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22-06-2013 | Non-melanoma skin cancer | Article

5. Basal Cell Carcinoma: Molecular and Pathological Features

Publisher: Springer New York

Abstract

Basal cell carcinoma is the most common malignant tumour of humans, recording a progressive increase in incidence during the last decades. Basal cell carcinomas are locally destructive malignancies, mainly involving sun-exposed areas, such as head and neck skin. Basal cell carcinoma derives from basaloid epithelia located in the follicular bulges, and its development seems to be related to the deregulation of Hedgehog signalling pathway, primarily studied in the Gorlin-Goltz syndrome, characterised by a wide range of developmental abnormalities and predisposition to neoplasm, such as basal cell carcinomas. Basal cell carcinoma shows a clinical favourable behaviour, but some pathological features could suggest a more aggressive clinical course. In addition, the high incidence is responsible of a significant increasing workload for the health service, in relation to their treatment. Thus, novel therapy approaches have been developed in order to improve the treatment.
Glossary
ALA-5
Aminolevulinic acid
BCC
Basal cell carcinoma
ECT
Electrochemotherapy
GLI
Glioblastoma
MAL
Methyl aminolevulinic
MMS
Mohs micrographic surgery
PDT
Photodynamic surgery
SHH
Sonic Hedgehog homologue
SMO
Smoothened
UV
Ultraviolet
Literature
1.
Garner KL, Rodney WN. Basal and squamous cell carcinoma. Prim Care. 2000;27(2):447–58.PubMed
2.
Roewert-Huber J, Lange Asschnfeldt B, Stockfleth E, et al. Epidemiology and aetiology of basal cell carcinoma. Br J Dermatol. 2007;157 Suppl 2:47–51.PubMed
3.
Scrivener Y, Grosshans E, Cribier B. Variations of basal cell carcinomas according to gender, age, location and histopathological subtypes. Br J Dermatol. 2002;147:41–7.PubMed
4.
Skelton LA. The effective treatment of basal cell carcinoma. Br J Nurs. 2009;18:346–50.PubMed
5.
Youssef KK, Van Keymeullen A, Lapounge G, et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nat Cell Biol. 2010;12:299–305.PubMed
6.
Lear JT, Harvey I, de Berker D, Strange RC, Fryer AA. Basal cell carcinoma. J R Soc Med. 1998;91: 585–8.PubMed
7.
Betti R, Inselvini E, Carducci M, Crosti C. Age and site prevalence of histologic subtypes of basal cell carcinomas. Int J Dermatol. 1995;34(3):174–6.PubMed
8.
Fusaro RM, Gol RW. Histochemically demonstrable carbohydrates of appendageal tumor of the skin. II. Benign apocrine gland tumor. J Invest Dermatol. 1962;38:37.
9.
Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J Photochem Photobiol B. 2001;63:8–18.PubMed
10.
Bernard P, Dupuy A, Brun P, et al. Therapeutic modalities and economic assessment in the treatment of superficial basal cell carcinomas and multiple actinic keratoses by French dermatologists. Ann Dermatol Venereol. 2007;134(6–7):527–33.PubMed
11.
Han J, Coldtz G, Hunter DJ. Risk factor for skin cancer: a nested casa control study within the Nurses Health study. Int J Epidemiol. 2006;35:1514–21.PubMed
12.
Madan V, Hoban P, Stange RC, Fryer AA, Lear JT. Genetic and risk factor basal cell carcinoma. Br J Dermatol. 2006;154 Suppl 1:5–7.PubMed
13.
Greinert R. Skin cancer: new marker for better prevention. Pathobiology. 2009;76:64–81.PubMed
14.
Dipgen TL, Mattedi V. The epidemiology of skin cancer. Br J Dermatol. 2002;146 Suppl 61:1–6.
15.
Bastiaens MT, Hoefnagel JJ, Bruin JA, et al. Differences in age, site, distribution and sex between nodular and superficial basal cell carcinoma indicate different types of tumors. J Invest Dermatol. 1998;110(6):880–4.PubMed
16.
