Basal Cell Carcinoma: Pathophysiology

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Basal cell carcinoma (BCC) is the most common skin cancer in humans, which typically ... or the nevoid BCC syndrome (NBCCS) have emphasized on the.

May/June 2014

Volume 12 • Issue 3

Core curriculum Virendra N. Sehgal, MD, Section Editor

Basal Cell Carcinoma: Pathophysiology Virendra N. Sehgal, MD;1 Kingshuk Chatterjee, DNB;1 Deepika Pandhi, MD;2 Ananta Khurana, MD2

Basal cell carcinoma (BCC) is the most common skin cancer in humans, which typically appears over the sun-exposed skin as a slowgrowing, locally invasive lesion that rarely metastasizes. Although the exact etiology of BCC is unknown, there exists a well-established relationship between BCC and the pilo-sebaceous unit, and it is currently thought to originate from pluri-potential cells in the basal layer of the epidermis or the follicle. The patched/hedgehog intracellular signaling pathway plays a central role in both sporadic BCCs and nevoid BCC syndrome (Gorlin syndrome). This pathway is vital for the regulation of cell growth, and differentiation and loss of inhibition of this pathway is associated with development of BCC. The sonic hedgehog protein is the most relevant to BCC; nevertheless, the Patched (PTCH) protein is the ligand-binding component of the hedgehog receptor complex in the cell membrane. The other protein member of the receptor complex, smoothened (SMO), is responsible for transducing hedgehog signaling to downstream genes, leading to abnormal cell proliferation. The importance of this pathway is highlighted by the successful use in advanced forms of BCC of vismodegib, a Food and Drug Administration-approved drug, that selectively inhibits SMO. The UV-specific nucleotide changes in the tumor suppressor genes, TP53 and PTCH, have also been implicated in the development of BCC. (SKINmed. 2014;12:176–181)

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utaneous malignancies may arise either from keratinocytes or adnexal structures. Hair follicles and eccrine, apocrine, and sebaceous glands are its usual sites. They may arise from multiple origins. Skin cancers have been broadly divided into melanoma and nonmelanoma skin cancer (NMSC). NMSC consists of squamous cell carcinoma and basal cell carcinoma (BCC). Among them, BCC accounts for 75% to 90% of skin cancers and has been regarded as the most common human malignancy.1,2 “Ulcus rodens/Jakob”3 was coined for the first time for the entity known as BCC today. “Carcinoma epitheliale adenoides”4 was described in 1900 to define BCC as a malignant, locally invasive, and destructive cancer. Three years after, the term “Basalzellenkrebs”5 was developed, proposing a classification of skin tumors, using histo-genetic principles, emphasizing that the tumor originated in the basal layer of the epidermis or hair follicle; thereafter, many workers6 have proposed different names for the tumor, and the controversy prevails regarding the cellular origin of BCC due to its locally aggressive but overall benign course and rare tendency to metastasize. This has also triggered a debate of whether BCC is truly a malignant tumor or just a “semi-malignant tumor;” nevertheless, the World Health Or-

ganization’s7 classification has retained the term BCC. Significant scientific research has been performed since 1974 to focus on the ultrastructural, biochemical, genetic, molecular, and immunologic undertones to define their role. Accordingly, several mysteries surrounding BCC have been resolved, while a few remain. BCC affects men more commonly than women. Risk Factors The most significant risk factor for BCC to develop appears to be exposure to UV radiation.8 Early exposure during childhood and adolescence is associated with a significant increase in risk of the disease. In general, all NMSCs are more common in persons with fair skin, blond/red hair, and light eye color and those who have Fitzpatrick9 skin types I and II. Apart from that, cumulative occupational exposure for an individual during their lifetime is another important variable that has been recognized in BCC; however, sufficient data with substantial conclusions are lacking in order to incriminate occupational UV exposure in the development of the disease. This subject must continue to be further researched.10

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, and the Department of Dermatology Bankura Sammilani Medical College West Bengal;1 and the Department of Dermatology and STD, University College of Medical Sciences, and Associated Guru Teg Bahadur Hospital, Shahdara,2 Delhi, India Address for Correspondence: Virendra N. Sehgal, MD, DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033, India • E-mail: [email protected]

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According to the available epidemiologic data, predilection for BCC has been noted in childhood, in the age group of 0 to 19 years, in individuals with a history of intense exposure to UV radiation. Lesions most commonly occur on a background of chronic photo-damaged skin. They are typically located over the head and neck region.8 The presence of large numbers of nevi, freckles, and solar elastosis are the other predisposing risk factor(s); however, a history of acne is protective11,12 (Table I).

