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Background
This is one of the most common skin cancers, accounting for about 70% of all skin malignancies. For every case of a squamous cell carcinoma, there are 5 cases of basal cell carcinoma (BCC). They are almost always found on sun-exposed areas such as the head and neck and are common in fair-skinned individuals. There are also case reports of cases occurring in areas such as the penis, vulva, and below the nails. The classic appearance is a raised flesh to pink-red nodule with a pearly translucent edge and variable telangiectasia. Ulceration may be frequent and occasionally pigment may be observed. Although sun exposure is the best documented risk factor, other risk factors include irradiation, immunosuppression, nevus sebaceus of Jadassohn, xeroderma pigmentosum, basal cell nevus syndrome, and Bazex's syndrome.
Although this is a carcinoma, the actual risk of metastasis is exceedingly rare, occurring in 0.05% of all cases. Yet, these carcinomas are locally aggressive and from 5-9% may have multiple recurrences. If metastasis do occur, it is usually with large and ulcerated tumors (such as rodent ulcers) and may have metatypical or squamous features. Metastatic sites include the regional lymph nodes, bones, lungs, and livers.
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Basal cell epithelioma
BCCINCIDENCE N Engl J Med 1992;327:1649-1662
Very common-among Caucasians, it is the most common malignancy
70% of all skin malignancies300/100,000 1000/100,000 SEX (MALE:FEMALE) Both sexes are affected though in women, the lower limbs are more commonly affected AGE RANGE-MEDIAN Adults
DISEASE ASSOCIATIONS CHARACTERIZATION Basal cell nevus syndrome (Gorlin Syndrome) Bazez's syndrome Immunosuppression Nevus sebeceus of Jadassohn Smoking
Basal cell carcinoma in young women: An evaluation of the association of tanning bed use and smoking.Boyd AS, Shyr Y, King LE Jr.
Departments of Medicine (Dermatology), Pathology, and Preventive Medicine, Vanderbilt University and Nashville Administration Medical Center.
J Am Acad Dermatol 2002 May;46(5 Pt 1):706-9 Abstract quote Basal cell carcinomas (BCCs) typically occur in middle-aged to elderly patients but less commonly in younger ones. In our experience, most BCCs seen in patients younger than 40 years are found in women.
We evaluated 30 women with biopsy-proven BCC and 30 control patients matched for sex, age, and skin type to determine potential risk factors for this population. Tanning bed visits, pack-years of cigarette smoking, recreational sun exposure, number of blistering sunburns, and use of sunscreens were determined for both groups. Among patients with a BCC, the histologic type of tumor, site of involvement, method of treatment, follow-up period, incidence of recurrence, and presence of actinic keratoses were also evaluated. Patients with a BCC had a statistically greater number of pack years of smoking (P =.045), and a greater percentage of these women had experienced blistering sunburns (P =.028). Although women with a BCC had, on average, almost twice as many tanning salon visits (152.2 vs 83.1), this was not statistically significant. Sunscreen use and amount of recreational ultraviolet light exposure were essentially equal between the two groups.
Young women with a BCC are more likely to have a past or current history of cigarette smoking and blistering sunburns. Repeated exposure to tanning beds may also be a contributory factor.
Sun or radiation exposure Risk Factors for Basal Cell Carcinoma in a Mediterranean Population Role of Recreational Sun Exposure Early in Life
Rosamaria Corona, DSc, MD; Eugenia Dogliotti, DSc; Mariarosaria D'Errico, DSc; Francesco Sera, DStat; Ivano Iavarone, DSc; Giannandrea Baliva, MD; Luca M. Chinni, MD; Tommaso Gobello, MD; Cinzia Mazzanti, MD; Pietro Puddu, MD; Paolo Pasquini, MD, MPH
Arch Dermatol. 2001;137:1162-1168 Abstract quote
Objective
To investigate the role of pigmentary traits, different patterns of sun exposure, artificial sources of UV radiation, and lifestyle-related factors on the risk of basal cell carcinoma (BCC) in a Mediterranean population from central-southern Italy.Design
Hospital-based case-control study.Setting
A referral dermatological hospital in Rome, Italy.Patients
A convenience sample of 166 case patients with histologically confirmed BCC and 158 cancer-free control subjects with minor dermatological conditions observed between March 1995 and June 1997.Results
In the multivariate analysis, the mean number of weeks per year spent at the beach before the age of 20 years was significantly associated with BCC. A dose-response trend was found for subjects who had spent 3 to 4 (odds ratio, 1.8; 95% confidence interval, 0.8-4.4), 5 to 8 (odds ratio, 3.7; 95% confidence interval, 1.5-9.0), or more than 8 (odds ratio, 4.5; 95% confidence interval, 1.9-10.5) weeks per year at the beach (P = .01 for trend). There was a significant association with the presence of actinic keratoses or solar lentigines, whereas no effect was found for skin type, history of sunburns, exposure to nonsolar UV radiation, and lifestyle-related habits such as cigarette smoking, alcohol consumption, and coffee drinking. Subjects reporting a family history of skin cancer had an extremely increased risk of BCC.Conclusion
The definite association with recreational sun exposure during childhood and adolescence and the strong relation with family history of skin cancer suggest that genetic predisposition and peculiar exposure patterns to UV radiation are key independent risk factors for the development of BCC in a southern European population.Trauma
Basal cell carcinoma arising from surgical scars: a case and review of the literature.Ozyazgan I, Kontacs O.
Department of Plastic and Reconstructive Surgery, Erciyes University, Faculty of Medicine, Kayseri, Turkey.
Dermatol Surg 1999 Dec;25(12):965-8 Abstract quote BACKGROUND: Scar malignancies are generally known as Marjolin's ulcer and the majority of them are epidermoid carcinomas. In addition to epidermoid carcinomas, Basal cell carcinoma (BCC) also can grow in various scars. Basal cell carcinoma cases developing in surgical scars are extremely rare; only 5 cases have been encountered in available English literature.
METHOD: A 68-year-old woman who has a BCC originating from a surgical scar due to a previous inguinal hernia operation was presented.
CONCLUSION: Trauma has been suggested as one of the etiologic factors for BCC; but the role of trauma or resulting scar in BCC pathogenesis is not known. This unresolved issue can be explained with advanced studies revealing biochemical tissue changes occurring during wound healing and trauma.
Xeroderma pigmentosum
High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum.Bodak N, Queille S, Avril MF, Bouadjar B, Drougard C, Sarasin A, Daya-Grosjean L.
Laboratory of Molecular Genetics, Institut de Recherches Scientifiques sur le Cancer, Boite Postale 8, 94801 Villejuif, France.
Proc Natl Acad Sci U S A 1999 Apr 27;96(9):5117-22 Abstract quote Recently, hptc, a human gene homologous to the Drosophila segment polarity gene patched (ptc), has been implicated in the nevoid basal-cell carcinoma (BCC) syndrome, and somatic mutations of hptc also have been found in sporadic BCCs, the most frequent cancers found in the white population.
We have analyzed the hptc gene, postulated to be a tumor suppressor gene, in 22 BCCs from patients with the hyperphotosensitive genodermatosis xeroderma pigmentosum (XP). Patients with XP are deficient in the repair of UV-induced DNA lesions and are characterized by their predisposition to cancers in sun-exposed skin. Analysis using PCR-single-strand conformation polymorphism of the hptc gene identified 19 alterations in 16 of 22 (73%) of the BCCs examined. Only two (11%) deletions of the hptc gene were found in XP BCCs compared with >30% rearrangement observed in non-XP sporadic BCCs, and 17 of 19 (89%) were base substitutions. Among the 17 base substitutions, 11 (65%) were CC --> TT tandem mutations, and 4 (23%) were C --> T substitutions, all targeted at bipyrimidine sites. Hence, a significantly higher number (15 of 19; 79%) of UV-specific alterations are seen in XP tumors, in contrast to non-XP sporadic BCCs. Interestingly, we have found that in 7 of 14 (50%) XP BCCs analyzed, both hptc and the tumor suppressor gene p53 are mutated.
Not only have our data indicated the key role played by hptc in the development of BCCs, they also have substantiated the link between unrepaired UV-induced DNA lesions and skin carcinogenesis, as exemplified by the UV-specific alterations of different genes in the same tumors.
PATHOGENESIS CHARACTERIZATION GENERAL The tumor has several immunologic aberrations which help it to evade the immune system:
Absence of class II MHC (HLA-DR) and intercellular adhesion molecule 1 (CD54)
Production of IL-10 which suppresses expression of costimulatory molecules CD80 and CD86 by dendritic cells, inhibiting ability to activate T-cells
Overexpression of cell survival gene products such as bcl-2
Failure to express Fas antigen (CD95) avoiding killing by Fas ligand (CD95L) bearing cytotoxic T cellsBASIGIN Expression of Basigin in human fetal, infantile and adult skin and in basal cell carcinoma
Xiang Chen, etal.
J Cutan Pathol 2001;28 (4):184-190 Abstract quote
Background: Basigin is a glycosylated transmembrane protein belonging to the immunoglobulin superfamily and is thought to be associated with cell development and differentiation. We investigated the relation between Basigin expression and epidermal development in this study.
Methods: Basigin expression was immunohistochemically investigated during organogenesis of human skin and in human basal cell carcinoma (BCC).
Results: Human fetal skin showed negative staining at 10 weeks of gestation. At 20 weeks, the cytoplasm and membranes of adnexal germ and hair follicular cells were strongly positive, while epidermal basal cells showed weakly positive staining. After birth, basal cells, suprabasal cells, anagen hair follicular cells and eccrine glandular cells showed positive staining. Membranes of basal cells expressed more Basigin compared to other cell components. Basigin was not detectable in granular cells and telogen hair follicular cells. Sixteen of 30 BCCs were entirely negative for Basigin. However, cells at budding areas of tumor masses were positive in 14 of the 30 BCCs.
Conclusions: These findings suggest that 1) Basigin is associated with epidermal proliferation and differentiation, 2) most parts of BCCs might be derived from early fetal epidermal basal cells, and 3) that a part, only the budding area of BCCs, has the characteristics of epithelial germ cells.
BAX
Bax expression and growth behavior of basal cell carcinomas
Claudia M. L. J. Tilli, Angela J. W. Stavast-Kooy, Frans C. S. Ramaekers and H. A. Martino Neumann
J Cutan Pathol 2002;29:79-87 Abstract quote
Background:To understand the typical growth behavior of basal cell carcinoma (BCC) we searched for the correlation between proliferation and apoptosis and progression of BCC.Methods:Expression of Bcl-2, Bax, and Ki-67 was immunohistochemically investigated in both normal skin and BCC cells, as well as in the epidermis overlying BCC.
Results:The results showed that in normal epidermis, Bcl-2 was homogeneously expressed in the basal cell compartment, whereas Ki-67 expression was largely restricted to the parabasal layer, the layer just above the basal cell layer, and exhibited a more scattered staining pattern. Bax was occasionally expressed in the basal layer and widely in the suprabasal compartment. Strikingly, the apparently normal epidermis overlying BCC showed an increased Bcl-2 staining. In BCC, cells stained homogeneously for Bcl-2, whereas Bax and Ki-67 showed scattered staining patterns. Simultaneous expression was seen for Bcl-2 and Bax in 80±7% of the tumor cells, and co-expression of Bcl-2 and Ki-67 in 20±7% of the tumor cells. The cells expressing Bcl-2 and Ki-67, but lacking expression of Bax, the progressive fraction, comprised on average 7±3% of the tumor cell population.
Conclusion:These results suggest that this small progressive fraction of tumor cells, in combination with the relatively high percentage of cells still prone to apoptosis, can explain the indolent growth behavior of BCC.
CD95 (FAS) J Clin Pathol 1995;48:242 Regression of basal cell carcinoma by intralesional interferon-alpha treatment is mediated by CD95 (Apo-1/Fas)-CD95 ligand-induced suicide.
Buechner SA, Wernli M, Harr T, Hahn S, Itin P, Erb P.
Department of Dermatology, University of Basel, Kantonsspital, Petersgraben 4, CH4031 Basel, Switzerland.
J Clin Invest 1997 Dec 1;100(11):2691-6 Abstract quote Basal cell carcinoma (BCC) is the most common skin cancer in humans, and although metastasis rarely occurs, the tumor cells are nevertheless able to invade and destroy the surrounding tissue. Intralesional injection of IFN-alpha has been found to be highly effective in inducing BCC regression by an unknown mechanism.
We show that in untreated patients, BCC cells express CD95 ligand, but not the receptor, which may allow tumor expansion by averting the attack of activated CD95 receptor-positive lymphoid effector cells. The CD95 ligand of BCC cells is functional as CD95-positive cells incubated on BCC cryosections become apoptotic and are lysed. In IFN-alpha-treated patients BCC cells express not only CD95 ligand but also CD95 receptor, whereas the peritumoral infiltrate that mainly consists of CD4+ T cells predominantly contains CD95 receptor and only few CD95 ligand-positive cells.
Thus, in treated patients BCC most likely regresses by committing suicide through apoptosis induction via CD95 receptor-CD95 ligand interaction.
Prostaglandin E2 inhibits T cell activation-induced apoptosis and Fas-mediated cellular cytotoxicity by blockade of Fas-ligand induction.Porter BO, Malek TR.