Vlajinac HD, Adanja BJ, Lazzar ZF, et al. Risk factors for basal cell carcinoma. Acta Oncol. 2000;39:611–6.PubMed
17.
Gohara MA. Skin cancer in skins of color. J Drugs Dermatol. 2008;7:441–5.PubMed
18.
Gloster Jr HM, Brodland DG. The epidemiology of skin cancer. Dermatol Surg. 1996;22:217–26.PubMed
19.
Pennello G, Devesa S, Gail M. Association of surface ultraviolet B radiation levels with melanoma and nonmelanoma skin cancer in United States blacks. Cancer Epidemiol Biomarkers Prev. 2000;9(3):291–7.PubMed
20.
Dessinotti C, Antoniou C, Katsambas A, et al. Basal cell carcinoma: what’s new under the sun. Photochem Photobiol. 2010;86:481–91.
21.
Miller A, Tsao H. New insights into pigmentary pathways and skin cancer. Br J Dermatol. 2010;162:22–8.PubMed
22.
Dessinotti C, Stratigos AJ, Rigopoupulos DAJ, et al. A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes. Exp Dermatol. 2009;18:741–9.
23.
Hafner C, Landthaler M, Vogt T. Activation of the PI3K/AKT signalling pathway in non melanoma skin cancer is not mediated by oncogenic PIK3CA and AKT1 hotspot mutations. Exp Dermatol. 2010;19:e222–7.PubMed
24.
Goldberg LH. Basal cell carcinoma. Lancet. 1996;347:663–7.PubMed
25.
Hoban PR, Ramachandran S, Strange RC. Environment, phenotype and genetic: risk factors associated with BCC of the skin. Expert Rev Anticancer Ther. 2002;2:570–9.PubMed
26.
Karagas MR, Nelson HH, Zencell MS, et al. Squamous and basal cell carcinoma of the skin in relation to radiation therapy and potential modification of risk by sun exposure. Epidemiology. 2007;18:776–84.PubMed
27.
Cabrera HN, Gomez ML. Skin cancer induced by arsenic in the water. J Cutan Med Surg. 2003;7:106–11.PubMed
28.
Ozyazgan I, Kontas O. Previous injuries or scars as risk factor for the development of basal cell carcinoma. Scand J Plast Reconstr Surg Hand Surg. 2004;38:11–5.PubMed
29.
Spiewak R. Pesticides as cause of occupational skin disease in farmer. Ann Agric Environ Med. 2001;8:1–5.PubMed
30.
Fredman DM, Sigurdson A, Dody MM, Mabuchi K, Linet MS. Risk of basal cell carcinoma in relation to alcohol intake and smoking. Cancer Epidemiol Biomarkers Prev. 2003;12:1540–3.
31.
Sahl WJ, Glore S, Garrison P, Oakleaf K, Johnson SD. Basal cell carcinoma and lifestyle characteristics. Int J Dermatol. 1995;34:398–402.PubMed
32.
Heffernan TP, Kawasumi M, Blasina A, Anderes K, Conney AH, Nghiem P. ATR-Chk1 pathway inhibition promotes apoptosis after UV treatment in primary human keratinocytes potential basis for the UV protective effects of caffeine. J Invest Dermatol. 2009;129:1805–15.PubMed
33.
Lu YP, Lou YR, Xie JG, Peng QY, Zhou S, Lin Y, et al. Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-1 mice. Carcinogenesis. 2007;28:199–206.PubMed
34.
Abel EL, Hendrix SO, McNeeley SG, Johnson KC, Rosenberg CA, Mossavar-Rahmani Y, et al. Daily coffee consumption and prevalence of nonmelanoma skin cancer in Caucasian women. Eur J Cancer Prev. 2007;16:446–52.PubMed
35.