Table I. Basal Cell Carcinoma: Risk Factors UV radiation Ionizing radiation13 Immunosuppression drugs,14 renal transplantation15 Arsenic16 Psoralen and UV-A radiation17 Genodermatoses

Predisposing Genodermatoses The presence of single/multiple BCC in the absence of any predisposing factor(s), manifesting early in life, should arouse doubt in the clinician about the possibility of heritable disorders. These disorders18 are classified into 3 well-known groups, with oculo-cutaneous albinism19 as another addition (Table II). Pathophysiology Genodermatoses studies have led to major breakthroughs in the understanding of molecular changes that are now being mooted towards the formation of BCC. During the past 80 years, different hypotheses have been proposed to explain the nature and origin of cells of BCC. Histopathologic variability of this tumor has not been in consonance with derivation from any individual epithelial structure. This tumor is generally considered to originate from pluri-potent cells of epidermis, which may explain the propensity of the tumor to differentiate to any of the epithelial structures, under the control of signaling pathways20 and genetic constitution.21

The relevance of recent numerous studies, focusing on the newer insights into the pathogenesis of BCC should be taken into perspective. Embryologically, both the bulge and hair matrix regions of the fetal hair follicle are a rich source for stem cells, the rapidly proliferating cells, more so with their abilities to facilitate molecular signaling between the mesenchymal dermal papillae and the developing hair follicle. This physiologic conversion22 has been found critical in the histo-genesis of BCC. BCC has positively been associated with human leukocyte antigen-DR1 (HLA-DR1) and human leukocyte antigen-DR7 (HLA-DR7), in the immunocompetent population, but substantial evidence is lacking.23 Numerous studies24,25 on the Goltz-Gorlin syndrome or the nevoid BCC syndrome (NBCCS) have emphasized on the role of the hedgehog (Hh) signaling pathway, resulting from a germline mutation of the Patched (PTCH) gene on the chromosome 9q26–3q27, coding a receptor for the Hh pathway.

Table II. Basal Cell Carcinoma: Predisposing Genodermatoses Genetic Syndromes With BCC as a Prominent Feature Gorlin syndrome Bazex–Dupré–Christol syndrome Rombo syndrome Generalized follicular basaloid hamartoma syndrome Happle-Tinschert syndrome

Genetic Syndromes With BCC as an Ancillary Feature Bloom syndrome

Syndromes With Dubious Association With BCC Sturge–Weber syndrome

Werner syndrome

Klippel–Trenaunay syndrome

Rothmund–Thomson syndrome

Wyburn–Mason syndrome

Cowden syndrome Schöpf–Schulz–Passarge syndrome Epidermodysplasia verruciformis Oculo-cutaneous albinism Fitzpatrick9 skin type I and II, IV, V, and VI Hermansky-Pudlak syndrome

Abbreviation: BCC, basal cell carcinoma. SKINmed. 2014;12:176–181

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Recently, PTCH mutations have been identified in sporadic BCCs as well.28 The Hh family consists of a large number of intercellular signaling proteins that play an essential role in patterning invertebrate as well as vertebrate embryos.29 This family of proteins owes its name to the appearance of the mutant fruit fly, with abnormal proteins, simulating a curled-up hedgehog. They were identified, at first, to regulate the segment polarity and tissue organization in Drosophila melanogaster (fruit fly).30 It is now well-established that the Hh pathway has a significant role in human development and cutaneous carcinogenesis. Contrary to fruit flies, vertebrates have evolved 3 different types of homologs for the Hh gene, including the sonic, desert and Indian types. The differences in these 3 types of genes lie in their patterns of expression in different animals. The Hh protein of the vertebrate sonic-type gene (SHH) has two terminals. The Cterminal peptide diffuses from the cell, whereas the N-terminal is associated with the cell surface. PTCH is a membrane receptor that acts as a human tumor suppressor protein. Binding of SHH to PTCH is paramount in activating signals that regulate growth and patterning embryos.31 Another important component of the SHH pathway is a transmembrane protein called smoothened (SMO). It is inhibited by PTCH, in the absence of Hh, blocking the expression of the target genes. This inhibitory effect of PTCH is nullified by the binding of Hh to PTCH. Two types of PTCH genes have been implicated in carcinogenesis. PTCH-1 is crucial for embryonic development, and its germline inactivation has been linked to the development of BCC. For BCC, rather than acting on an individual basis, the PTCH-2 modulates carcinogenesis in association with PTCH-1 haploinsufficiency.32,33 The hedgehog interacting protein (HIP) has recently been identified as a novel component of the vertebrate signaling pathway. It seems to encode a membrane glycoprotein that binds to the SHH protein with an affinity comparable to that of PTCH-1. There are other components of this complex signaling pathway. A simplified model has been described34 (Figure 1), according to which PTCH-1 mutation may lead to aberrant activation of the SHH pathway, with increased target gene activation; however, the precise mechanisms leading to abnormal cell proliferation and differentiation have not yet been elucidated.35 Nevertheless, it is worthwhile to take stock of the plausible sequence of events that activate the pathway to comprehend its intricacies. Two components, namely off-state (first) and activated (second), seem to play a significant role. The former (first) PTCH-1 represses SMO activity. Gli2 and Gli3, the effectors of the Hh pathway, are phosphorylated by a kinase cascade, which includes PKA, CK1, and GSK3β. They are directed to the proteasomal SKINmed. 2014;12:176–181