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33101, USA.
Eur J Immunol 1999 Jul;29(7):2360-5 Abstract quote Prostanoids exhibit both pro-apoptotic and anti-apoptotic functions depending on the maturation stage and tissue localization of target cells.
Prostaglandin (PG) E2 has been shown to protect T lymphocytes from TCR-mediated activation-induced cell death, but the mechanism by which PGE2 inhibits apoptosis of T cells has not been established.
We show that this protection involves the down-regulation of Fas-ligand (Fas-L) mRNA levels in T cells. Modulation of cell surface Fas-L expression by physiological concentrations of PGE2 was shown to be both anti-apoptotic as well as capable of inhibiting Fas-L-mediated cytotoxicity of Fas-transfected P815 target cells.
Thus, this study provides direct evidence of the likely biological means by which PGE2 down-regulates T cell apoptosis.
Expression of CD95 (Fas) in sun-exposed human skin and cutaneous carcinomas.Filipowicz E, Adegboyega P, Sanchez RL, Gatalica Z.
Division of Surgical Pathology, Department of Pathology, University of Texas Medical Branch, Galveston, Texas.
Cancer 2002 Feb 1;94(3):814-9 Abstract quote BACKGROUND: Carcinomas of the skin are by far the most common human malignancies. Continuous exposure to ultraviolet (UV) light facilitates the development of precancerous lesions (actinic keratosis [AK]) that may progress to invasive squamous carcinomas. Apoptosis, triggered by the activation of CD95 (Fas), is one of the most important defense mechanisms against UV light-induced carcinogenesis in experimental models, but the dynamics of CD95 expression in patients with sun-induced lesions are largely unknown.
METHODS: The authors studied the expression of CD95 (Fas) in biopsy samples of normal skin (not exposed to sun) and compared it with chronically sun-exposed skin (as evidenced by solar elastosis), AK, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), and keratoacanthomas (KA).
RESULTS: Normal skin keratinocytes expressed CD95 in cytoplasmic membranes and intercellular bridges in the basal layer. In chronically sun-exposed keratinocytes (solar elastosis, no evidence of dysplasia), CD95 expression was up-regulated and was observed throughout the entire thickness of the epidermis. However, in actinic keratosis there was a complete absence of Fas in approximately two-thirds of the cases (8 of 12). In invasive SCC, CD95 was expressed focally and weakly only at the sites of contact with stromal lymphocytes. Keratoacanthomas consistently expressed CD95 at the interface with the inflammatory cells. No staining was observed in BCC.
CONCLUSIONS: CD95 (Fas) up-regulation in chronically sun-exposed keratinocytes indicates an important role in the control of sun-induced damage. Further sun exposure results, however, in significant down-regulation of this defense mechanism, proportional to the degree of dysplasia.
CHROMOSOMAL ABNORMALITIES
Nonrandom karyotypic features in basal cell carcinomas of the skin.Jin Y, Martins C, Salemark L, Persson B, Jin C, Miranda J, Fonseca I, Jonsson N.
Department of Clinical Genetics, University Hospital, S-221 85, Lund, Sweden.
Cancer Genet Cytogenet 2001 Dec;131(2):109-19 Abstract quote Cytogenetic analysis of short-term cultured 44 basal cell carcinomas (BCC) revealed clonal karyotypic abnormalities in 38 tumors.
Relatively complex karyotypes (at least four structural and/or numerical changes per clone) with unbalanced structural as well as numerical aberrations were found in eight (approximately 21%) of the BCC, while the remaining BCC (79%) had simple karyotypes (1 to 3 aberrations per clone). Numerical changes only were found in 16 tumors, 15 BCC displayed both numerical and structural aberrations, and the remaining 7 BCC showed only structural aberrations. Extensive intratumoral heterogeneity, in the form of cytogenetically unrelated clones, was found in 21 tumors, whereas related subclones were present in 10 tumors. In order to obtain an overall karyotypic picture in BCC, the findings of our previously published 25 BCC have been reviewed.
Our combined data indicate that BCC are characterized by nonrandom karyotypic patterns. A large subset of BCC is characterized by nonrandom numerical changes, notably, +18, +X, +7, and +9. Structural rearrangements often affect chromosomes 1, 4, 2, 3, 9, 7, 16, and 17. A number of chromosomal bands are frequently involved, including 9q22, 1p32, 1p22, 1q11, 1q21, 2q11, 4q21, 4q31, 1p36, 2q37, 3q13, 7q11, 11p15, 16p13, 16q24, 17q21, and 20q13. When the genomic imbalance is assessed, it has been shown that several chromosome segments are repeatedly involved in losses, namely loss of the distal part of 6q, 13q, 4q, 1q, 8q, and 9p. A correlation analysis between the karyotypic patterns and the clinico-histopathologic parameters has been undertaken in the 44 BCC of the present series.
The cytogenetic patterns show a significant correlation with tumor status (P=.025), that is, that cytogenetically more complex tumors are also those clinically the most aggressive. Also, the frequency of cytogenetically unrelated clones is significantly higher in recurrent BCC than that in primary lesions (P=.05). No clear-cut association has been found between the karyotypic patterns and histologic subtypes or tumor sites.
CYTOKINES
Cytokine profiles in spontaneously regressing basal cell carcinomas.Wong DA, Bishop GA, Lowes MA, Cooke B, Barnetson RS, Halliday GM.
Department of Medicine (Dermatology), The University of Sydney at Royal Prince Alfred Hospital, Gloucester House, Missenden Road, Camperdown, NSW 2050, Australia.
Br J Dermatol 2000 Jul;143(1):91-8 Abstract quote BACKGROUND: Basal cell carcinomas (BCCs) can cause considerable morbidity due to their ability to enlarge progressively and to destroy underlying tissues. However, some BCCs may undergo spontaneous regression in the absence of therapy capable of inducing antineoplastic effects. Histological criteria for this process have been described, and previous studies have suggested that it may be mediated by infiltrating activated CD4-positive T cells.
OBJECTIVES: The purpose of this study was to compare the expression of cytokines in actively regressing and non-regressing BCCs, to ascertain if active regression is associated with a particular cytokine profile.
METHODS: Reverse transcriptase-polymerase chain reaction, a sensitive, quantitative technique allowing analysis of multiple cytokines from small tumour samples, was used.
RESULTS: Interferon (IFN)-gamma was significantly elevated in actively regressing BCCs compared with non-regressing BCCs. Furthermore, interleukin (IL)-2, tumour necrosis factor (TNF)-beta and CD3 delta tended to be elevated in actively regressing tumours, although not to statistically significant levels. IFN-gamma, IL-2, IL-10, TNF-beta, granulocyte-macrophage colony-stimulating factor and Fas ligand showed strong positive correlations with CD3 delta, indicating an association between infiltrating T cells and these cytokines.
CONCLUSIONS: These findings support a role for T-helper 1 type cytokines in mediating spontaneous regression of BCCs.
HUMAN PAPILLOMAVIRUS
Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals.Harwood CA, Surentheran T, McGregor JM, Spink PJ, Leigh IM, Breuer J, Proby CM.
Department of Academic Dermatology, Royal Hospitals NHS Trust, London, United Kingdom.
J Med Virol 2000 Jul;61(3):289-97 Abstract quote The role of human papillomavirus (HPV) in anogenital carcinogenesis is established firmly, but a similar role in non-melanoma skin cancer remains speculative. Certain immunosuppressed individuals have an increased incidence of both viral warts and non-melanoma skin cancer, that has prompted the suggestion that HPV may play a pathogenic role. Differences in the techniques used to detect HPV DNA in skin, however, have led to discrepancies in the prevalence and spectrum of HPV types reported in these malignancies.
This study describes the use of a comprehensive degenerate PCR technique to compare the HPV status of 148 Non-melanoma skin cancers from immunosuppressed and immunocompetent individuals. HPV DNA was detected in 37/44 (84.1%) squamous cell carcinomas, 18/24 (75%) basal cell carcinomas and 15/17 (88.2%) premalignant skin lesions from the immunosuppressed group compared with 6/22 (27.2%) squamous cell carcinomas, 11/30 (36.7%) basal cell carcinomas and 6/11 (54. 4%) premalignancies in the immunocompetent group. Epidermodysplasia verruciformis HPV types prevailed in all lesion types from both groups of patients. In immunosuppressed individuals, cutaneous HPV types were also identified at high frequency, and co-detection of multiple HPV types within single tumours was commonly observed.
This study represents the largest and most comprehensive analysis of the HPV status of non-melanoma skin cancers yet undertaken; whereas there are clearly significant differences in non-melanoma skin cancers from immunosuppressed and immunocompetent populations, we provide evidence that the prevalence and spectrum of HPV types does not differ in squamous cell carcinomas, basal cell carcinomas or premalignancies within the two populations.
These data have important implications for future investigation of the role of HPV in cutaneous carcinogenesis at a functional level.
p53
Overexpression of p53 protein in basal cell carcinomas of human skin.Shea CR, McNutt NS, Volkenandt M, Lugo J, Prioleau PG, Albino AP.
Department of Pathology, New York Hospital-Cornell Medical Center, New York 10021.
Am J Pathol 1992 Jul;141(1):25-9 Abstract quote Basal cell carcinoma (BCC) of the skin is the most common human cancer, but its molecular-genetic pathogenesis is unclear. In many other types of cancer, mutations of the tumor-suppressor gene p53 occur frequently and may lead to overexpression of a long-lived mutant form of p53 protein.
In this study, overexpression of p53 protein was detected immunohistochemically in 30 (83%) of 36 specimens of BCC of the head and neck. The same regions of tumor typically were reactive both with a monoclonal antibody (PAb240) specific for the mutant protein and with one (PAb1801) directed against an epitope common to both wild-type and mutant p53 protein. Keratinocytes of chronically sun-exposed epidermis adjacent to BCCs also focally overexpressed p53 protein in the majority of cases, whereas those of sun-protected buttock skin did not.
Mutation of p53 may form an important part of the pathogenetic sequence in a majority of cases of BCC.
p53 protein in aggressive and non-aggressive basal cell carcinoma.
De Rosa G, Staibano S, Barra E, Donofrio V, Salvatore G, Vessecchia G, Boscaino A.
Institute of Pathology, II Faculty of Medicine and Surgery, Naples, Italy.
J Cutan Pathol 1993 Oct;20(5):429-34 Abstract quote Basal cell carcinoma (BCC) is the most frequent cutaneous neoplasm, with a generally favorable clinical behavior. Sometimes, indeed, it recurs after therapy and/or metastasizes. As point mutations in the coding sequence of the p53 tumor suppressor gene have been implicated in the progression of many human tumors, we studied the expression of p53 protein on this neoplasia.
We tested immunohistochemically the positivity for p53 protein (NCL-p53-CM1, YLEM) on 19 cases of morphologically "non aggressive" BCC (BCC1) and on 19 "aggressive" BCC (BCC2), all with one or more relapses and 3 with distant metastases also. Results were related to clinico-pathological and follow-up data. All but one BCC2 were found positive for p53 protein. Conversely, only 2 cases of BCC1 exhibited low immunoreactivity for p53 protein, with high statistical differences between the two groups. No correlation was found between the immunoreactivity, age of patients, and site of the lesions.
The availability of immunohistochemistry and the relatively easy interpretation of the results make screening for p53 protein a possibly useful tool in the prognostic evaluation of BCC.
p53 gene mutations in human skin cancers and precancerous lesions: comparison with immunohistochemical analysis.Kubo Y, Urano Y, Yoshimoto K, Iwahana H, Fukuhara K, Arase S, Itakura M.
Department of Dermatology, School of Medicine, University of Tokushima, Japan.
J Invest Dermatol 1994 Apr;102(4):440-4 Abstract quote Mutations of exons 3 through 9 of the p53 gene in skin lesions were screened in 23 cases of squamous cell carcinoma (SCC), 25 cases of basal cell carcinoma (BCC), two cases of Bowen's disease, 10 cases of solar keratosis, and five cases of keratoacanthoma by polymerase chain reaction--single strand conformation polymorphism analysis. Mutations of the p53 gene were detected in seven of 23 SCCs (30%), three of 25 BCCs (12%), and none in all cases of Bowen's disease, solar keratosis, or keratoacanthoma.
Of 23 cases of SCC, mutations were detected in four of 15 SCCs (27%) that originated in the sunlight-exposed skin region, in two of three SCCs (67%) that originated in the scar tissue, and in one of three SCCs (33%) that originated in radiation dermatitis. Mutations of C-->T transition predominated in SCC and BCC that originated in the sunlight-exposed skin region. Mutations of C-->A or CC-->AT observed in tumors that originated in the predisposed conditions, presumably unrelated to UV light, are different from those found in UV light-related SCC or BCC. Twelve cases of SCC were comparatively analyzed with the immunohistochemical staining with anti-p53 antibody. Two of four cases with positive staining had missense mutations, and three of eight cases with negative staining had nonsense mutations.
Based on these findings, immunohistochemical results do not necessarily mean the presence or absence of p53 gene mutations in skin tumors, and sequence analysis is essential for determining whether the gene is mutated.