Martin RC, Edwards MJ, Cawte MJ, et al. Basosquamous carcinoma. Analysis of prognostic factors influencing recurrence. Cancer. 2000;88(6):1365–9. 136–42.PubMed
36.
Richmond-Sinclair NM, Pandey N, Williams GM, Neale RE, van der Pols JC, Green AC. Clinical signs of photodamage are associated with basal cell carcinoma multiplicity and site: a 16 year longitudinal study. Int J Cancer. 2010;127:2622–9.PubMed
37.
Hooper JE, Scott MP. Communicating with Hedgehogs. Nat Rev Mol Cell Biol. 2005;6:306–7.PubMed
38.
Tang JY, So P-L, Epstein Jr EH. Novel Hedgehog pathway targets against basal cell carcinoma. Toxicol Appl Pharmacol. 2007;224:257–64.PubMed
39.
Xie J, Murone M, Luoh SM, et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391:90–2.PubMed
40.
Tojo M, Kiyosawa H, Iwatsuki K, et al. Expression of the GLI2 oncogene and its isoforms in human basal cell carcinoma. Br J Dermatol. 2003;148:892–7.PubMed
41.
Hatta N, Hirano T, Kimura T, et al. Molecular diagnosis of basal cell carcinoma and other basaloid cell neoplasms of the skin by the quantification of GLI1 transcript levels. J Cutan Pathol. 2005;32:131–6.PubMed
42.
Regl G, Kasper M, Schnidar H, et al. The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells. Oncogene. 2004;23:1263–74.PubMed
43.
Johnson R, Rothman A, Xie J, et al. Human homolog of patched a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668–71.PubMed
44.
Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8:743–54.PubMed
45.
Wang GY, Wang J, Mancianti ML, Epstein Jr EH. Basal cell carcinoma arise from hair follicle stem cells in PTCH1+/− mice. Cancer Cell. 2011;19:114–24.PubMed
46.
Barnes EA, Kong M, Ollendorff V, Donoghue DJ. Patched1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J. 2001;20:2214–23.PubMed
47.
Wetmore C, Eberhart DE, Currann T. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res. 2001;61:513–6.PubMed
48.
Grachtchouk M, Pero J, Yang SH, et al. Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations. J Clin Invest. 2011;121:1768–81.PubMed
49.
Reifenberger J, Wolter M, Weber RG, et al. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1998;58:1798–803.PubMed
50.
Reifenberger J, Wolter M, Knobbe SB, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol. 2005;152:43–51.PubMed
51.
Crowson AN, Magro CM, Kadin M, et al. Differential expression of Bcl-2 oncogene in human basal cell carcinoma. Hum Pathol. 1996;27:355–9.PubMed
52.
Crowson AN. Basal cell carcinoma: biology, morphology and clinical implications. Mod Pathol. 2006;19:S127–47.PubMed
53.
Bavinck JNB, de Boer A, Vermeer BJ, et al. Sunlight, keratotic skin lesions and skin cancer in renal transplant recipients. Br J Dermatol. 1993;129:242–9. 91.PubMed
54.
Rady RL, Yen A, Rollefson JL, et al. Herpes virus-like DNA sequences in non-Kaposi’s sarcoma skin lesions of transplant patients. Lancet. 1995;345:1339–40.PubMed
55.
Sitz KV, Keppen M, Johnson DF. Metastatic basal cell carcinoma in acquired immunodeficiency syndrome related complex. JAMA. 1987;257:340–3.PubMed
56.
Oram Y, Orengo I, Griego RD, et al. Histologic patterns of basal cell carcinoma based upon patient immunostatus. Dermatol Surg. 1995;21:611–4.PubMed
57.
Aoyagi S, Nouri K. Difference between pigmented and nonpigmented basal cell carcinoma treated with Mohs micrographic surgery. Dermatol Surg. 2006;32:1375–9.PubMed
58.
Betti R, Gualandri L, Cerri A, et al. Clinical features and histologic pattern analysis of pigmented basal cell carcinoma in an Italian population. J Dermatol. 1998;25:691–4.PubMed
59.
