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Molecular Pathology of Skin Neoplasms of the Head and Neck.

While almost all skin cancers can be seen in the head and neck region, certain types, especially the ones linked to a UV-mediated pathogenesis, are more common in the head and neck region. These include common nonmelanoma skin cancers, such as basal cell and squamous cell carcinoma, and certain types of melanoma. In addition, some adnexal neoplasms are also more commonly seen on the head and neck. In the following review, cutaneous neoplasms that show a predilection for the head and neck region, and their molecular alterations, are described.

BASAL CELL CARCINOMA

Epidemiology and Risk Factors

Basal cell carcinoma (BCC) is the most common cancer in white persons. Approximately 80% of the nonmelanoma skin cancers that are diagnosed annually in the United States--estimated at more than 2 million--are BCCs, with the remainder being mostly squamous cell carcinomas (SCCs); thus, their prevalence is approximately equal to that of all other cancers combined, reported at more than 1.5 million. (1-5) Worldwide annual incidence increases of 3% to 10% are estimated. (1) Basal cell carcinoma is slightly more common in men than in women, and sporadic BCC typically occurs after the fourth decade of life. (5-7) It predominantly affects patients with a light skin phenotype, especially with blue eyes, light or red hair, and easy freckling. (1,6)

The skin of the head and neck region is by far the most commonly affected site, with 70% to 80% of all BCCs occurring here. (8,9) This may be due in part to UV exposure, which is the predominant risk factor for BCC. (2,5,10) In contrast to SCC, intermittent strong exposure, such as from recreational activities and starting at a young age, appears to be a more important risk factor than chronic sun exposure. (2,11) Other risk factors include ionizing radiation (eg, in the head and neck area due to treatment of tinea capitis, lymphoma, or port-wine stains) and immunosuppression (transplant patients, hematolymphoid malignancies, human immunodeficiency virus [HIV] infection, and acquired immunodeficiency syndrome). (1,2,7)

Clinical and Histopathologic Features

Basal cell carcinoma can be an indolent or locally aggressive tumor, which, especially in the head and neck region, can cause significant morbidity, for example, due to invasion into cartilage and bone. This can lead to destruction of the nose, or invasion of the eye and nerves, and rarely, invasion into the brain. Overall recurrence rates are estimated to be 1% to 10%, with variation based on subtype and location but, in general, facial BCCs show higher local recurrence rates, especially those around the nose and ears. (12-15) This may be due to difficulty in achieving negative margins in these anatomic locations, and not surprisingly, there is an inverse correlation between distance to margins and recurrence. (16) However, metastases are extremely rare with an estimated 0.0028% to 0.55% frequency overall (reviewed in Gropper et al (17)). In contrast to SCC, there is no precursor lesion.

The main clinical BCC subtypes are nodular, micronodular, superficial, infiltrative (including morpheaform/sclerotic BCC), and fibroepithelioma of Pinkus. These subtypes also have distinct histologic correlates. The most common subtype (with an estimated 60%-75% overall) is the nodular (or nodulocystic) subtype, which is especially common in the head and neck area, with 89.6% of nodular BCCs occurring in this location. (9) Clinically, it presents as a translucent waxy papule with telangiectasias. It sometimes ulcerates, generating typical "rolled" borders. Histologically, this type consists of a nodular arrangement of lobules of tumor cells within a mucin-rich stroma (Figure 1, A). The cells have dark hyperchromatic nuclei with little cytoplasm and show a palisading arrangement in the periphery of the lobules. Often a retraction artifact is seen between tumor nests and stroma. Superficial BCC occurs less commonly in the head and neck area. In one study, (9) 39.9% of superficial BCCs were found in the head and neck region, while 45.9% were found on the trunk. Clinically, it often presents as an erythematous patch, and histologically the tumor lobules are attached to the epidermis with minimal extension into the dermis (Figure 1, B). Infiltrative BCC and its variations, morpheaform and sclerotic BCC, have a predilection for the head and neck region (eg, 94.8% of morpheaform BCCs were found in that region (9)). Clinically, it presents as a pale plaque with a scarlike appearance, and borders are difficult to discern. Histologically, it is composed of small, irregularly shaped narrow nests and strands of tumor cells without prominent palisading and retraction (Figure 1, C). This variant often shows deeply infiltrative growth and perineural invasion, and is associated with higher recurrence rates. (13-15,18) One study (19) found a 26.5% recurrence rate for infiltrative BCC, compared to 6.4% for nodular BCC. Metatypical BCC or basosquamous carcinoma is a controversial entity with different definitions, but overall is probably best described as a variation of infiltrative BCC with squamous differentiation, and is thought to possess greater metastatic potential. (10,20,21) Micronodular BCC shows smaller tumor nests than nodular BCC. Some (19,22,23) have suggested that this variant may behave more aggressively, possibly owing to deeper extension than the other subtypes. Fibroepithelioma of Pinkus is a polypoid variant that most often occurs on the back. In summary, BCCs in the head and neck region more often show an aggressive subtype than in other sites and may also behave more aggressively owing to anatomic limitations in achieving negative margins.