Characterization of p53 gene mutations in basal-cell carcinomas: comparison between sun-exposed and less-exposed skin areas.
Matsumura Y, Nishigori C, Yagi T, Imamura S, Takebe H.
Department of Radiation Genetics, Faculty of Medicine, Kyoto University, Japan.
Int J Cancer 1996 Mar 15;65(6):778-80 Abstract quote Mutations in the p53 gene in 32 basal-cell carcinomas (BCC) developed in Japanese patients were identified by the polymerase chain reaction and single-strand-conformation polymorphism analysis, followed by sequencing the DNA.
Among 16 BCC developed in continuously sun-exposed areas, 6 tumors showed 7 base substitutions, most of which were G:C to A:T transitions, mainly at the dipyrimidine sites. Seven out of 16 BCC developed in less-exposed areas showed 8 base substitutions, but the majority (75.0%) of them were transversions.
These results suggest that the mutation in the p53 gene plays a significant role in the tumorigenesis of BCC developed in less-exposed areas as well as those in sun-exposed areas in Japanese patients. There must be therefore causative factors other than UV irradiation for BCC in less-exposed areas.
Genomic analysis of single cells from human basal cell cancer using laser-assisted capture microscopy.Ponten F, Williams C, Ling G, Ahmadian A, Nister M, Lundeberg J, Ponten J, Uhlen M.
Department of Pathology, University Hospital, Uppsala, Sweden.
Mutat Res 1997 Sep;382(1-2):45-55 Abstract quote In this study, we show that direct mutational analysis of genomic DNA can be performed on single somatic cells extracted from a frozen, immunohistochemically stained tissue section using laser-assisted capture microscopy.
Eighty-nine single tumor cells were separately dissected from one case of human basal cell cancer (BCC) and p53 mutations were analyzed by direct semi-automated sequencing of PCR fragments. Amplification was obtained for at least one of the two analyzed exons from approximately 50% of the single tumor cells. Identical p53 mutations were found in widely spread areas of the tumor, suggesting a clonal proliferation originating from one cell. Interestingly, comparison between results of immunohistochemistry and genetic analysis of the single cells revealed the same p53 mutations irrespective of the p53 immunoreactivity.
We propose that this approach has a great potential to allow investigation of genotypic differences in single cells and more specifically to resolve important and fundamental questions determining cancer heterogeneity.
p53 mutations in basal cell carcinomas arising in routine users of sunscreens.Rosenstein BS, Phelps RG, Weinstock MA, Bernstein JL, Gordon ML, Rudikoff D, Kantor I, Shelton R, Lebwohl MG.
Department of Radiation Oncology, Mount Sinai School of Medicine of NYU, New York 10029, USA.
Photochem Photobiol 1999 Nov;70(5):798-806 Abstract quote Sun exposure histories were obtained from a series of patients age 35 or younger following diagnosis and removal of a basal cell carcinoma (BCC).
The DNA was extracted from tumor biopsy samples derived from BCC of 10 patients who reported that they did not use sunscreens during youth (age 18 or younger) and 10 patients who routinely employed sunscreens during this age period. Exons 5-9 of the p53 gene were then amplified in three fragments from these samples using a nested polymerase chain reaction (PCR) approach and screened for mutations using an RNA heteroduplex assay. All PCR products displaying evidence of a mutation were sequenced. It was found that 6 of the 10 patients who were not routine sunscreen users displayed mutations in these p53 exons. All of the mutations were located at dipyrimidine sites, five of the six were C-->T transitions and one mutation was a tandem double mutation, consistent with a role for solar UVB in BCC formation. In contrast, only one p53 mutation was detected in the group of 10 patients who routinely employed sunscreens during childhood and adolescence. Hence, a significantly (P = 0.029) lower level of p53 mutations was detected in the BCC obtained from sunscreen users compared with tumors derived from nonusers.
These findings suggest that the mechanisms involved in the etiology of skin carcinogenesis differ in sunscreen users compared with people who did not routinely employ sunscreens. These data are also indicative of a protective effect associated with sunscreen use against the formation of p53 mutations.
It is possible that the patients who were diagnosed with BCC despite their use of sunscreens possessed a genetic susceptibility for skin cancer formation and developed BCC through a p53-independent pathway. Alternatively, solar UVA wavelengths, that were generally not blocked by the suncare products employed by the sunscreen users, may have played a significant role in BCC development through induction of a mutation(s) in an oncogene and/or a tumor suppressor gene, other than p53, for these patients.
Analysis of p53 and BAX mutations, loss of heterozygosity, p53 and BCL2 expression and apoptosis in basal cell carcinoma in Korean patients.Cho S, Hahm JH, Hong YS.
Department of Dermatology, Ewha Womans University, Tongdaemun Hospital, 70 Chongro-6-ka, Chongro-ku, Seoul, 110-126, Korea.
Br J Dermatol 2001 Apr;144(4):841-8 Abstract quote BACKGROUND: Apart from some Japanese studies, there are few data on the gene mutations involved in the development of basal cell carcinomas (BCC) in Koreans or other Asians. Objective To gain insight into the molecular pathogenesis of BCC in Koreans.
METHODS: A collection of 33 cases of BCC were screened for mutations of p53 and BAX genes, p53 and BCL2 expression, loss of heterozygosity (LOH) and apoptosis.
RESULTS: Mutations of p53, found in 9% (three of 33) of the cases, were all mis-sense mutations (G-->C transversions) at codon 246 on exon 7. In 6% (two of 33), BAX gene showed frameshift mutations resulting from deletions in the poly(G) tract. LOH on chromosome 9q was seen in 58% (14 of 24), and p53 mutations developed only among the 9q LOH+ cases; LOH on chromosome 18q, where BCL2 gene is located, was found in 13% (four of 30). Immunohistochemical expression of p53 was seen in 27% (nine of 33), and its expression did not coincide with p53 mutations. BCL2 expression was seen in 39% (13 of 33). Apoptosis was revealed in 21%. In BCC, 9q LOH and p53 mutations seem to be closely related; the immunoreactivity of p53 and its mutations were not directly related; and p53 and BCL2 expression were negatively correlated. Frameshift mutations of the BAX gene in BCC are documented for the first time.
CONCLUSIONS: Various molecular mechanisms operate with redundant complexity in the pathogenesis of BCC. The LOH on chromosome 9q is the most frequent genetic alteration, as in other races; however, p53 mutations are much less frequent in Koreans than in Caucasians and suggest aetiologies other than ultraviolet radiation.
p63 (CUSP)
CUSP/p63 expression in basal cell carcinoma.Dellavalle RP, Walsh P, Marchbank A, Grayson TE, Su LJ, Parker ER, DeGregori J, Penheiter K, Aszterbaum M, Epstein Jr EH, Lee LA.
Department of Dermatology, Department of Medicine, Department of Biochemistry and Molecular Genetics, and Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA; Department of Dermatology, University of California, San Francisco, California, USA; Veterans' Affairs Medical Center, Denver, Colorado; Dermatology Service, Department of Medicine, Denver Health Medical Center, Denver, Colorado, USA.
Exp Dermatol 2002 Jun;11(3):203-208 Abstract quote Chronic ulcerative stomatitis protein (CUSP), the most abundant cutaneous isoform of p63, is a p53-related gene essential for epithelial development. CUSP lacks the N-terminal transactivation domain found on other p53 family members and has been shown to inhibit p53 function in vitro.
In this study, biopsies of normal skin (21 of 21), benign neoplasms [seborrheic keratosis (3 of 3), acrochordon (2 of 3), and verruca plana (3 of 3)], and squamous cell carcinomas (SCC) (4 of 4) displayed strong nuclear CUSP immuno-reactivity in epidermal cells. In contrast few basal cell carcinomas (BCC) (7 of 27) and sebaceous nevi (1 of 2) displayed this pattern of CUSP immunoreactivity.
Thus, biopsies of cutaneous conditions characterized by sonic hedgehog (SHH) pathway dysregulation were more than 86 times as likely to lack CUSP/p63 immunofluorescence as were other cutaneous samples. Adjacent normal-appearing skin from patients with basal cell nevus syndrome (BCNS) (2 of 3) also lacked CUSP immuno-staining. Lastly, a BCC arising in a patched heterozygous mouse also lacked CUSP immuno-staining. Because CUSP mRNA and protein were detected via Northern and Western analysis in BCC samples lacking CUSP immuno-staining, we sequenced the coding region of CUSP from two non-staining BCCs but found no mutations.
Therefore, CUSP appears to be present, unmutated, and yet frequently undetectable by immunofluorescence in cutaneous lesions in both humans and mice that are associated with SHH pathway dysregulation (BCCs, BCNS, and nevus sebaceous).
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.
PTCH GENE MUTATIONS Science 1996;272:1668-71.
Cell 1996;85:841-51.
Lancet 1992;339:581-2.
Nat Genet 1996;14:78-81.
Cancer Res 1997;57:2369-72.
Human homologue of the Drosophila patched gene, PTCH, is the second tumor suppressor gene (after p53) implicated in the development of BCCPTCH gene has been mapped to chromosome 9q22.3 where a locus for NBCCS had been previously located
Sequence analysis of DNA from NBCCS individuals has shown a series of germline mutations in the PTCH gene
Subsequently, somatic mutations in the PTCH gene have also been identified in 20% to 30% of the sporadic BCCs studied
Mutations detected in the PTCH genes from sporadic BCC also contain UV-specific C to T and CC to TT nucleotide changes
Most of the PTCH mutations detected have been nonsense mutations, deletions, and insertions, which lead to altered PTCH proteins.
Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation.Unden AB, Holmberg E, Lundh-Rozell B, Stahle-Backdahl M, Zaphiropoulos PG, Toftgard R, Vorechovsky I.
Karolinska Institute, Department of Biosciences at Novum, Center for Nutrition and Toxicology, Huddinge, Sweden.
Cancer Res 1996 Oct 15;56(20):4562-5 Abstract quote The nevoid basal cell carcinoma (Gorlin) syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple developmental defects and cancer susceptibility, in particular to basal cell carcinoma. The human homologue of Drosophila patched (PTCH) was recently identified, mapped to the NBCCS locus on chromosome 9q22.3, and found mutated in patients with NBCCS and also in sporadic basal cell carcinomas.
Here we show germ-line PTCH mutations in three families with NBCCS. We demonstrate that a germ-line PTCH frameshift deletion in one patient with NBCCS was accompanied by loss of the normal copy of PTCH in a tumor developed in the same patient. Another basal cell carcinoma from this patient did not show the loss of the normal copy of PTCH, instead a missense mutation in a highly conserved residue was identified in the nondeleted allele, illustrating two different mechanisms of PTCH inactivation in different tumors derived from the same NBCCS patient. We also show somatic PTCH mutations in 4 basal cell carcinomas identified by analyzing 18 non-NBCCS patients with sporadic tumors.
These data provide further support for PTCH as an important tumor suppressor gene in the development of the most common human cancer.
Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma.Unden AB, Zaphiropoulos PG, Bruce K, Toftgard R, Stahle-Backdahl M.
Department of Dermatology, Karolinska Hospital, Stockholm, Sweden.
Cancer Res 1997 Jun 15;57(12):2336-40 Abstract quote Recently, a human homologue of the Drosophila patched gene, PTCH, was identified as a putative tumor suppressor mutated in both hereditary and sporadic basal cell carcinomas. Because PTCH controls its own transcription, inactivating mutations in PTCH may lead to overexpression of mutant PTCH mRNA due to loss of autoregulation.
The present study is aimed at evaluating whether deregulation of PTCH mRNA expression is a general feature of BCCs of varying histological growth pattern and malignant potential. Irrespective of histological subtype, PTCH mRNA was overexpressed consistently as determined by in situ hybridization in all of the sporadic (n = 16) and hereditary (n = 20) tumors examined. PTCH expression was found in all of the tumor cells but appeared stronger in the peripheral palisading cells. PTCH mRNA was not detected in adjacent nontumor epidermal cells or in other parts of the epidermis. In the majority of tumors (20 of 36), nuclear immunostaining for p53 was found in scattered cells, whereas seven tumors completely lacked p53 immunoreactivity.
Our finding of an up-regulation of PTCH mRNA levels in all of the BCCs analyzed indicates that deregulation of the PTCH signaling pathway constitutes an early rate-limiting event in BCC development.
Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice.Aszterbaum M, Epstein J, Oro A, Douglas V, LeBoit PE, Scott MP, Epstein EH Jr.
Department of Dermatology, University of California San Francisco, Building 100, Room 269, 1001 Potrero Ave, San Francisco, California 94110, USA.
Nat Med 1999 Nov;5(11):1285-91 Abstract quote Basal cell carcinomas, the commonest human skin cancers, consistently have abnormalities of the hedgehog signaling pathway and often have PTCH gene mutations.
We report here that Ptch+/- mice develop primordial follicular neoplasms resembling human trichoblastomas, and that exposure to ultraviolet radiation or ionizing radiation results in an increase in the number and size of these tumors and a shift in their histologic features so that they more closely resemble human basal cell carcinoma. The mouse basal cell carcinomas and trichoblastoma-like tumors resemble human basal cell carcinomas in their loss of normal hemidesmosomal components, presence of p53 mutations, frequent loss of the normal remaining Ptch allele, and activation of hedgehog target gene transcription.