Mc Nuth NS. Ultrastructural comparison of the interface between epithelium and stroma in basal cell and control human skin. Lab Invest. 1976;35:132.
60.
Farmer ER, Helwing EB. Metastatic basal cell carcinoma: a clinicopathologic study of seventeen cases. Cancer. 1980;46:748.PubMed
61.
Howell JB. The basal cell nevus. Arch Dermatol. 1959;79:67.
62.
Viksnis P, Berlin A. Follicular atrophoderma and basal cell carcinoma. Arch Dermatol. 1977;113:948.
63.
Pilosila M, Kiistala R, Niemi KM, et al. The Bazex syndrome: follicular atrophoderma with multiple basal cell carcinoma, hypotricosis and hypohidrosis. Clin Exp Dermatol. 1981;89:598.
64.
Mongomery H. Basal squamous cell epithelioma. Arch Dermatol Syph. 1928;18:50.
65.
Borel DM. Cutaneous basosquamous carcinoma: review of the literature and report of 35 cases. Arch Pathol. 1973;95:293.PubMed
66.
Foot NC. Adnexal carcinoma of the skin. Am J Pathol. 1947;23:1.PubMed
67.
Kato N, Ueno H. Infundibulocystic basal cell carcinoma. Am J Dermatopathol. 1993;15:265–7.PubMed
68.
Ali F, Brown A, Gottwald L, et al. Basal cell carcinoma with matrical differentiation in a transplant patient: a case report and review of the literature. J Cutan Pathol. 2005;32:445–8.PubMed
69.
Elston DM, Bergfeld WF, Petroff N. Basal cell carcinoma with monster cells. J Cutan Pathol. 1993;20:70–3.PubMed
70.
Hanke CW, Temofeew RK. Basal cell carcinoma with eccrine differentiation (eccrine epithelioma). J Dermatol Surg Oncol. 1986;12:820–4.PubMed
71.
Misago N, Satoh T, Narisawa Y. Basal cell carcinoma with ductal and glandular differentiation: a clinicopathological and immunohistochemical study of 10 cases. Eur J Dermatol. 2004;14:383–7.PubMed
72.
Misago N, Mihara I, Ansai S-I, et al. Sebaceoma and related neoplasms with sebaceous differentiation. Am J Dermatopathol. 2002;24:294–304.PubMed
73.
Pinkus H. Premalignant fibroepithelial tumors of the skin. Arch Dermatol Syph. 1953;67:598.
74.
Pinkus H. Epithelial and fibroepithelial tumors. Arch Dermatol. 1965;91:24–37.PubMed
75.
Lerchin E, Rahbari H. Adamantinoid basal cell epithelioma. Arch Dermatol. 1975;111:1064.
76.
Barr RJ, Graham JH. Granular basal cell carcinoma. Arch Dermatol. 1979;115:1064.PubMed
77.
Mrak RE, Baker GF. Granular basal cell carcinoma. J Cutan Pathol. 1987;14:37.PubMed
78.
Barnadas MA, Freeman RG. Clear cell basal epithelioma. J Cutan Pathol. 1988;15:1.PubMed
79.
Dixon AY, Lee SH, Mc Gragor DH. Factor predictive of recurrence of basal cell carcinoma. Am J Dermatopathol. 1989;11:222.PubMed
80.
Griffiths RW. Audit of histologically incompletely excised basal cell carcinomas: recommendations for management by re-excision. Br J Plast Surg. 1999;52:24–8.PubMed
81.
Wilson AW, Howsam G, Santhanam V, et al. Surgical management of incompletely excised basal cell carcinomas of the head and neck. Br J Oral Maxillofac Surg. 2004;42:311–4.PubMed
82.
De Silva SP, Dellon AL. Recurrence rate of positive margin basal cell carcinoma: results of a five-year prospective study. J Surg Oncol. 1985;28:72–4.PubMed
83.
