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Squamous Cell Carcinoma.

By contrast to basal cell carcinomas, there is no inherited single gene defect associated with squamous cell carcinomas. Thus, most studies of the molecular genetics of squamous cell

carcinoma have examined defects in sporadic tumors and their precursors (actinic keratoses), and the relationships between these defects and sun exposure.[56] The incidence of

mutations in p53 in Caucasian patients with actinic keratoses is high, suggesting that sunlight causes alterations at the early stages of carcinogenesis. [57] However it is not known

whether lesions with p53 mutations are more likely to progress to carcinomas than lesions without the mutation. The immediate effects of UV light on p53 are positive, involving its

induction, resulting in cell-cycle arrest in G1 to permit DNA repair, or elimination by apoptosis of the damaged cells that are beyond repair (see Chapter 7 ). When this protective

function of p53 is lost because of unrepaired UV-induced damage of the gene through production of pyrimidine dimers, [58] continuous division of the mutant cells is favored. Such

mutations are found in some but not all invasive squamous cell carcinomas. Unlike basal cell carcinomas, aneuploidy is very common in squamous cell carcinomas, and loss of

heterozygosity involving chromosomes 3, 9, and 17 occurs in approximately 30% of cases. With the exception of the p53 locus on chromosome 17, putative tumor suppressor genes

localized in the other chromosomes have not been identified.

HPV types 5 and 8, among others (see Chapter 7 ), are involved in the molecular pathogenesis of a rare condition, epidermodysplasia verruciformis, associated with formation of

numerous cutaneous squamous cell carcinomas. A decreased immune response also seems to play a role, since this condition may be found in severely immunosuppressed individuals.

[59]

Melanomas.

It is estimated that 10% to 15% of melanomas arise in a familial setting.[60] This was first observed in families whose members have large numbers of dysplastic nevi. As already

mentioned, some dysplastic nevi develop into melanoma, as in the familial BK mole syndrome, also known

as dysplastic nevus syndrome, familial atypical multiple mole-melanoma syndrome, or simply familial melanoma syndrome (FMS). Unlike NBCCS, which has a clear Mendelian mode

of inheritance, FMS does not display distinct and predictable inherited phenotypic abnormalities.[44] The situation is even more complex because not all familial melanomas develop in

the setting of multiple dysplastic nevi; conversely, melanomas can occur in patients with multiple sporadic dysplastic nevi. To complicate matters, there is no complete agreement about

the histopathologic criteria for the diagnosis of dysplastic nevi. [61] [62] [63]

The main locus associated with familial predisposition to melanomas has been mapped to chromosome 9p21[64] and it encodes p16INK4A (also known as cyclin-dependent kinase

inhibitor 2, or CDNK2). It is frequently deleted in melanomas. [65] [66] As you may recall from the discussions of the cell cycle, lack of functional p16INK4A leads to unrestricted



phosphorylation of RB, release of E2F, and uncontrolled cell growth. p16INK4A is the most commonly mutated gene in

Figure 25-16Model of the hedgehog signaling pathway. PTCH and SMD form a receptor complex that binds Sonic Hedge Hog (SHH). In the absence of SHH, the PTCH protein

prevents SMO from activating signal transduction. Binding of the SHH to the two large extracellular domains of PTCH releases SMO from its association with PTCH and allows

downstream activation of hedgehog target genes via an intracytoplasmic signal cascade and generation of transcription factors, the most notable one being GLI1. Unopposed gene

expression leads to basal cell carcinoma and development of anomalies seen in the nevoid basal cell carcinoma syndrome (NBCCS). Perturbations of this pathway are also important in

sporadic forms of basal cell carcinoma.

Figure 25-17 A, Benign fibrous histiocytoma (dermatofibroma). B, C, On excision, this firm, tan papule on the leg shows a localized nodular proliferation of benign-appearing

fibroblasts within the dermis. Note the characteristic overlying epidermal hyperplasia and the tendency of fibroblasts to surround individual collagen bundles.

Figure 25-18Langerhans cell histiocytosis. A, Lesions may appear clinically as papules and nodules or, as in this case, as erythematous scaling plaques mimicking the infantile form of

seborrheic dermatitis. B, Dermal infiltration by bland mononuclear cells with infolded nuclei presents a nonspecific histologic pattern. C, Immunohistochemical demonstration of CD1a

antigen confirms the origin of these mononuclear cells from Langerhans cells.

Figure 25-19Cutaneous T-cell lymphoma. The histologic correlate of ill-defined, erythematous, often scaling, and occasionally ulcerated plaques (A) is an infiltrate of atypical

lymphocytes that show a tendency to accumulate beneath the epidermal layer (B) and to invade the epidermis as small microabscesses.

Figure 25-20Mastocytosis. A, Solitary mastocytoma in a 1-year-old child. B, By routine histology, numerous ovoid cells with uniform, centrally located nuclei are observed in the

dermis. C, Giemsa staining reveals purple, "metachromatic" granules within the cytoplasm of the cells.

Figure 25-21Ichthyosis. Note prominent fishlike scales (A) and compacted stratum corneum (B).

Figure 25-22Urticaria. Clinically, there are erythematous, edematous, often circular plaques covered by a normal epidermal surface.

Figure 25-23Urticaria. Histologically, there is superficial dermal edema and dilated lymphatic and blood-filled vascular spaces. The edema is manifested by widening of spaces that

separate the collagen bundles.

Figure 25-24Stages of eczema development. A, Initial dermal edema and perivascular infiltration by inflammatory cells is followed within 24 to 48 hours by epidermal spongiosis and

microvesicle formation (B). C, Abnormal scale, including parakeratosis, follows, along with progressive epidermal hyperplasia (D) and hyperkeratosis (E) as the lesion enters into a more

chronic stage.

TABLE 25-4-- Classification of Eczematous Dermatitis


Date: 2016-04-22; view: 936


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