The Ptch mutant mice provide the first mouse model, to our knowledge, of ultraviolet and ionizing radiation-induced basal cell carcinoma-like tumors, and also demonstrate that Ptch inactivation and hedgehog target gene activation are essential for basal cell carcinoma tumorigenesis.
The spectrum of patched mutations in a collection of Australian basal cell carcinomas.Evans T, Boonchai W, Shanley S, Smyth I, Gillies S, Georgas K, Wainwright B, Chenevix-Trench G, Wicking C.
Institute for Molecular Bioscience, University of Queensland, Australia.
Hum Mutat 2000;16(1):43-8 Abstract quote Inactivating mutations in the human patched (PTCH) gene have been identified in both familial and sporadic basal cell carcinomas (BCCs). In some tumors mutations have been detected in both alleles thereby supporting the role of PTCH as a tumor suppressor gene.
We have analyzed 22/23 coding exons of PTCH for mutations in 44 sporadic BCCs, and detected 10 novel mutations in nine tumors. In two of the mutant tumors the remaining allele was inactivated by loss of heterozygosity. Five novel PTCH polymorphisms were also identified. Most of the variations found were C>T substitutions at dipyrimidine sites, supporting previous studies which indicate a role for ultraviolet-B in the genesis of sporadic BCCs.
Role of PTCH and p53 genes in early-onset basal cell carcinoma.Zhang H, Ping XL, Lee PK, Wu XL, Yao YJ, Zhang MJ, Silvers DN, Ratner D, Malhotra R, Peacocke M, Tsou HC.
Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Am J Pathol 2001 Feb;158(2):381-5 Abstract quote Basal cell carcinoma (BCC) is the most common skin cancer in the Western world. Ultraviolet (UV) exposure, race, age, gender, and decreased DNA repair capacity are known risk factors for the development of BCC. Of these, UVB irradiation from sunlight is the most significant risk factor. The incidence of sporadic BCC increases in individuals older than age 55, with the greatest incidence reported in individuals who are older than 70, and is rare in individuals who are younger than 30.
In this study, we analyzed 24 BCC samples from individuals who had BCC diagnosed by the age of 30. Fifteen single-stranded conformation polymorphism variants in the PTCH gene were identified in 13 BCC samples. Sequence analysis of these single-stranded conformation polymorphism variants revealed 13 single nucleotide changes, one AT insertion, and one 15-bp deletion. Most of these nucleotide changes (nine of 15) were predicted to result in truncated PTCH proteins. Fifteen p53 mutations were also found in 11 of the 24 BCC samples. Thirty-three percent (five of 15) and 60% (nine of 15) of the nucleotide changes in the PTCH and p53 genes, respectively, were UV-specific C-->T and CC-->TT nucleotide changes.
Our data demonstrate that the p53 and PTCH genes are both implicated in the development of early-onset BCC. The identification of UV-specific nucleotide changes in both tumor suppressor genes suggests that UV exposure is an important risk factor in early onset of BCC.
UV-specific p53 and PTCH mutations in sporadic basal cell carcinoma of sun-exposed skin.Ratner D, Peacocke M, Zhang H, Ping XL, Tsou HC.
Department of Dermatology, College of Physicians and Surgeons of Columbia University, New York, Ny, USA.
J Am Acad Dermatol 2001;44:293-7 Abstract quote
UVB irradiation is known to produce DNA damage at mutation hotspots in the p53 tumor suppressor gene, leading to the development of skin cancers. Mutations in the PTCH tumor suppressor gene, which is known to be responsible for the development of nevoid basal cell carcinoma syndrome, have also been identified in sporadic basal cell carcinomas (BCCs).
We describe the case of an 80-year-old welder in whom 3 novel p53 mutations, as well as UV-specific PTCH mutations, were detected in two BCC samples from sun-exposed skin.
The simultaneous presence of UV-specific p53 and PTCH mutations in the same BCC sample has not previously been reported.
PATCHED and p53 gene alterations in sporadic and hereditary basal cell cancer.Ling G, Ahmadian A, Persson A, Unden AB, Afink G, Williams C, Uhlen M, Toftgard R, Lundeberg J, Ponten F.
Department of Genetics and Pathology, Rudbeck Laboratory, University Hospital, Uppsala University, S-751 85 Uppsala, Sweden.
Oncogene 2001 Nov 22;20(53):7770-8 Abstract quote It is widely accepted that disruption of the hedgehog-patched pathway is a key event in development of basal cell cancer. In addition to patched gene alterations, p53 gene mutations are also frequent in basal cell cancer.
We determined loss of heterozygosity in the patched and p53 loci as well as sequencing the p53 gene in tumors both from sporadic and hereditary cases. A total of 70 microdissected samples from tumor and adjacent skin were subjected to PCR followed by fragment analysis and DNA sequencing. We found allelic loss in the patched locus in 6/8 sporadic basal cell cancer and 17/19 hereditary tumors. All sporadic and 7/20 hereditary tumors showed p53 gene mutations. Loss of heterozygosity in the p53 locus was rare in both groups. The p53 mutations detected in hereditary tumors included rare single nucleotide deletions and unusual double-base substitutions compared to the typical ultraviolet light induced missense mutations found in sporadic tumors.
Careful microdissection of individual tumors revealed genetically linked subclones with different p53 and/or patched genotype providing an insight on time sequence of genetic events. The high frequency and co-existence of genetic alterations in the patched and p53 genes suggest that both these genes are important in the development of basal cell cancer.
SCID-BEIGE MICE
Anaplastic neoplasms arising from basal cellcarcinoma xenotransplants into SCID-beige mice.Carlson JA, Combates NJ, Stenn KS, Prouty SM.
Divisions of Dermatopathology and Dermatology, Albany Medical College, Albany, New York, USA, Skin Biology TRC, Johnson and Johnson, Skillman, New Jersey, USA.
J Cutan Pathol 2002 May;29(5):268-78 Abstract quote Background: An animal model for the study of basal cell carcinoma (BCC) is required to better understand its biology. Several attempts to grow BCC in immuno-incompetent animals have been only modestly successful.
Methods: To test the ability of BCC to grow in a mouse with complete and severe immuno-incompetence, 14 individual BCC were transplanted into the subcutaneous tissue of 18 SCID-beige mice (T, B and natural killer cell deficient). Light microscopy and immunophenotypic analyses were performed on primary BCC and first and seventh passage tumors.
Results: Transplantation of three BCC yielded rapidly growing anaplastic tumors for a tumor take of 18% (3/18). SCID-beige mice without tumor growth had mostly scars or epidermoid cysts at the transplant sites. The three patients whose BCC gave rise to the anaplastic tumors were significantly older than those without tumor growth (87 vs. 64, p = 0.001), but they did not differ with respect to BCC type or general health. These three anaplastic tumors were histologically and immunophenotypically similar, being composed of dyscohesive, pleomorphic cells that expressed vimentin and smooth muscle actin. In the first passage mice these tumors were locally invasive, tumor-forming nodules associated with an expansion of donor inflammatory cells (T and B lymphocytes and plasma cells), rare remnants of BCC epithelium and epidermoid cysts. By the seventh passage, the tumors were homogenous and metastasized widely throughout the mice. Changing transplantation location to the dermis to wound environment or supplementing the tumor with BCC-derived fibroblasts did not alter the phenotype or growth rate in SCID-beige mice. Anaplastic tumors also grew easily in SCID mice (T and B cell deficient). However, transplantation of the anaplastic tumors into normal mice (CB-17) or less severely immunodeficient mice (NCr and Balb/c: T and natural killer cell deficient) did not allow for growth. Furthermore, tumor growth could not be maintained in vitro.
Conclusion: Empirically, these data suggest that BCC has the potential to become an aggressive metastatic neoplasm, given the right immune and stromal environment. Moreover, a functional B lymphocyte system appears to prevent this growth. As human lymphocytes also engraft in SCID-beige mice, the original host immune response could be responsible for the lack of tumor growth in the majority of xenografts. Furthermore, the anaplastic and metastatic phenotype of these BCC derived neoplasms may be the experimental equivalent of metastatic BCC and BCC associated with carcinosarcoma.
TUBERIN
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.
LABORATORY/RADIOLOGIC/OTHER TESTS CHARACTERIZATION Laboratory Markers DNA Ploidy and Cyclin D1 Expression in Basal Cell Carcinoma of the Head and Neck
Stefania Staibano, MD, PhD,1 Lorenzo Lo Muzio, MD, PhD,4 Giuseppe Pannone, DDS,1 Ernesto Mezza, BD,1 Giuseppe Argenziano, MD,2 Antonio Vetrani, MD,1 Antonio Lucariello, MD,3 Renato Franco, MD,1 Maria E. Errico MD,1 and Gaetano De Rosa, MD
Am J Clin Pathol 2001;115:805-813 Abstract
Basal cell carcinomas (BCCs) may be subdivided into primary with a favorable biologic course (BCC1) and recurrent and/or metastatic (BCC2). No clear association between primary tumor location, histologic subtype, or other clinicopathologic variables and predisposition for BCC2 has been found. Histopathologic criteria are limited for prognostication.
To identify prognostic factors useful for planning therapy, we studied cyclin D1 immunohistochemical expression, DNA ploidy, and epiluminescence light microscopic (ELM) patterns in 60 cases of BCC (30 BCC1 and 30 BCC2) in the head and neck region, half of which were hyperpigmented. Cyclin D1 was absent in 27 cases, expressed at low level in 4 cases, and overexpressed in 30 cases. Seven BCCs were euploid, 28 exhibited a mixed cellular population, and 25 were aneuploid. Among aneuploid tumors, hypodiploidy was found in 12. Among the 30 pigmented carcinomas, only 15 showed a typical ELM pattern. No association between pigmentation and more aggressive biologic behavior of BCC was found.
These results and follow-up data seem to indicate that an unfavorable outcome can be predicted by hyperexpression of cyclin D1, aneuploidy, and an atypical ELM pattern for pigmented cases. A definite hypodiploid peak was associated with worse prognosis.The analysis of cyclin D1 expression and DNA ploidy may help identify BCC with an aggressive phenotype and a poor clinical outcome.
CONFOCAL SCANNING LASER MICROSCOPY
Real-time, in vivo confocal reflectance microscopy of basal cell carcinoma.Gonzalez S, Tannous Z.
Wellman Laboratories of Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School.
J Am Acad Dermatol 2002 Dec;47(6):869-74 Abstract quote BACKGROUND: Real-time, near-infrared confocal laser scanning microscopy may provide a way to diagnose basal cell carcinoma in vivo and might potentially eliminate the need for invasive diagnostic biopsies in the future.
OBJECTIVE: The purpose of this study is to define the in vivo histologic features of basal cell carcinoma by using a high-resolution imaging technique.
METHODS: Five fair-skinned white patients with 8 basal cell carcinoma lesions were recruited for this study. Near-infrared reflectance confocal microscopy imaging was used to characterize the histologic features of these lesions in vivo. Subsequently, the confocal histologic features were correlated with the corresponding routine hematoxylin-and-eosin-stained sections obtained from invasive biopsies.
RESULTS: A uniform population of basal cell carcinoma cells with characteristic elongated nuclei oriented along the same axis was always present. Abundant blood vessels demonstrating prominent tortuosity were seen, as well as prominent, predominantly mononuclear inflammatory infiltrate admixed or in close apposition with basal cell carcinoma cells. Trafficking of leukocytes was visualized in real time.
CONCLUSION: Our results demonstrate that near-infrared confocal microscopy may facilitate diagnosis of basal cell carcinoma with the use of in vivo high-resolution confocal features. Accuracy studies to evaluate these in vivo histologic criteria are warranted.
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION General VARIANTS BUCCAL MUCOSA Basal Cell Carcinoma of the Buccal Mucosa
Raul N. Del Rosario, M.D.; Ronald J. Barr, M.D.; Jerald L. Jensen, D.D.S.; Kenneth A. Cantos, M.D.
Laboratory Service (Oral Pathology) Veterans Administration Medical Center Long Beach, CA (J.L.J.); Dermatopathology Laboratory, University of California Irvine Medical Center (R.D.R., R.J.B., K.A.C.).
Am J Dermatopathol 2001;23:203-205Abstract quote
True basal cell carcinoma (BCC) involving the oral mucous membranes is extraordinarily rare. Most of those described as occurring in the oral cavity usually involve the gingiva and are not true BCCs but peripheral ameloblastomas.
A true BCC, which arose on the buccal mucosa of a 69-year old man, is reported. It presented as a 1.3 cm ulcerated plaque without gingival connection. Histologically, the lesion exhibited classic features of BCC with palisading and retraction spaces, and focally communicated with the overlying squamous epithelium.
Although it is possible that this lesion also arose from a heterotopic odontogenic rest, the anatomical location, focal squamous (metatypical) features, and positive staining for Ber-EP4 support an origin from the basal cell layer of stratified squamous mucosa.
LINEAR
Linear basal cell carcinoma: report of seventeen cases and review of the presentation and treatment.Lim KK, Randle HW, Roenigk RK, Brodland DG, Bernstein SC, Marcil I.