Hereditary Conditions and Molecular Pathology

Basal cell nevus syndrome or nevoid basal cell carcinoma syndrome (BCNS; Gorlin syndrome) is a rare autosomal, dominantly inherited condition with variable expressivity, although 30% to 50% of cases are due to spontaneous mutations. (2,24-27) Early on patients develop BCCs (up to thousands), usually during adolescence but sometimes as early as childhood, which can develop aggressive growth at a later stage. Typically, the BCCs initially develop on the central part of the face, followed by chest, back, and scalp. (26) Most of these patients typically also develop keratocystic odontogenic tumors of the jaw bones, which show destructive growth. Other characteristic findings are palmoplantar pits, cutaneous cysts, skeletal abnormalities, a characteristic coarse facial appearance, and, less commonly, ovarian and cardiac fibromas, medulloblastomas, meningiomas, rhabdomyosarcomas, and mesenteric cysts.

Bazex-Dupre-Christol syndrome is a rare genodermatosis with X-linked dominant inheritance, in which patients also develop BCCs from early in life, typically in the second to third decade. (28-31) Basal cell carcinomas occur especially on the face. Other adnexal lesions, such as basaloid follicular hamartomas and trichoepitheliomas, are also common. Other characteristic findings include follicular atrophoderma, which is characterized by widened follicular ostia forming depressions, especially on the extremities; hypotrichosis; and localized hypohidrosis. Rombo syndrome shows an autosomal dominant inheritance and produces a similar phenotype except that it is associated with vermiculate atrophoderma. The patients show no hypohidrosis. (32,33) Other inherited conditions associated with BCCs are linear unilateral basal cell nevus (34) and xeroderma pigmentosum (see "Squamous Cell Carcinoma").

Basal cell nevus syndrome is associated with mutations of the PTCH1 (patched 1) gene, the human homologue of the Drosophila patched gene, on chromosome band 9q22. (35-37) The protein product PTCH is part of the Hedgehog (HH) signaling pathway, which was originally described in embryonic development, and controls proliferation, differentiation, and apoptosis. PTCH is found in association with smoothened (SMO) within the cell membrane. Upon activation of HH signaling by binding of 1 of the 3 mammalian HH proteins (sonic hedgehog, Indian hedgehog, desert hedgehog) to PTCH, SMO is released and then activates interacting proteins such as suppressor of fused (SUFU), ultimately leading to activation of Gli (Gli family zinc finger) transcription factors Glil, Gli2, and Gli3, whose function is controlled by phosphorylation and proteolytic degradation (Figure 2). (2,38,39) Gli transcription factors then induce cell activation and proliferation through a variety of target genes, including Gli itself, transforming growth factor b, the antiapoptotic B-cell lymphoma 2 (Bcl-2) protein, or the platelet-derived growth factor receptor. (2,10)

Many different PTCH1 mutations (deletions, insertions, splice site alterations, nonsense or missense mutations) have been described in BCNS, but most often they lead to premature protein truncations. (40,41) These mutations render PTCH incapable of suppressing SMO. Thus, PTCH1 functions as a tumor suppressor gene. PTCH1 mutations appear randomly distributed throughout the gene without a distinct hot spot, although clustering is seen in the regions coding for the 2 large extracellular loops and the large intracellular loop. (40,42) Different types of mutations do not appear to correlate with the phenotype, that is, number and onset of BCCs. (41,43)

The yet-unidentified gene for Bazex-Dupre-Christol syndrome has been localized to chromosome region Xq24-27 30 and has very recently been narrowed to an 11.4-Mb interval on Xq25-27.1. (44) The underlying genetic defect in Rombo syndrome is still unknown.