Figure. The hedgehog (Hh) signaling pathway.

degradation pathway via the SPOP complex. A fraction of the Gli2/3 protein is processed into a repressor form, Gli-R, which inhibits Hh target gene transcription. Whereas the activated (second) Hh ligand binding to PTCH-1 abrogates its inhibitory effect on SMO, allowing SMO to translocate into the primary cilium and induce accumulation of the Gli-Sufu complex at the tip of the primary cilium. Activation of the Hh pathway results in accumulation of Gli-A and initiation of the transcription of Hh target genes such as PTCH1, GLI1, and HHIP 3. Germline mutation of one PTCH-1 gene is seen in NBCCS. Mutations of both the alleles are required. PTCH-1 mutations have been identified in 30% to 40% of sporadic BCCs.36,37 Recently, mutation of the PTCH-2 gene localized on chromosome 1p32.1–32.3 has also been identified in a case of sporadic BCC.38 Studies have shown consistent overexpression of the PTCH-1 mRNA in sporadic BCC by RT-PCR and in situ hybridization methods. PTCH-2 levels are high not only in BCC but also in normal epidermis.39 Mutation of SMO has also been identified in sporadic BCC.40 Several reports41,42 have highlighted an increase in Gli-1 mRNA correlating with the overexpression of PTCH mRNA, as well as Gli-1 protein levels, in sporadic BCC and in the basal layer of epidermis in the tumorigenic regions. Unchanged expression of Gli-2 mRNA in sporadic BCC and unequivocal expression of Gli-3 mRNA levels in normal epidermis and sporadic BCC have also been observed. Activation of SHH target genes expression, including HIP and Wnt, has also been observed in sporadic BCC.43,44 Thus, both PTCH and SMO mutations can trigger overactivation of the SHH pathway and result in the increased expression of the

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downstream target genes via the Gli family of transcriptional factors. Gli-1 activates platelet-derived growth factor receptor-α polypeptide (PDGFRA), which, in turn, upregulates the RASMAPK1/RAS-ERK pathway. Activation of the RAS-MAPK1 pathway causes cell proliferation by inhibiting apoptosis. Increased expression of PDGFRA has been observed in mouse and human models and may be important in BCC pathogenesis.45 Forkhead box (FOX) proteins have also been incriminated in the physiopathology of BCC. These proteins regulate cell proliferation, growth, differentiation, longevity, and transformation. The FOXE1 transcription factor is likely a direct downstream target gene of Gli-2. FOX E1 has been documented to be expressed in human basal keratinocytes and BCC. Also, the 1B isoform of the FOXM1 gene is upregulated in BCC.46 Cadherin-associated protein, beta 1 (CTNNB1), also known as b-catenin, is a nuclear effector of WNT and a downstream mediator of the SHH pathway. CTNNB1 activity increases transcription of genes involved in tumor formation. Among these genes are MYCN and cyclin D1, which contribute to cellular proliferation and matrix meta-llopeptidase 7 (MMP 7), whose gene product may facilitate stromal invasion by tumors. In BCC, however, whether SHH pathway misregulation, WNT pathway upregulation, nuclear CTNNB1 accumulation, and cellular proliferation are mechanistically linked remains a matter of dispute.47,48

The connection between BCC pathogenesis and misregulation of the SHH pathway due to inactivating PTCH1 mutations and activating SMO mutations is well-documented. Upregulation of Hh signaling is the pivotal abnormality in BCC.47 Approximately 90% of sporadic BCCs have loss of function in at least one allele of PTCH-1 and 10% have activating mutations of the downstream SMO protein.48,49,50 The loss-of-function mutation of the PTCH-1 includes germline mutations found in the Gorlin syndrome. With these mutations and dysregulations of the Hh pathway, SMO is active, resulting in continuous target gene activation. The expression of mRNAs from these target genes is increased in BCCs. Mutations of the p53 tumor suppressor gene has been documented in 50% of cases of sporadic BCC.51 Conclusions BCC is the most frequently encountered human malignancy. It seems to emanate from the epidermis, the precise origin of which is still unknown and thus not clearly elucidated. The underlying pathophysiology of this tumor includes an interaction among various proteins involved in cellular proliferation and differentiation. The Hg and PTCH pathways seem to be the clues to help understand the pathophysiology of this malignancy, for which further research is needed. References