Department of Dermatology, Mayo Clinic Scottsdale, Arizona, USA.
Dermatol Surg 1999 Jan;25(1):63-7 Abstract quote BACKGROUND: Linear basal cell carcinoma was first described as a distinct clinical morphologic variant in 1985. Subsequently, twelve cases were reported.
OBJECTIVE: To review and identify cases of linear basal cell carcinoma in our institutions and determine optimal treatment based on review of our cases and those in the literature.
METHODS: Primary basal cell carcinomas treated at the three campuses of Mayo Clinic and the University of Montreal were reviewed retrospectively, as were the twelve cases in the literature.
RESULTS: Seventeen cases of linear basal cell carcinoma were identified. The age and sex ratios were similar to those of patients with standard basal cell carcinomas. Based on the review of the few reported cases of linear basal cell carcinoma (29), the percentage of aggressive histologic subtypes (38%) was increased compared with that in a general population. The average number of Mohs layers required for treatment was higher than that reported for standard basal cell carcinoma, an indication of increased subclinical spread.
CONCLUSION: Linear basal cell carcinoma is an uncommonly recognized morphologic variant. Based on the small number of cases, these tumors have more aggressive histologic subtypes. Because of the possibility for increased subclinical spread, Mohs micrographic surgery can be considered for treatment. Further studies are needed to confirm these findings.
PORE
Basal cell carcinoma presenting as a large pore.Benedetto AV, Benedetto EA, Griffin TD.
MCP Hahnemann School of Medicine.
J Am Acad Dermatol 2002 Nov;47(5):727-32 Abstract quote BACKGROUND: Certain facial lesions clinically appear as large pores, and when examined microscopically, they are found to be basal cell carcinomas (BCCs).
OBJECTIVES: The purposes of this study were to determine the clinical and histologic characteristics of certain large-pore facial lesions, which, on microscopic examination, are found to be BCCs and to identify, if any, a clinical profile of the patients who might be prone to development of such large-pore BCCs.
METHODS: Microscopic examination of biopsy tissue, obtained from patients who presented clinically with characteristic large-pore lesions of the face during the years 1988 to 2000, was performed.
RESULTS: Eleven biopsy specimens from 10 patients who presented with long-standing, gaping pores in the center of the face were shown to be BCCs with features of follicular differentiation and focal keratinization. These patients also had thick, sebaceous skin, and most were users of tobacco.
CONCLUSION: Enlarged pores or pits in the center of the face, present for a long period in patients with thick sebaceous skin, should be examined for evidence of BCC. These large-pore lesions may be BCCs with histologic features of follicular differentiation.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Am J Dermatopathol 2000;22:123-125
The pathologist should always indicate if the tumor is of the micronodular, infiltrative, or sclerosing histologic subtype
These three subtypes follow a much more aggressive course and should be treated more aggressively. In addition, the multifocal superficial type is also more likely to recur.
The heterogenous nature of in vivo basal cell carcinoma.Jones MS, Maloney ME, Billingsley EM.
Department of Dermatology, Hershey Medical Center, PA 17033, USA.
Dermatol Surg 1998 Aug;24(8):881-4 Abstract quote BACKGROUND: There have been nearly 70 different histologic subtypes of basal cell carcinoma (BCC) described. Some of the subtypes have been shown to have clinical relevance. The degree to which one type may merge to another, within the same tumor mass, has been poorly studied.
OBJECTIVE: To determine if BCCs maintain biopsy histology throughout the entire architecture of the tumor.
METHOD: Tumors were evaluated with a prospective histologic analysis of all primary BCCs using the Mohs "removal in layers" technique. All BCCs that required more than a single Mohs stage to clear were included in analysis.
RESULTS: One hundred forty-nine tumors were examined. Fourteen of these were of mixed histologic subtype on biopsy and were not included in the analysis. Six biopsy specimens were inadequate to make a subtype diagnosis and were excluded from calculation. Of the remaining 129 tumors 59% maintained their biopsy diagnosis at first Mohs stage, and 49% at the second Mohs stage. Infiltrative tumors were the most likely to maintain their histologic subtype classification. Of the tumors that showed nodular BCC on biopsy, 13% were infiltrative or micronodular at first Mohs stage.
CONCLUSION: While many BCCs demonstrate a single histological subtype, roughly 40% change in their microscopic appearance at the subclinical extension. This finding has the potential to alter therapy
Basal Cell Carcinoma Clues to Its Presence in Histologic Sections When the Initial Slide Is Nondiagnostic
Helen M. Haupt, M.D.; Jere B. Stern, M.D.; Mouta S. Dilaimy, M.D.
From the Pennsylvania Hospital, Philadelphia, PA, U.S.A. (H.M.H.); Dermatopathology Consultation Services, Damascus, Maryland, U.S.A. (J.B.S.); and Quest Diagnostics, Baltimore, Maryland, U.S.A. (J.B.S., M.S.D.).
Am J Surg Pathol 2000;24:1291-1294 Abstract quote
Initial sections of skin biopsies may not be diagnostic of basal cell carcinoma (BCC). Are there histologic predictors of BCC that should prompt deeper sections?
Ninety-four cases in which the clinical diagnosis was BCC or ``rule-out BCC,'' and the initial histologic slides were nondiagnostic, were submitted for deeper sections on three additional slides.
Of the 94 cases, 50 (53%) demonstrated BCC on deeper sections. This relatively high incidence suggests that deeper sections should be taken in all cases of clinically suspected BCCs unless alternate histologic findings adequately account for the clinical lesion.
The results of this study suggest that additional sections are more likely to yield BCC when the initial nondiagnostic slide demonstrates focal epidermal atypia, equivocal adnexae, stromal fibrosis, empty dermal space, and microcalcifications, criteria which may be useful in determining the need to do deeper sections in cases in which BCC is not clinically suspected.
Am J Dermatopathol 2001;23:24-28
Study of 10 cases
Dendritic melanocytes distributed at periphery (5/10) or evenly throughout the tumor nests (5/10)-no clusters identifiedLangerhans cells in 9/10 cases
A case with BCC infiltrated by malignant melanocytes of a melanoma in situ showed a higher melanocyte density and clusters of melanocytes
VARIANTS Reticulate pattern, usually in combination with other types Areas of squamous differentiation merging with basal cell Central degeneration of the tumor cells Granular Ber-EP4 and MNF-116 in a Previously Undescribed Morphologic Pattern of Granular Basal Cell Carcinoma
Anna Abraham Hayden, M.D.; H. Nicholas Shamma, M.D.
From the Dermatopathology Laboratory of Central States, and the Division of Dermatology, Wright State University School of Medicine, Dayton, Ohio, U.S.A
Am J Dermatopathol 2001;23:530-532 Abstract quote
Granular basal cell carcinoma (GBCC) is a rare subtype of basal cell carcinoma (BCC) with only seven previously described cases in the literature.
A 65-year-old man presented with a papule on his cheek that was subsequently removed. Histopathologic examination revealed that the neoplasm had no connection to the overlying epidermis and that the neoplasm had two different morphologies; nodules composed solely of granular cells and other nodules with a rim of basaloid cells and central granular cells.
The neoplasm stained for both Ber-EPF4 and MNF-116 thus confirming it as a subtype of BCC. GBCC should be considered in the differential diagnosis of nodular neoplasms containing granular cells.
Soft nodular lesion usually on the back or feet with thin anastomosing strands of basaloid cells in loose stroma
Fibroepithelioma of pinkus with tumor giant cells.Val-Bernal JF, Gomez-Ortega JM, Fernandez-Llaca H, Gomez-Roman JJ.
Department of Anatomical Pathology (J.F.V.-B., J.M.G.-O., J.J.G.-R.) and Dermatology Service (H.F.-L.), Marques de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain.
Am J Dermatopathol 2002 Aug;24(4):336-9 Abstract quote A case of fibroepithelioma of Pinkus with pleomorphic epithelial giant cells is reported. The lesion was an ovoid polypoid nodule measuring 4 mm x 3 mm x 2 mm and was located close to the right axilla in an 86-year-old woman. The immunohistochemical features of the epithelial giant cells indicate that most of these cells are not cycling.
We suggest that these cellular changes may represent a senescent event. Giant cells showed a mean nuclear major diameter more than twice that of small cells. Flow cytometric study of the tumor showed a hypodiploid DNA content and an intermediate grade S-phase fraction of the aneuploid component.
To the best of our knowledge, a pleomorphic variant of Pinkus fibroepithelioma has not been reported to date. In fibroepithelioma of Pinkus, the correct diagnosis depends primarily on the architectural pattern of the tumor rather than on its cytologic features.
Small well circumscribed variant with nests resembling hair follicles Infundibulocystic basal cell carcinoma: a newly described variant.
Walsh N, Ackerman AB.
Department of Dermatopathology, New York University Medical Center, New York.
Mod Pathol 1990 Sep;3(5):599-608 Abstract quote
A report by Tozawa and Ackerman (Am J Dermatopathol 9(6):474, 1987) upon a distinctive type of basal cell carcinoma with a particular type of follicular differentiation has stimulated lively correspondence in the literature of dermatopathology. The lesion in question presents itself clinically as a basal cell carcinoma on the face and histopathologically as a neoplasm typified by small size, sharp circumscription, and a unique combination of kinds of follicular differentiation, namely, follicular germs and infundibula. The principal point of contention concerning this neoplasm has been whether it is truly a special variant of basal cell carcinoma or whether it is actually a trichoepithelioma. More extensive studies of this singular neoplasm, including its occurrence in patients with nevoid basal cell carcinoma syndrome, and review of the very few portrayals of it in the literature, have consolidated our view that it is indeed a special variant of basal cell carcinoma.
We now present (a) new information about an early stage in the evolution of the neoplasm in point, (b) evidence to validate classification of it as a basal cell carcinoma, and (c) a critical appraisal of other lesions that might pose problems in differential diagnosis. Finally, justification is provided for the designation "infundibulocystic basal cell carcinoma."
Tumors are poorly circumscribed, have an irregular spiky appearance at the edges
Infiltrating nests and cords of basaloid cells with larger islands toward the center and thinner strands toward the periphery
Islands have poorly developed peripheral palisading and scant mucinous retractionLacks desmoplastic stroma
Siegle RJ, MacMillan J, Pollack SV.
J Dermatol Surg Oncol 1986 Aug;12(8):830-6 Abstract quote Infiltrative basal cell carcinoma is a distinct histologic subtype of basal cell carcinoma (BCC). Criteria for its diagnosis are presented and its nonsclerotic nature emphasized.
Analysis of 174 consecutive BCCs referred for Mohs micrographic surgery showed the infiltrative subtype (29 tumors) to be significantly more destructive and difficult to treat than the more common nodular BCC.
Large islands of keratinization Basal cells merge with areas of larger paler cells May infiltrate widely through the dermis
Micronodular basal cell carcinoma. A deceptive histologic subtype with frequent clinically undetected tumor extension.Hendrix JD Jr, Parlette HL.
Department of Dermatology, University of Virginia School of Medicine, Charlottesville.
Arch Dermatol 1996 Mar;132(3):295-8 Abstract quote BACKGROUND AND DESIGN: Micronodular basal cell carcinoma (BCC) is thought to have a greater potential for clinically surreptitious tumor spread compared with the majority of BCCs that are nodular. However, most supporting data are anecdotal. This study gives objective evidence that micronodular BCCs have wider and deeper tumor extensions than nodular BCCs of similar clinical size. In this retrospective study, 69 cases of micronodular BCC excised by Mohs' micrographic surgery (MMS) were matched to a control group of 69 cases of nodular BCC that were similarly excised. They were paired by site, size, number of recurrences, age, gender, and previous treatment type. The cases were selected and paired by computer from 1070 consecutive BCCs (primary and recurrent) referred for MMS over a 4-year period. The MMS technique allowed us to quantitate and compare the extent of tumor spread using three measurements: the number of surgical stages required for complete removal of the tumor, the width of tissue required to remove subclinical extension of tumor, and the depth of defect at completion of MMS.
RESULTS: Analysis showed the micronodular BCC to have significantly more covert tumor extension, making it more difficult to detect and to eradicate than the nodular BCC. The number of surgical stages required for complete removal of tumor, the width of tissue required to remove subclinical extension of tumor, and the depth of defect at completion of MMS were all greater with micronodular BCCs when compared with nodular BCCs regardless of whether cases were primary or recurrent. These differences were all statistically significant.
CONCLUSIONS: Micronodular BCCs can be significantly more destructive than nodular BCCs because tumor extension is difficult to detect clinically. When treating micronodular BCC, clinicians should keep in mind its potential for clandestine invasion.
10-15% of all cases
Tend to occur in younger patients (57 years vs. 63 years)
Commonly on the trunk and limbsMelanin pigment within tumor cells and stroma
Pigmented basal cell carcinoma: investigation of 70 cases.Maloney ME, Jones DB, Sexton FM.
Department of Medicine, College of Medicine, Pennsylvania State University, Hershey.
J Am Acad Dermatol 1992 Jul;27(1):74-8 Abstract quote BACKGROUND: Pigmented basal cell carcinoma (PBCC) is a clinical and histologic variant of BCC.