Molecular Pathology of Sporadic BCCs

It is now clear that upregulated HH signaling is the most important molecular aberration also in sporadic BCC, and elevated Gli transcription factor activity, either due to PTCH1 inactivation or SMO activation, appears to be sufficient for carcinogenesis. (2,45,46) While earlier studies suggested lower numbers, (47,48) it appears that 67% to 90% of sporadic BCCs show mutations or loss of one or both PTCH1 alleles and 10% to 20% show mutations in SMO. (1,2,49-51) Most commonly, point mutations leading to a truncated protein and loss of heterozygosity (LOH) at 9q (which harbors PTCH1) are observed. (42,49,50,52) Absent or truncated PTCH1 protein is then unable to suppress SMO, leading to constitutively active HH signaling (Figure 2). SMO mutations render the molecule resistant to PTCH1 inactivation (Figure 2). (2,51) As a consequence of increased HH signaling, the transcription factor Gli1, which otherwise is found in the hair follicle, is often overexpressed in sporadic BCCs. (53) In addition to these truncating mutations, a Pro/Pro polymorphism in PTCH1 may be a risk factor for the development of more aggressive BCCs. (54,55)

Regarding the downstream consequences of upregulated HH signaling, Gli2 has been shown to induce G1-S cell cycle progression. (56) HH signaling has also been implicated in G2-M progression. (57,58) Candidate target genes for Gli transcription factors encode Gli itself (in a positive feedback loop), (59) PTCH1 (in a negative feedback loop), platelet-derived growth factor receptor, antiapoptotic Bcl-2, (56) proapoptotic CD95/FasL (which is negatively regulated by Gli), transforming growth factor [beta], and forkhead box protein E1 and forkhead box protein M1 transcription factors (the latter has been shown to cause more aggressive behavior in other tumors) (58) (also see Epstein (2) for overview). In addition, there appears to be synergism with phosphoinositide-3 kinase/Akt signaling and Wnt (Wingless and INT-1) signaling, (2,60) which is also supported by the observation of upregulated [beta]-catenin levels in sporadic BCCs. (61,62) Epidermal growth factor receptor-derived signals may also play a supportive role. (63)

The pivotal role of HH signaling in BCC pathogenesis has been supported by mouse models with genetic inactivation of various HH signaling components. For example, mice overexpressing sonic hedgehog, SMO with activating mutations, and Gli1 or Gli2, as well as mice with absent expression of PTCH1 (PTCH mice, which then develop a deletion at the wild-type allele), develop BCCs. (2,51,64-67) Interestingly, UV and ionizing radiation enhance growth and number of BCCs, as does p53 deletion. (2,64)

p53 overexpression is seen in BCC, especially in aggressive variants. (10) Forty percent to 65% of sporadic BCCs show mutations of the TP53 tumor suppressor gene, often with a "UV signature" that is comparable to the mutations seen in SCC (ie, dipyrimidine sites with a "CC" to "TT" or "C" to "T" mutation), underscoring the role of UV damage in BCC pathogenesis. (49,68,69) In contrast to other cancers, allelic loss of TP53 is rare in BCC. Biallelic point mutations are seen in 45% of cases. (69,70) TP53 mutations are also seen in p53-over-expressing clones in noncancerous skin of patients with BCC and SCC, which may represent an early precursor lesion at a molecular level. (70,71) Basal cell carcinomas are often morphologically heterogeneous (eg, infiltrative BCC arising in an otherwise nodular BCC). Interestingly, the histologically different areas within a BCC typically show a common TP53 mutation, but then form subclones with different additional TP53 mutations. (70) In addition, mouse models have shown that TP53 loss contributes to HH-induced tumorigenesis. (2,72) Interestingly, PTCH1 and SMO mutations are also most commonly UV-signature mutations. (58)

Molecular alterations in the tumor suppressors [p14.sup.ARF] (p14 alternate reading frame) and [p16.sup.INK4a] at the CDKN2A (cyclin-dependent kinase inhibitor 2A) locus have also been reported, but appear to occur only in a small fraction of BCCs. (73,74) Despite the higher risk for BCC in patients with xeroderma pigmentosum (XP), the role of DNA repair defects in sporadic BCC remains controversial. (2) Basal cell carcinoma, especially the less aggressive variants, shows less genomic instability than many other tumors, possibly contributing to its low propensity to metastasize. (2,10)