Smith V, Walton S. Treatment of facial Basal cell carcinoma: a review. J Skin Cancer. 2011;2011:380371.PubMed
84.
Malhotra R, Wennberg AM, Larko O, Stenquist B. Five-year results of Mohs’ micrographic surgery for aggressive facial basal cell carcinoma in Sweden. Acta Derm Venereol. 1999;79:370–2.
85.
Huilgol SC, Huynh NT, Selva D. The Australian Mohs database, part II: periocular basal cell carcinoma outcome at 5-year follow-up. Ophthalmology. 2004;111:631–6.PubMed
86.
Wennberg M, Lark¨o O, Stenquist B. Five-year results of Mohs’ micrographic surgery for aggressive facial basal cell carcinoma in Sweden. Acta Derm Venereol. 1999;79:370–2.PubMed
87.
Leibovitch SC, Huilgol Selva D, Richards S, Paver R. Basal cell carcinoma treated with Mohs surgery in Australia II. Outcome at 5-year follow-up. J Am Acad Dermatol. 2005;53:452–7.PubMed
88.
Rowe DE, Carroll RJ, Day CL. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992;26(6):976–90.PubMed
89.
Kopf W, Bart RS, Schrager D. Curettage electrodesiccation treatment of basal cell carcinomas. Arch Dermatol. 1977;113:439–43.PubMed
90.
Kuflik EG. Cryosurgery for skin cancer: 30-year experience and cure rates. Dermatol Surg. 2004;30:297–300.PubMed
91.
Rowe DE, Carroll RJ, Day CL. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. Dermatol Surg Oncol. 1989;15:315–28.
92.
Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5 % cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol. 2004;50:722–33.PubMed
93.
Gollnick H, Barona C, Fra RGJ, et al. Recurrence rate of superficial basal cell carcinoma following successful treatment with imiquimod 5 % cream: interim 2-year results from an ongoing 5-year follow-up study in Europe. Eur J Dermatol. 2005;15:374–81.PubMed
94.
Morton CA, McKenna KE, Rhodes LE. Guidelines for topical photodynamic therapy: update. Br J Dermatol. 2008;159:1245–66.PubMed
95.
Testori A, Tosti G, Martinoli C, et al. Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach. Dermatol Ther. 2010;23:651–61.PubMed
96.
Xie J, Aszterbaum M, Zhang X, et al. A role of PDGFRα in basal cell carcinoma proliferation. Proc Natl Acad Sci U S A. 2001;98:9255–9.PubMed
97.
Carneiro BA, Watkin WG, Mehta UK, Brockstein BE. Metastatic basal cell carcinoma: complete response to chemotherapy and associated pure red cell aplasia. Cancer Invest. 2006;24:396–400.PubMed
98.
Binns W, Jame LF, Shupe JL, Everett G. A congenital cyclopian-type malformation in lambs induced by maternal ingestion of a range plant. Veratrum californicum. Am J Vet Res. 1963;24:1164–75.PubMed
99.
Tabs S, Avci O. Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity. Eur J Dermatol. 2004;14:96–102.PubMed
100.
Cooper MK, Porte JA, Young KE. Beachy Teratogen-mediated inhibition of target tissue response to Shh signaling. Science. 1998;280:1603–7.PubMed
101.
Incardona JP, Gaffield W, Kapur RP, Roelink H. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development. 1998;125:3553–62.PubMed
102.
Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002;16:2743–8.PubMed
103.
Chen JK, Taipale J, Cooper MK, et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature. 2000;406:1005–9.PubMed
104.
Van Hoff DD, et al. Efficacy data of GDC-0449, a systemic Hedgehog (Hh) pathway antagonist, in a first-in-human, first-in-class, phase I study with locally advanced, multifocal or metastatic basal cell carcinoma patients. Proceedings of the 99th annual meeting of the American Association for Cancer Research. 2008; abstract LB-138.