OBJECTIVE: Our purpose was to identify the histologic subtypes of BCC that were most often associated with pigment and to determine whether this correlated with outcome after excision.
METHODS: A series of PBCC was identified and the histologic subtype noted. Margins of all excisions were examined for residual tumor. These results were then compared with a series of nonpigmented BCCs.
RESULTS: In a series of 1039 consecutive BCCs, 70 (6.7%) contained pigment. The histologic growth pattern most frequently associated with pigment was the nodular/micronodular pattern (12.4%) followed by the nodular (7.7%), superficial (7.2%), micronodular (4.0%), and the nodular/micronodular/infiltrative (3.4%) patterns. Margins were examined for evidence of residual tumor in the 40 cases that were excised. In only one case (2.5%) was the margin positive for tumor. This was statistically significant (p less than 0.05) compared with 388 excisions of nonpigmented BCCs with comparable growth patterns in which 69 (17.7%) showed positive margins.
CONCLUSION: PBCC, as a clinical variant, is more frequently excised with adequate margins than are tumors of comparable histologic subtypes that do not contain pigment.
Arch Dermatol 1996;132:320
75-84% of BCCs in Japanese show pigmentation versus less than 10% in CaucasiansJ Cutan Pathol 2001;28:34-43
Ultrastructural study identified melanocytes along the basal membrane and also interspersed between tumor cells with large dendritesMelanocytes in pigmented areas were twice the size of those in non-pigmented basal layer
Melanosomes were almost completely in the apoptotic tumor cells and the phagocytosis of the melanosome-containing apoptotic cells by the neighboring tumor cells followed the formation of melanosome complexes
Polypoid Megahed M.
Department of Dermatology, Heinrich-Heine-University, Moorenstr. 5, 40225 Dusseldorf, Germany.
Br J Dermatol 1999 Apr;140(4):701-3 Abstract quote Basal cell carcinoma (BCC), the most common malignant neoplasm of the skin, has many different clinical and histological appearances. Four patients with a new distinctive form, polypoid BCC, are described.
Polypoid BCC is clinically distinguished from other types of BCC by being pedunculated and having a stalk that connects it to the skin surface.
Histologically, it is distinctive in that the tumour aggregations are restricted to the exophytic polypoid zone.
5% of all cases with dense stroma surrounding infiltrative nests with angular, spiky appearance
Some distinguish between sclerosing and morpheaform with desmoplastic stroma associated with infiltrative type nests defined as sclerosing and dense sclerotic stroma found around thin tumor cords and single cell strands with poor peripheral palisading and retraction spaces in the morpheaform type
Signet Ring Cell Basal Cell Carcinoma A Basal Cell Carcinoma With Myoepithelial Differentiation
You Chan Kim, M.D.; Daniel P. Vandersteen, M.D.; Yoon Jae Chung, M.D.; Na Hye Myong, M.D.
From the Department of Dermatology (Y.C.K.), Plastic Surgery (Y.J.C.), and Pathology (N.H.M.), Dankook University, College of Medicine, Cheonan, Korea; and Department of Pathology (D.P.V.), St. Mary's/Duluth Clinic Health System, Duluth, Minnesota, U.S.A.
Am J Dermatopathol 2001;23:525-529 Abstract quote
Basal cell carcinoma (BCC) can show a variety of routes of differentiation, but myoepithelial differentiation has rarely been described.
We describe a case of BCC showing histologic and immunohistochemical features of myoepithelial differentiation. Histologically, the lesion showed well-demarcated tumor nodules composed of two different components. One component was typical of BCC, and the other component was composed of tumor cells containing abundant cytoplasm, eccentric nuclei, and no peripheral palisading, with scattered signet ring–shaped cells.
Immunohistochemically, the tumor cells in the typical BCC component stained with CKAE1/AE3 and smooth muscle actin (SMA), but not with S-100 protein. They stained weakly with CAM5.2, epithelial membrane antigen, and glial fibrillary acidic protein (GFAP). The tumor cells in the other component stained strongly with CKAE1/AE3 and SMA, moderately with epithelial membrane antigen and GFAP, and weakly with CAM5.2. In a small area, the tumor cells stained with S-100 protein.
Most common-70% of cases
SPECIAL STAINS/IMMUNOHISTOCHEMISTRY CHARACTERIZATION CYTOKERATINS Cytokeratins as Markers of Follicular Differentiation An Immunohistochemical Study of Trichoblastoma and Basal Cell Carcinoma
Hjalmar Kurzen, M.D.; Lorenz Esposito; Lutz Langbein, Ph.D.; Wolfgang Hartschuh, M.D.
From the Department of Dermatology, University of Heidelberg (H.K., L.E., W.H.), and Division of Cell Biology, German Cancer Research Center (L.L.), Heidelberg, Germany
Am J Dermatopathol 2001;23:501-509 Abstract quote
Trichoblastoma(s) (TB) are benign neoplasms of follicular differentiation frequently found in nevus sebaceus. Many morphologic features are shared with nodular basal cell carcinoma(s) (BCC), sometimes rendering the differential diagnosis difficult.
Because both neoplasms can simulate components of mature hair follicles histologically, we attempted to corroborate this by immunohistochemical examination of cytokeratins and hair keratins differentially expressed in the hair follicle. Trichoblastoma(s) and BCC showed homogenous expression of CK14 and CK17. The innermost cells of the tumor nodules in all TB and in 72% of BCC were positive for CK6hf. Using a specific CK15 antibody, 38% of TB showed a focal labeling and all BCC remained negative; 70% of TB and 22% of BCC expressed CK19. CK8 was expressed by numerous Merkel cells present in all TB but in none of the BCC examined. All type I and II hair keratins tested, (especially hHa1, hHa5, and hHa8) remained negative in all tumors examined.
Trichoblastoma(s) and BCC show consistent expression of CK6hf, CK14, and CK17; variable expression of CK15 and CK19; and absence of hair keratins. This indicates a differentiation toward the outer root sheath epithelium or the companion layer and not toward the inner root sheath, matrix, or cortex.
p27
Expression of p27kip1 in Basal Cell Carcinomas and Trichoepitheliomas.Cesinaro AM, Migaldi M, Corrado S, Maiorana A.
Section of Pathological Anatomy, Department of Morphologic and Forensic Sciences, University of Modena and Reggio-Emilia, Modena, Italy.
Am J Dermatopathol 2002 Aug;24(4):313-8 Abstract quote Immunohistochemical analysis was used to evaluate p27kip1 expression in normal hair follicles and in a series of 39 basal cell carcinomas (BCC) (13 of superficial type, 7 infiltrating, 7 morphea-like, 12 nodular) and 20 trichoepitheliomas (TE) (9 of classic type, 9 immature, 2 desmoplastic).
The labeling index (LI) was derived semiautomatically by means of a computer-assisted cellular image analyzer, and statistical analysis was carried out using the Student t test. A positive reaction for p27kip1 was detected in the hair germ papillae, in supramatrical cells, and in the inner pilar sheath, whereas matrical cells and the outer pilar sheath were negative. All BCC and TE cases showed a positive immunoreaction for p27kip1, but the staining pattern was different in the two groups of lesions, being patchy with focal peripheral accentuation in TE and more diffusely dispersed in BCC. The quantitative study showed lower p27kip1 expression in BCC (LI = 27.51 +/- 12.55) than in TE (LI = 45.27 +/- 20.27) (P < 0.0001). Statistically significant differences were also observed between TE subgroups and nodular or infiltrating BCC subtypes.
The occurrence of a wide overlap of LI values hampers the practical application of a p27kip1 LI in the differential diagnosis between BCC and TE in difficult cases, however.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES BASALOID FOLLICULUAR HYPERPLASIA Basaloid/follicular hyperplasia overlying connective tissue/mesenchymal hamartomas simulating basal cell carcinomas
LCDR Mitchell E. Stashower, MC, USNR
Kathleen Smith, MD
David Corbett, DO
Henry G. Skelton, MD
Bethesda, MarylandJ Am Acad Dermatol 2001;45:886-91 Abstract quote
Background: Basaloid hyperplasia has been described overlying dermatofibromas as well as in the epidermis overlying nevus sebaceus. Although the morphology of these areas may resemble that of basal cell carcinoma (BCC), in the majority of cases aggressive behavior of the proliferation is not seen. In fact, the basaloid proliferation often shows follicular differentiation and may be stimulated and maintained by its relationship with the underlying stromal cells.
Objective: We wanted to determine whether immunohistochemical staining for antibodies, which may suggest differences in pathogenesis, were different in basaloid hyperplasia overlying connective tissue/mesenchymal hamartomas and BCC.
Methods: We report 3 cases of connective tissue/mesenchymal hamartomas with overlying basaloid hyperplasia, in which the areas of the basaloid proliferation showed follicular differentiation. Immunohistochemical stains included Ber-EP4, PCNA, Ki-67, Bcl-2, p53, SM-Actin, CD31, factor XIIIa, KP-1, and CD34.
Results: There was a diffuse positive reaction for Ber-EP4 in all specimens and there was increased nuclear staining for PCNA and Ki-67. There was focal cytoplasmic staining for Bcl-2 in the areas of basaloid hyperplasia. Immunohistochemical staining for p53 showed only scattered positive cells except in a small focus in the areas of basaloid hyperplasia. The connective tissue component of all lesions showed diffuse staining for CD34 surrounding areas of basaloid hyperplasia in the mesenchymal component as well as in abundant S-100+ nerves.
Conclusion: The areas of basaloid hyperplasia in these hamartomas exhibited an immature phenotype similar to that seen in both BCCs and follicular tumors; however, the patterns of proliferation markers, p53, Bcl-2, and the surrounding stromal cell markers were similar to those of benign follicular tumors. Thus the staining pattern for this group of antibodies suggests that areas of basaloid hyperplasia are not BCC.
CD-34 and Ki-67 staining patterns of basaloid follicular hamartoma are different from those in fibroepithelioma of Pinkus and other variants of basal cell carcinoma
J. M. Naeyaert*, C. Pauwels*, M. L. Geerts and P. Verplancke
Department of Dermatology, Ghent University Hospital, Ghent, Belgium
Journal of Cutaneous Pathology 2001;28 (10), 538-541Abstract quote
Background and aims: Basaloid follicular hamartoma is a rare disorder regarded as a developmental malformation. It may be solitary or generalized, linear or regionalized, and is sometimes associated with myasthenia gravis or alopecia. We compared immunohistochemical staining patterns of selected markers in order to differentiate this hamartoma from fibroepithelioma of Pinkus, a basal cell carcinoma variant it can be confused with.
Methods: The expression of three immunohistochemical markers – CD-34, Ki-67, bcl-2 – was studied in a basaloid follicular hamartoma and in a fibroepithelioma of Pinkus. Two basal cell carcinomas, a nodular and a fibrosing type, and a trichoepithelioma were included as controls.
Results: Basaloid follicular hamartoma shows a low proliferation index and an at least focally circumferential expression of CD-34 around the epithelial strands. This compares to the findings in trichoepithelioma. In contrast, fibroepithelial tumor of Pinkus and two other basal cell carcinoma subtypes display a high proliferative index and an absence of CD-34 expression around the epithelium.
These findings support the non-neoplastic nature of basaloid follicular hamartoma.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS In general, the type and adequacy of the initial treatment will determine the local recurrence rate and potential complications
J Am Acad Dermatol 2001;44:224-30
Multicenter retrospective study of BCC excisions submitted to the respective Departments of Pathology at 4 major university medical centers
Outcome measure was presence of histologic evidence of tumor present in surgical margins of excision specimens (incomplete excision)
Clinician experience was defined as the number of excisions that a clinician performed during the study interval
The analytic sample pool included 1459 tumors that met all inclusion and exclusion criteria
Analyses included univariate and multivariate techniques involving the entire sample and separate subsample analyses that excluded 2 outlying dermatologistsResults: Tumor was present at the surgical margins in 243 (16.6%) of 1459 specimens. A patient's sex, age, and tumor size were not significantly related to the presence of tumor in the surgical margin
Physician experience did not demonstrate a significant difference either in the entire sample (P < .09) or in the subsample analysis (P > .30)
Tumors of the head and neck were more likely to be incompletely excised than truncal tumors in all the analyses (P < .03)Compared with dermatologists, otolaryngologists (P < .02) and plastic surgeons (P < .008) were more likely to incompletely excise tumors; however, subsample analysis for plastic surgeons found only a trend toward significance (P < .10).
Dermatologists and general surgeons did not differ in the likelihood of performing an incomplete excision (P > .4)The physician specialty may affect the quality of care in the surgical management of BCC
bcl-2
bcl-2 protein expression in aggressive and non-aggressive basal cell carcinomas.Ramdial PK, Madaree A, Reddy R, Chetty R.
Department of Pathology, Faculty of Medicine, University of Natal, Durban, South Africa.
J Cutan Pathol 2000 Jul;27(6):283-91 Abstract quote bcl-2, the well known anti-apoptotic gene, cloned more than a decade ago, promotes cell viability without promoting cell proliferation. With few exceptions, high bcl-2 protein expression is associated with a favourable outcome in epithelial tumours. bcl-2 immunoreactivity in basal cell carcinomas (BCCs) is contradictory, with 67-100% immunopositivity being reported. Although BCCs are traditionally regarded as low-grade, indolent tumours, aggressive BCCs (A-BCCs) are mutilative, locally destructive tumours that often recur. bcl-2 protein expression as a predictor of BCC aggressiveness is poorly documented in the English-language literature.