Melanin pigment forms small crescents overlying the nuclei of keratinocytes, especially in the basal layer, protecting them from the damaging effects of UV radiation. Melanocortin-1 receptor (MC1R) is highly polymorphic in white persons. Binding of [alpha]-melanocyte-stimulating hormone ([alpha]-MSH) to this receptor leads to production of photoprotective eumelanin ("brown/black" melanin) through cyclic adenosine monophosphate and microphthalmia transcription factor (MiTF). Certain defective MC1R variants are associated with a phenotype that shows red hair, fair skin, and predominance of nonphotoprotective pheomelanin ("red/yellow" melanin). (75,76) Individuals with these MC1R variants show an increased risk of melanoma, SCC, and BCC, even when differences in pigmentation are accounted for. (55,75,77,78) More recently, other determinants of pigmentation such as ASIP (agouti-signaling protein, an [alpha]-MSH antagonist at MC1R) and TYR (tyrosinase) have been identified in white persons, whose variants lead to a mildly increased risk of melanoma and BCC. (79) The same group reported other genetic risk factors for BCC that are not involved in skin pigmentation, such as variants of the keratin 5 and CDKN2A/B genes. (80)

Studies using HH inhibitors for therapy of BCCs have been published or are currently under way, for example, with the topical retinoid tazarotene, the plant alkaloid cyclopamine, and derivatives such as vismodegib (GDC-044), which target SMO. (2,58,81) Vismodegib has recently been shown to be effective in a subset of patients with metastatic or locally advanced BCC in a phase II trial, and in patients with BCNS, although adverse events in the latter study were common. (82,83) It has recently been approved in the United States for the treatment of locally advanced or metastatic BCC. Such novel approaches to treatment underscore the need to develop molecular diagnostics tools to guide therapy for BCC in the future.

SQUAMOUS CELL CARCINOMA

Clinical Features

Cutaneous SCC is the second most common cutaneous malignancy after BCC, representing approximately 20% of the nonmelanoma skin cancers seen annually in the United States, now estimated at more than 2 million. (3,4,84) Squamous cell carcinoma typically occurs in older age groups and is more common in men than in women, and in fair-skinned individuals. (84) The head and neck region is the most commonly affected area, accounting for approximately 65% of all SCCs in lighter-skinned individuals. (1) Certain head and neck regions, such as the ears and lower lip, are more likely to develop SCC than BCC. (85) Often, SCCs in this region behave more aggressively, with SCCs of the central face, ears, lips, and scalp showing an elevated recurrence and metastasis risk. (85) In darker-skinned individuals, only 35% of cutaneous SCC occur in the head and neck region. (86,87)

Chronic UV damage (as opposed to acute intermittent UV damage, which has been implicated in BCC) is the most important etiologic factor for the development of cutaneous SCC and its precursor, actinic keratosis. (84) Thus, cumulative total lifetime exposure to sunlight is directly related to the risk for developing actinic keratoses and SCC. (88) White persons living in areas with higher UV exposure and lower latitude (11) are at increased risk for SCC.

UVB (280-320 nm) exposure, which produces free radicals leading to thymidine dimer formation in DNA, also affects DNA repair and cellular immunity. (89) Immunosuppression is also an important etiologic factor for SCC. For example, transplant patients undergoing immunosuppressive therapy are much more prone to develop cutaneous SCCs (up to 50% develop SCC after long-term therapy), which also behave more aggressively. (90-92) A higher incidence of SCCs, often associated with aggressive behavior, has also been reported in nontransplant patients receiving immunosuppressive therapy and in HIV-infected patients. (93-95)

Other etiologic factors for the development of SCCs are ionizing radiation, chronic inflammatory processes, human papillomavirus (HPV) infection (especially at anogenital sites, but in the setting of epidermodysplasia verruciformis, also in the face), and certain chemicals such as arsenic.

Clinically, SCC often presents as a firm, skin-colored or pink, hyperkeratotic or smooth, often slow-growing nodule or plaque, which can be ulcerated. (84) It often arises in or is associated with actinic keratoses. These are usually less than 1 cm, erythematous, hyperkeratotic, and often appear as multiple lesions, which are commonly seen on sun-exposed skin of fair-skinned, older individuals, especially the head and neck region, but also on hands and forearms. The lifetime risk for progression of actinic keratoses to invasive SCC has been estimated to be 8%. (96) Squamous cell carcinoma in situ often has an "eczematous" clinical appearance with erythematous, often scaly and/or crusted, patches or plaques. Squamous cell carcinoma can also be associated with many inflammatory or other skin lesions. In the head and neck region, acne conglobata, vitiligo, burn scars, or lupus vulgaris (a form of cutaneous tuberculosis) may play a role. (7)

Keratoacanthoma typically occurs at sun-exposed sites, especially on the face, shows rapid growth, and has the potential for spontaneous regression. (84) However, there are reports of some cases that have behaved aggressively. Clinically, it typically appears as a dome-shaped papule or nodule with a craterlike center plugged with keratin.

