.

From the Dermatopathology Laboratory, University of California Irvine, Orange, California.
Am J Dermatopathol. 2005 Jun;27(3):250-4. Abstract quote  

Squamous cell carcinoma is one of the most common primary cutaneous carcinomas but on rare occasion, metastatic squamous cell carcinoma from a distant site or solid organ can present as a cutaneous lesion. Most metastases occur as dermal nodules or involve the dermal lymphatics, but when they are intimately associated with the epidermis, distinguishing the lesion as primary or metastatic may be extremely difficult and usually requires a clinical history or high index of suspicion.

A 71-year-old woman presented with multiple eruptive nodules over her chest, flank, and back. Histologically the lesions appeared to be arising from the surface epithelium and consisted of atypical, predominantly spindle cells, some of which streamed off of the epidermis. Following the initial evaluation, a history of breast carcinoma with subsequent radiation therapy and ultimate mastectomy was obtained, and the original breast biopsy and mastectomy material was reviewed.

After performing additional studies, it became clear that the origin of the carcinomas was metastatic from an underlying metaplastic breast carcinoma.

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, Marqués 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.

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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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