The bcl-2 protein immunoprofile of 50 clinically non-aggressive (NA-BCCs) and 25 clinically A-BCCs was investigated. Of the latter, 17 manifested with one, two or three recurrences. bcl-2 protein expression in each of the recurrences was also evaluated. bcl-2 expression was scored as follows: 0-5% positive cells=negative, 6-25%=1+, 26-50%=2+, 51-75%=3+, >75%=4+. "High" labeling encompassed 3+ or 4+ labeling while "low" labeling referred to 1 + or 2 + labeling. Although bcl-2 positivity was noted in all BCCs, low bcl-2 labeling was a statistically significant feature of A-BCCs (p < 0.01). High bcl-2 labeling of NA-BCCs was a reflection of the bcl-2 labeling of the dominant constituent nodular or superficial subtypes. Micronodular BCCs revealed 2+ or 3+ labeling. Initial and recurrent A-BCCs with a pure or predominantly infiltrative component, demonstrated 1+ or 2+ bcl-2 labeling.
The differential bcl-2 expression in the various clinicopathological subtypes of BCCs suggests that, despite the common derivation of these tumours from a primitive basaloid stem cell and a limited potential for metastasis, they form a heterogeneous group of tumours that differ markedly in histologic and biological behaviour.
While the superficial and nodular BCCs are indolent slow-growing tumours with high bcl-2 labeling, the aggressive BCCs are infiltrative, desmoplastic tumours with low bcl-2 labeling. In mixed tumours, heterogeneity of labeling is a distinctive feature and is contributed to in part by the labeling trends of the different histological subtypes. The micronodular BCC shows varied bcl-2 labeling but in combined tumours occupies a niche intermediate between the non-aggressive nodular and superficial and the aggressive infiltrative subtypes.
The initial and subsequent biopsies of recurrent, adequately excised BCCs share a pure or mixed, predominantly infiltrative, stroma-rich histomorphology with low bcl-2 labeling, reflecting the immunoprofile of a more aggressive growth pattern.
Clin Plast Surg 1997;24:673-686
Micronodular, infiltrative, or sclerosing histologic subtypes are associated with more aggressive local behavior
Mixed pattern most common
Histologic pattern analysis of basal cell carcinoma. Study of a series of 1039 consecutive neoplasms.Sexton M, Jones DB, Maloney ME.
Department of Pathology, M. S. Hershey Medical Center, Pennsylvania State University, Hershey.
J Am Acad Dermatol 1990 Dec;23(6 Pt 1):1118-26 Abstract quote This study attempts to define histologic patterns in 1039 consecutive cases of basal cell carcinoma and to correlate these patterns with adequacy of margins of surgical excision.
Five major histologic patterns were identified: nodular, 218 cases (21%); superficial, 181 cases (17%); micronodular, 151 cases (15%); infiltrative, 77 cases (7%); and morpheic, 11 cases (1%). A mixed pattern (two or more major histologic patterns) was present in 401 cases (38.5%).
Our study indicates that nodular and superficial basal cell carcinomas can be completely removed by simple surgical excision in a high percentage of cases (93.6% and 96.4%, respectively) whereas the micronodular, infiltrative, and morpheic basal cell carcinomas have a higher incidence of positive tumor margins (18.6%, 26.5%, and 33.3%, respectively) after excision.
Mixed patterns that consisted of combinations of the nodular, micronodular, or infiltrative types exhibited a behavior similar to the pattern that resulted in a greater chance of incomplete surgical removal.
Correlation of histologic subtypes of primary basal cell carcinoma and number of Mohs stages required to achieve a tumor-free plane.Orengo IF, Salasche SJ, Fewkes J, Khan J, Thornby J, Rubin F.
Harvard Medical School, Boston, Massachusetts, USA.
J Am Acad Dermatol 1997 Sep;37(3 Pt 1):395-7 Abstract quote BACKGROUND: Certain histologic subtypes of basal cell carcinoma (BCC) behave more aggressively and require more aggressive treatment.
OBJECTIVE: The aim of this study was to see whether certain subtypes of BCC require more Mohs stages to achieve tumor-free margins.
METHODS: A retrospective study of 342 primary BCCs treated with Mohs micrographic surgery (MMS) was performed identifying the histologic subtype of BCC present and the number of stages required to clear the tumor.
RESULTS: The aggressive subtypes (infiltrative, morpheaform, micronodular, and mixed) were most frequently found when high numbers of Mohs stages were required for cure.
CONCLUSION: The more aggressive subtypes of BCC require more MMS stages to achieve tumor-free margins, which is consistent with the concept that these subtypes usually require more aggressive treatment from the start.
Immune Status Histologic patterns of basal cell carcinoma based upon patient immunostatus.
Oram Y, Orengo I, Griego RD, Rosen T, Thornby J.
Department of Dermatology, VA Medical Center, Houston, Texas, USA.
Dermatol Surg 1995 Jul;21(7):611-4 Abstract quote BACKGROUND. The biologic behavior of basal cell carcinoma (BCC) seems to be dictated by the histologic subtype. Moreover, BCCs in immunosuppressed patients appear to show a more aggressive biologic behavior.
OBJECTIVE. The purpose of this study was to retrospectively investigate different histologic subtypes of BCC to determine whether a particular subtype would predominate in immunosuppressed patients.
METHODS. The histologic patterns of 112 primary BCCs from 77 immunosuppressed patients and 60 primary BCCs from 46 patients who are endogenously immunocompromised, due to diabetes mellitus and/or chronic renal failure, were examined. The results were compared with 488 primary BCCs of 318 immunocompetent patients.
RESULTS. The nodular subtype was the predominant pattern among all patients. However, a statistical difference was found in the immunosuppressed patients in that there was a lower percentage of nodular pattern (P = .0038), and a higher percentage of infiltrative pattern (P = .0002). The higher frequency of the infiltrative pattern in the immunosuppressed group was particularly prominent among chronic alcoholics.
CONCLUSION. In immunosuppressed patients, the higher frequency of the infiltrative subtype of BCC, particularly among chronic alcoholics, may have a predictive role in the management of these cases.
Am J Surg Pathol 2000;24:1291-1294.
There are several situations where the pathologist receives a skin biopsy with the diagnosis, Rule out BCC. If there is no tumor on the slide, the alert pathologist will take the extra effort and obtain deeper sections through the paraffin block. This is done because occasionally the tumor may still be the remainder of the tissue embedded in paraffin. One interesting study examined 94 cases of skin biosies submitted as, rule out BCC. The initial diagnosis revealed no tumor and was non-diagnostic. Thus deeper levels were obtained. In 53% of cases (50/94), a BCC was demonstrated.
Histologic findings suggestive of a hidden BCC include:
Focal epidermal atypia
Equivocal adnexae
Stromal fibrosis
Empty dermal space
MicrocalcificationsAm J Dermatopathol 2000;22:123-125
3% of 507 cases of histologically aggressive basal cell carcinoma
Recurrence Clin Geriatr Med 1997;13:339-361
5-9% have multiple recurrences, after surgical treatment
Recurrences dependent upon type of treatment
Recurrent basal cell carcinoma after incomplete resection.Robinson JK, Fisher SG.
Division of Dermatology, Cardinal Bernardin Cancer Center, Loyola University Stritch School of Medicine, 2160 S First Ave, Room 341, Maywood, IL 60153, USA.
Arch Dermatol 2000 Nov;136(11):1318-24 Abstract quote
BACKGROUND: Because the probability of basal cell carcinoma (BCC) recurrence was thought to be 30% to 50%, surgical tradition became not to perform additional resection when the margin was positive.
OBJECTIVE: To determine whether there is an association among age or sex of the patient, anatomic location, histologic type, or reconstructive procedures and the signs and symptoms of the recurrence, interval between incomplete resection and Mohs micrographic surgery (MMS), or extent of MMS resection.
DESIGN: During 20 years, all patients with incompletely excised BCC of the head referred for MMS were sequentially prospectively accrued into the cohort.
SETTING: An outpatient MMS practice.
PATIENTS: Nine hundred ninety-four patients.
MAIN OUTCOME MEASURES: Interval to tumor recurrence, interval to MMS, and extent of MMS as determined by mean surface area resected, depth of resection, and number of tumor nests.
RESULTS: The interval to signs or symptoms of recurrence and to MMS from incomplete resection was greater for men, patients older than 65 years, those having a tumor on the nose or cheek, those with aggressive or fibrosing BCC, and those who underwent flap reconstruction (P =.001). The extent of MMS resection was greater for those with flap and split-thickness skin graft repairs. The number of tumor nests identified by MMS was significantly greater in those treated with split-thickness skin graft and flap (P =.001).
CONCLUSION: Because it is more difficult to control recurrent BCC, treating tumor remaining at the margin of resection in the immediate postoperative period could result in less extensive surgery.
5 Year Recurrence Rate (Average) 8.7% 8.7% 8.7% 1% 8.7% May be as high as 50% 19% at 1 year METASTASIS Very rare
0.05%PERSISTENCE AFTER INCOMPLETE EXCISION
The significance of tumor persistence after incomplete excision of basal cell carcinoma.Berlin J, Katz KH, Helm KF, Maloney ME.
Department of Dermatology, Cleveland Clinic Foundation, Cleveland, OH, USA.
J Am Acad Dermatol 2002 Apr;46(4):549-53 Abstract quote BACKGROUND: Physicians inevitably receive a pathology report after excision of a basal cell carcinoma that indicates that it is incompletely excised. The physician and patient are then left with the dilemma of whether immediate re-excision or close clinical follow-up is indicated.
OBJECTIVE: Our purpose was to identify characteristics of incompletely excised basal cell carcinomas that are at low risk for recurrence.
METHODS: We retrospectively reviewed the charts and pathology slides of all incompletely excised basal cell carcinomas from 1991 to 1994 in a university hospital tumor registry.
RESULTS: Incompletely excised basal cell carcinomas of superficial or nodular subtype, less than 1 cm in diameter, located anywhere except the nose or ears, with less than 4% marginal involvement on the initial inadequate excision had no evidence of tumor persistence.
CONCLUSION: When physicians receive a pathology report indicating the incomplete excision of a basal cell carcinoma, they face the dilemma of further management. The majority of patients should undergo immediate re-excision or Mohs micrographic surgery because tumor persistence was found in 28% of cases. Occasionally, for a small group of select patients, close clinical follow-up may be indicated if the risk of recurrence is very low.
TRISOMY 6
Trisomy 6 in basal cell carcinomas correlates with metastatic potential: a dual color fluorescence in situ hybridization study on paraffin sections.Nangia R, Sait SN, Block AW, Zhang PJ.
Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA.
Cancer 2001 May 15;91(10):1927-32 Abstract quote BACKGROUND: Most basal cell carcinomas (BCCs) are indolent lesions; a few become locally aggressive or even metastatic. Little is known about the molecular and genetic alterations in this malignant transformation. Conventional karyotyping in BCC has revealed a high frequency of nonclonal, structural rearrangements, with few cases that show multiple, unrelated, small clones suggestive of a multicellular origin. Trisomy 6 was described recently in a few BCCs, but the biologic significance of the appearance of trisomy 6 in BBCs was not clear.
METHODS: Thirty cases including 4 metastatic, 4 locally aggressive, and 22 conventional nonaggressive BCCs were studied. Fluorescence in situ hybridization (FISH) was performed on 4 microm tissue sections, using alpha-centromeric enumeration probes for chromosome 6 (SpectrumGreen, Vysis Inc., Downers Grove, IL) and chromosome 4 (SpectrumOrange, Vysis Inc., Downers Grove, IL, used as disomic cell control). Trisomy 6 was semiquantitated within tumor cells and nonneoplastic cells in each case.
RESULTS: Trisomy 6 was identified in all 4 metastatic BCCs within tumor cells and in corresponding BCCs at the primary cutaneous site in 2 of these 4 cases. Two locally aggressive BCCs, 1 of which had preceding radiation exposure, also showed trisomy 6. All nonaggressive BCCs and nonneoplastic cells were disomic for chromosome 6.
CONCLUSIONS: Trisomy 6 has been identified as a cytogenetic aberration representative of tumor cells in aggressive and metastatic BCC. None of the nonaggressive BCCs in this study demonstrated trisomy 6. Acquisition of trisomy 6 by tumor cells in BCC may lead to the emergence of metastatic potential. Additional studies to define the underlying mechanisms may be valuable in preventing aggressive behavior in BCC.
TREATMENT N Engl J Med 1992;327:1649-1662
Estimated cost of treating non-melanoma skin cancers in the United States is about $500 million/year
J Am Acad Dermatol 1998;39:698-703
1996 dollars of following treatments:
$1167 $1243 $1400 $1973 $4558 TREATMENT TYPES SURGICAL Kenneth H. Katz, MD, etal.
J Am Acad Dermatol 2001;45:231-8 Abstract quote
Background: Areas of dense inflammation are commonly removed during Mohs micrographic surgery for basal cell carcinoma because of the concern that they may mask areas of tumor.