Histologic Features and Immunohistochemistry

Invasive SCC often shows an epidermal origin with adjacent squamous dysplasia or in situ carcinoma. Well-differentiated SCCs are easily recognizable as such, with nests of eosinophilic, often keratinizing, squamous cells with intercellular bridges (Figure 3). Nuclear atypia can be minimal. Moderately differentiated SCCs show more atypia and mitoses, and keratinization is less pronounced, while poorly differentiated tumors are sometimes difficult to recognize as SCCs owing to absent or very limited keratinization and intercellular bridges. Immunohistochemistry with antibodies against keratins (especially against high-molecular-weight keratins or broad-spectrum anti-keratin antibodies) and p63 can help with the diagnosis of poorly differentiated tumors, although positivity can be focal and sometimes a panel of antibodies needs to be used to demonstrate squamous origin. Spindle cell SCC more commonly is found in sun-exposed areas, such as the head and neck region, and may resemble sarcoma histologically, requiring immunohistochemical confirmation in many cases.

Actinic keratoses are dysplastic lesions that show varying degrees of cytologic atypia in epidermal keratinocytes, with overlying hyperkeratosis or parakeratosis with retained nuclei in the corneal layer (Figure 3). If the dysplastic epithelium encompasses the full thickness of the epidermis, a diagnosis of SCC in situ is made, although both lesions are part of the same spectrum.

Invasive cutaneous SCCs show an overall recurrence risk of 3.7% to 10.9% and a metastasis rate of up to 3.3%. (97,98) Proposed risk factors for metastasis and recurrence are immunosuppression, location, lymph node status, poor differentiation, perineural invasion, and lesions arising in scars, burns, chronic ulcers, and areas of radiation. With regard to location, SCCs of the lip appear to behave more aggressively (as do penile and scrotal SCCs), with recurrence and metastasis rates greater than 10%. (98) Lesions measuring greater than 2 cm have a 3-fold risk of metastasis and a 2-fold risk of recurrence. (88,98) However, depth of invasion and tumor thickness also are important predictors of metastasis. (99) The importance of tumor thickness has been supported by a recent prospective study that included 653 patients during a median follow-up time of 43 months. (100) In this study, multivariate analysis showed that tumor thickness is the most important independent predictive parameter of metastasis with a hazard ratio of 4.79.

Keratoacanthoma histologically shows features of very well-differentiated SCC. In addition, it is characterized by its symmetric and crateriform architecture with the central keratin plug, and cells have a characteristic glassy pale eosinophilic cytoplasm usually with only mild cytologic atypia.

Hereditary Conditions and Molecular Pathology

Xeroderma pigmentosum is an autosomal recessive condition that is characterized by marked photosensitivity with the development of hyperpigmented and hypopigmented lesions, atrophy, xerosis (dry skin), telangiectasia (dilated vessels), and actinic keratoses, especially on sunexposed skin. (101) These patients show a markedly elevated risk (approximately 1000-fold) for the development of skin cancers, including SCC, BCC, and melanoma, which often develop in childhood (median age, 8 years). (102,103) The head and neck region is predominantly affected with 97% of SCCs and BCCs occurring at this site. (103,104) Other manifestations are internal malignancies, and ocular and neurologic, such as due to progressive neurodegeneration in certain subtypes. (102,103,105)

Oculocutaneous albinism is another hereditary condition leading to increased susceptibility for the development of SCCs, BCCs and, rarely, melanoma. (106) In this heterogeneous group of genetic abnormalities there is absence or decreased amounts of melanin pigment in skin, hair, and eyes. Depending on the subtype, patients show diminished skin coloration from brown to completely white. Histologically, normal numbers of melanocytes with a decrease or absence of melanin are seen.