Aberrant SHH signaling may also lead to BCC expressing increased levels of antiapoptotic proto-oncogene, BCL2 (B-cell CLL/lymphoma 2). BCL2 is expressed in the basal cell layer of the epidermis and a 2- to 3-fold increase is seen in BCCs. Although a link between SHH misregulation and BCL2 has been suggested, results on BCL2 gene expression in BCCs have been inconsistent.49 The N-myc proto-oncogene (MYCN) is a member of the Myc family of transcriptional activators and a potential downstream effector of the SHH pathway. MYCN upregulation has been associated with BCC. Immunohistochemistry and fluorescence in situ hybridization has depicted increased MYCN production in 73% of 220 BCCs. Aggressive infiltrative BCCs have higher MYCN gene expression than nodular and superficial BCCs.50 RUXN3, a member of the runt-related transcription factor (RUNX) gene family, is a tumor suppressor gene. It is normally expressed in the basal layers of the epidermis. Researchers51 demonstrated that the RUNX3 gene is overexpressed in BCCs, compared with expression in normal epidermis. The Hh pathway is an important regulator of embryologic development and is also involved in carcinogenesis. A proper understanding of this signaling pathway, its aberrant activation and associated molecular components, seems pertinent in the perspective of emerging targeted therapeutic modalities. SKINmed. 2014;12:176–181

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29 Athar M, Tang X, Lee JL, et al. Hedgehog signalling in skin development and cancer. Exp Dermatol. 2006;15:667– 677. 30 Barnes EA, Kong M, Ollendorf V, et al. Patched 1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J. 2001;20:2214–2223. 31 Gailani MR, Ståhle-Bäckdahl M, Leffel DJ, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996;14:78–81. 32 Kim MY, Park HJ, Baek SC, et al. Mutations of the p53 and PTCH gene in basal cell carcinomas: UV mutation signature and strand bias. J Dermatol Sci. 2002;29:1–9. 33 Smyth I, Narag MA, Evans T, et al. Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene in basal cell carcinoma and medulloblastoma on chromosome 1p32. Hum Mol General. 1999;8:291–297. 34 Undén AB, Zaphiropoulos PG, Bruce K. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res. 1997;57:2336–2340. 35 Lam CW, Xie JW, To KF, et al. A frequent activated smoothened mutation in sporadic basal cell carcinoma. Oncogene. 1999;18:833–836. 36 Dahmane N, Lee J, Robins P. Activation of the transcription factor Gli-1 and the Sonic hedgehog signalling pathway in skin tumours. Nature. 1997;389:876–881. 37 Green J, Leigh IM, Poulsom R, et al. Basal cell carcinoma development is associated with induction of the expression of the transcription factor Gli-1. Br J Dermatol. 1998;139:911–915. 38 Tojo M, Kiyosawa H, Iwatsuki K, et al. Expression of a sonic hedgehog signal transducer, hedgehog interacting protein, by human basal cell carcinoma. Br J Dermatol. 2002;146:69–73. 39 Xie J, Murone M, Luoh SM, et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391:90–92.

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41 Teh MT, Wong ST, Neill GW, et al. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res. 2002;62:4773–4780.

25 Murone M, Rosenthal A, De-Sauvage FJ. Hedgehog signal transduction from flies to vertebrates. Exp Cell Res. 1999;253:25–33.

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43 Saldanha G, Fletcher A, Slater DN. Basal cell carcinoma: a dermatopathological and molecular biological update. Br J Dermatol. 2003;148:195–202.

27 Lupi O. Correlations between the Sonic Hedgehog pathway and basal cell carcinoma. Int J Dermatol. 2007;46:1113–1117.

44 Howell BG, Solish N, Lu C, et al. Microarray profiles of human basal cell carcinoma: insights into tumor growth and behavior. J Dermatol Sci. 2005;39:39–51.

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46 Salto-Tellez M, Peh BK, Ito K, et al. RUNX3 protein is overexpressed in human basal cell carcinomas. Oncogene. 2006;25:7646–7649.

49 Xie J, Murone M, Luoh SM et al. Activating smoothened mutations in sporadic basal cell carcinoma. Nature. 1998;391:90–92.

47 Hutchin M. Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev. 2005;19:214–223.

50 Epstein E. Basal cell carcinoma: attack of the hedgehog. Nature. 2008;8:743–754.

48 Gailani MR, Stahle-Backdahl M, Leffell DJ et al. The role of human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996;14:78–81.

51 Ziegler A, Leffell DJ, Kunala S, et al. Mutation hotspots due to sunlight in the p53 gene of nonmelanoma ski cancers. Proc Natl Acad Sci USA. 1993;90:4216– 4220.

Historical Diagnosis and treatment Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of stereoscopic cards published in 1910 by The Stereoscopic Skin Clinic by, Dr S. I. Rainforth.

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