Objective: Our purpose was to determine whether inflammation masks tumor during Mohs surgery for primary basal cell carcinoma.
Methods: Twenty-five consecutive cases of primary basal cell carcinoma with areas of dense inflammation encountered during Mohs surgery were sectioned and stained with hematoxylin and eosin and Ber-EP4. Results: In no cases did the dense inflammation mask residual tumor.
Conclusion: Dense inflammation does not mask primary basal cell carcinoma during Mohs surgery and should be carefully evaluated before additional surgery is performed.
Predictors of extensive subclinical spread in nonmelanoma skin cancer treated with mohs micrographic surgery.Batra RS, Kelley LC.
Department of Dermatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215.
Arch Dermatol 2002 Aug;138(8):1043-51 Abstract quote BACKGROUND: In nonmelanoma skin cancer, the clinically visible portion may represent a small fraction of microscopic tumor spread. Previous studies have examined individual risk factors for subclinical spread based on patient and tumor characteristics. However, these risk factors have not been prioritized or studied in combination.
OBJECTIVE: To identify the most predictive risk factors for extensive subclinical tumor spread.
DESIGN: Retrospective analysis of 1131 Mohs micrographic surgical cases. Variables analyzed included patient age, sex, and immune status and lesion size, location, histologic subtype, and recurrence. Logistic regression was applied to identify important combinations of tumor characteristics and to quantify relative odds of spread.
SETTING: Academic referral center.
PATIENTS: Consecutive sample of all referred patients treated by a single Mohs micrographic surgeon in a 3-year period.
MAIN OUTCOME MEASURE: Number of Mohs micrographic surgical layers required to clear a tumor, with 3 or more layers defined as extensive subclinical spread.
RESULTS: The highest-risk tumors, with odds ratios greater than 6.0, were basosquamous and morpheaform basal cell carcinoma (BCC) on the nose, morpheaform BCC on the cheek, and those with a preoperative size greater than 25 mm. Other important risk factors were recurrent and nodular BCC on the nose; location on the eyelid, temple, or ear helix; neck tumors and recurrent BCC in men; and tumor size greater than 10 mm. Patients younger than 35 years were at lower risk. Increasing age and immunocompromise were not significant predictors.
CONCLUSION: Identification of lesions likely to exhibit extensive subclinical spread can help guide management to ensure complete tumor eradication and thereby reduce the risk of recurrence and its associated morbidity and cost.
RADIATION
Radiotherapy of recurrent basal and squamous cell skin carcinomas: a study of 249 re-treated carcinomas in 229 patients.Caccialanza M, Piccinno R, Grammatica A.
Department of Photoradiotherapy, Institute of Dermatological Sciences of the University, Ospedale Maggiore, IRCCS, Via Pace 9, 20122 Milan, Italy.
Eur J Dermatol 2001 Jan-Feb;11(1):25-8 Related Articles, Books, LinkOut
Radiotherapy of recurrent basal and squamous cell skin carcinomas: a study of 249 re-treated carcinomas in 229 patients.Caccialanza M, Piccinno R, Grammatica A.
Department of Photoradiotherapy, Institute of Dermatological Sciences of the University, Ospedale Maggiore, IRCCS, Via Pace 9, 20122 Milan, Italy. Paceskin@Imiucca.csi.Unimi.It
It is of great practical utility to assess which is the best therapeutic choice in the management of basal and squamous cell skin carcinomas recurring after different treatments (RBSCSC). To this aim, we have performed a retrospective review of 249 recurrent lesions in 229 patients treated with dermatological radiotherapy in the period 1982-1999. The total doses of ionizing radiations administered ranged from 45 to 70 Gy, with different dose fractionations, according to the technique employed. The five-year cure-rate was 83.62%. Cosmetic results were evaluated as "good" or "acceptable" in 92.62% of the treated lesions in complete remission. So far no complications or sequelae to the radiological treatment have been observed. Our results suggest two considerations about the choice in the treatment of RBSCSC (following non radiological therapies): 1. radiotherapy is a safe treatment and the most effective after Mohs surgery; 2. radiotherapy is a first-line treatment in those patients who cannot undergo extensive surgery for a variety of different reasons (age, general health conditions, etc.).
PHARMACOLOGIC IMIQUIMOD 5% CREAM Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: Results of a multicenter 6-week dose-response trial
Robin Marks, etal.
J Am Acad Dermatol 2001;44:807-13 Abstract quote
Background: Superficial basal cell carcinoma (sBCC) is an increasingly common tumor in fair-skinned populations throughout the world. Imiquimod, an immune response modifier that induces cytokines including interferons, has been shown in preliminary studies to have an effect when applied topically to BCC.
Objective: We conducted a multicenter, randomized, open-label dose-response trial of imiquimod 5% cream in the treatment of primary sBCC assessing efficacy and safety of different dose regimens.
Methods: Ninety-nine patients were randomized to 6 weeks' application of imiquimod in 1 of 4 treatment regimens: twice every day, once every day, twice daily 3 times/week, once daily 3 times/week. The treatment site was excised and examined histologically 6 weeks after cessation of imiquimod.
Results: Intention-to-treat analysis revealed 100% (3/3) histologic clearance in the twice-daily regimen, 87.9% (29/33) clearance in the once every day regimen, 73.3% (22/30) clearance in the twice-daily 3 times/week regimen, and 69.7% (23/33) clearance in the once-daily 3 times/week regimen. Dose-related inflammatory skin reactions at the site of application were common. The majority were well tolerated and only 1 patient withdrew from the trial as a result of a medication-related skin reaction.
Conclusion: Imiquimod 5% cream appears to have potential as a patient-administered treatment option in sBCC.
Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: A double-blind, randomized, vehicle-controlled study.Geisse JK, Rich P, Pandya A, Gross K, Andres K, Ginkel A, Owens M.
Solano Dermatology Associates, Vallejo; Northwest Cutaneous Research Specialists, Portland; University of Texas Southwestern Medical Center, Dallas; Skin Surgery Medical Group, Inc, San Diego; and 3M Pharmaceuticals, St Paul.
J Am Acad Dermatol 2002 Sep;47(3):390-8 Abstract quote BACKGROUND: Imiquimod 5% cream may provide an effective nonsurgical treatment for superficial basal cell carcinoma (sBCC) based on results of previous studies.
OBJECTIVE: The objective of this phase II dose-response study was to explore various dosing regimens using imiquimod 5% cream for sBCC to find the most effective frequency of dosing with tolerable side effects.
METHODS: Patients (n = 128) were dosed twice daily, once daily, 5 times a week, or 3 times a week in this 12-week, randomized, double-blind, vehicle-controlled study. At 6 weeks after treatment, the entire tumor area was clinically evaluated, excised, and examined exhaustively for histologic evidence of residual sBCC.
RESULTS: Complete response rates were 100% (10/10), 87.1% (27/31), 80.8% (21/26), and 51.7% (15/29) for patients in the twice daily, once daily, 5 times a week, and 3 times a week imiquimod groups, respectively, and 18.8% (6/32) in the vehicle group.
CONCLUSION: Imiquimod 5% cream was effective in the treatment of sBCC. Daily or 5 times a week dosing for 12 weeks demonstrated high efficacy results with acceptable safety profiles.
Efficacy of topical 5% imiquimod cream for the treatment of nodular Basal cell carcinoma: comparison of dosing regimens.Shumack S, Robinson J, Kossard S, Golitz L, Greenway H, Schroeter A, Andres K, Amies M, Owens M.
St George Dermatology and Skin Cancer Center, Level 3, 22 Belgrave St, Kogarah, Australia 2217.
Arch Dermatol 2002 Sep;138(9):1165-71 Abstract quote OBJECTIVE: To establish a safe and efficacious dosing regimen for the treatment of primary nodular basal cell carcinoma (BCC) using 5% imiquimod cream.
DESIGN: Two phase 2 studies were conducted: a 6-week, randomized, open-label, dose-response study evaluating 4 dosing regimens and a 12-week, randomized, vehicle-controlled, double-blind, dose-response study evaluating 4 dosing regimens.
SETTING: Twenty-four public and private dermatology clinics in Australia and New Zealand (6-week study) and the United States (12-week study) participated.
PATIENTS: The study populations comprised 99 patients enrolled in the 6-week study and 92 patients in the 12-week study. Patients were at least 18 years old and had a biopsy-confirmed diagnosis of nodular BCC.
INTERVENTIONS: In the 6-week study, imiquimod was applied once daily for 3 or 7 days per week or twice daily for 3 or 7 days per week. In the 12-week study, imiquimod or placebo cream (vehicle) was applied once daily for 3, 5, or 7 days per week, or twice daily for 7 days per week. The entire tumor area was excised 6 weeks after treatment and examined histologically for evidence of remaining BCC.
MAIN OUTCOME MEASURE: The proportion of patients having no histologic evidence of BCC in the posttreatment excision specimen.
RESULTS: Dosing once daily for 7 days per week resulted in the highest clearance rate, with 25 (71%) of 35 and 16 (76%) of 21 patients showing clearance of their tumor in the 6- and 12-week studies, respectively.
CONCLUSIONS: Topical 5% imiquimod cream is well tolerated and most effective in treating nodular BCC when applied once daily for 7 days per week for either 12 or 6 weeks.
Arch Dermatol 2001;137:319-324
Background:
Photodynamic therapy (PDT) using topical -aminolevulinic acid (-ALA) is an effective treatment for Bowen disease and certain basal cell carcinomas (BCCs), but its place in clinical practice remains to be established. Patients with large and/or multiple lesions of Bowen disease or BCC can represent a considerable therapeutic challenge. We suggest that -ALA PDT may be of particular benefit in such patients.Observation:
In an open study, 35 (88%) of 40 large patches of Bowen disease, all with a maximum diameter greater than 20 mm, cleared following 1 to 3 treatments of -ALA PDT, although 4 patches recurred within 12 months. -Aminolevulinic acid PDT was also used to treat 40 large BCCs, with an identical 88% initial clearance (after 1-3 treatments), with 4 recurrences within 34 months (range, 12-60 months). In 10 further patients with multiple (3) patches of Bowen disease, 44 (98%) of 45 patches cleared following -ALA PDT, although 4 lesions recurred over 12 months. In 3 patients with multiple BCCs, PDT cleared 52 (90%) of 58 lesions, with 2 recurrences during 41 months (range, 12-52 months). Treatments were well tolerated, with only 5 patients with solitary large lesions requiring local anesthesia.Conclusions:
-Aminolevulinic acid PDT is an effective tissue-sparing modality achieving good cosmesis. We propose that -ALA PDT be considered as a first-line therapy for large and/or multiple areas of Bowen disease and superficial BCCs.
Photodynamic therapy vs. cryosurgery of basal cell carcinomas: results of a phase III clinical trial.Wang I, Bendsoe N, Klinteberg CA, Enejder AM, Andersson-Engels S, Svanberg S, Svanberg K.
Departments of Oncology and Dermatology and Venereology, Lund University Hospital, SE-221 85 Lund, Sweden.
Br J Dermatol 2001 Apr;144(4):832-40 Abstract quote BACKGROUND: A previously reported randomized clinical trial showed treatment of Bowen's disease using photodynamic therapy (PDT) with topically applied delta-aminolaevulinic acid (ALA) to be at least as effective as cryosurgery and to be associated with fewer adverse effects.
OBJECTIVES: To compare ALA-PDT and cryotherapy in the treatment of histopathologically verified basal cell carcinomas (BCCs) in a non-blinded, prospective phase III clinical trial.
METHODS: One lesion from each of 88 patients was included. The BCCs were divided into superficial and nodular lesions. The follow-up period was restricted to 1 year with close follow-up for the first 3 months. Efficacy was assessed as the recurrence rate 12 months after the first treatment session, verified by histopathology. Tolerability was evaluated as the time of healing, pain and discomfort during and after the treatment, and final cosmetic outcome.
RESULTS: Histopathologically verified recurrence rates in the two groups were statistically comparable and were 25% (11 of 44) for ALA-PDT and 15% (six of 39) for cryosurgery. However, clinical recurrence rates were only 5% (two of 44) for PDT and 13% (five of 39) for cryosurgery. Additional treatments, usually one, had to be performed in 30% of the lesions in the PDT group. The healing time was considerably shorter and the cosmetic outcome significantly better with PDT. Pain and discomfort during the treatment session and in the following week were low, and were equivalent with the two treatment modalities.
CONCLUSIONS: In terms of efficacy, ALA-PDT is comparable with cryosurgery as a treatment modality for BCCs. Retreatments are more often required with PDT than with cryosurgery. This can easily be performed due to the shorter healing time, less scarring and better cosmetic outcome that follows ALA-PDT.
Adv in Dermatol 2000;16:299-319.
Basal Cell Nevus Syndrome-Syndrome characterized by multiple basal cell carcinomas, odontogenic keratocysts, pits on the palms and soles, skeletal and neurological abnormalities, and ectopic calcifications. There is an early age of onset with autosomal dominant inheritance and high gene penetrance.
Rodent ulcer -Large ulcerating destructive tumor, usually occurring on the face, sometimes measuring 20 cm or more.
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