Epidermodysplasia verruciformis is a rare autosomal recessive condition characterized by decreased cell-mediated immunity, which leads to warts induced by a group of HPV types, especially HPV 3, 5, and 8, some of which are often not commonly seen in warts in otherwise healthy individuals. Up to 30% of those patients develop SCCs, especially at sun-exposed sites, such as the forehead and ears, starting in young adulthood. (107) Histologically, the lesions of epidermodysplasia verruciformis show epidermal hyperplasia with hyperkeratosis or parakeratosis and the keratinocytes have a characteristic grey cytoplasm, especially in the granular cell layer. Some lesions display atypia amounting to in situ carcinoma and, ultimately, invasive SCC. However, the histopathologic picture is relatively nonspecific and HPV typing may be helpful in establishing a more definitive diagnosis.

Patients with XP show various defects in DNA nucleotide excision repair mechanisms upon UV-induced damage. (108,109) As mentioned above, UV damage is characterized by the formation of photoproducts such as cyclobutane pyrimidine dimers or pyrimidine(6,4)pyrimidone photoproducts, which may then lead to mutant gene expression, cell transformation, and tumor development. (89) In healthy individuals, the nucleotide excision repair mechanism, which consists of approximately 40 gene products, including endonucleases and exonucleases, leads to removal of a wide range of such lesions. (102) Xeroderma pigmentosum is a heterogeneous disease consisting of at least 7 "complementation groups," as determined by thymidine uptake of fibroblast cultures from patients as a measure of DNA repair activity. These differ in clinical phenotype and severity. The underlying genes for these groups are now known and correspond to different repair genes (XPA to XPG). For example, the XPA group, a common variant that produces a very severe phenotype, is the result of mutations of the XPA gene on 9q34.1. The XPA gene product is a zinc finger protein involved in verification of DNA damage through binding to DNA damaged by photoproduct formation. (110,111) Affected genes in other groups are proteins involved in DNA damage detection (XPC, XPE); DNA helicases, which open damaged DNA (XPB, XPD); or endonucleases involved in excision of damaged DNA sequences (XPF, XPG). (108,109) Approximately 10% to 20% of patients with XP do not show defects of the nucleotide excision repair mechanism. These XP variants show defective bypass replication of damaged DNA, for example, with pyrimidine dimers, due to polymerase g mutations. (112,113)

Oculocutaneous albinism (OCA) is a heterogeneous group of disorders with different defects of melanin synthesis pathways, most often with autosomal recessive inheritance. (106) In the United States, affected individuals are often compound heterozygotes, with a different mutation present in each affected allele. The most common types are OCA types IA and II. In OCA type IA, different mutations (single base, frameshift, missense, nonsense) in the tyrosine gene at 11q14-21 lead to complete absence of its enzymatic activity, essentially shutting down melanin synthesis. (114,115) In type II OCA, tyrosinase activity is unaffected, and mutations in the P gene on 15q11-12 are observed, producing a milder phenotype. (116,117) The function of the P gene is not well characterized, but it appears to be involved in regulation of melanosomal pH and tyrosinase processing and transport. (118,119) Melanocortin-1 receptor mutations appear to have a modifying effect on type II OCA phenotype. (120) Mutations in the TYRP1 gene, which encodes tyrosinase-related protein-1, and is involved in eumelanin production, are seen in type III OCA. (121) Syndromic forms of albinism such as Chediak-Higashi syndrome or Griscelli syndrome show different genetic defects (for an overview see Scheinfeld (122)).

The underlying genetic defect for Epidermodysplasia verruciformis is not yet well characterized. Susceptibility loci at 2p21-24 and 17q25 have been described, with 2 candidate genes adjacent to 17q25 (EVER1/TMC6 and EVER2/TMC8), which are predicted to code for integral membrane proteins in the endoplasmic reticulum. (123,124)

Molecular Pathology of Sporadic SCCs

The TP53 gene is a critical tumor suppressor gene that regulates cell cycle progression, DNA repair, and apoptotic cell death. (125,126) p53 molecules form a tetramer, such that mutated p53 exerts a dominant-negative effect upon oligomerization with wild-type p53. The TP53 gene in cutaneous SCC often shows a characteristic UV signature with "C" to "T" or "CC" to "TT" mutations at dipyrimidine sites. (127-130) These findings have been supported by the observation that p53-deficient mice develop UV-induced SCCs after relatively short UV exposure, underscoring the pivotal role of UV-induced damage in the development of cutaneous SCC. (131) Other UV-induced changes, such as single-strand DNA breaks or formation of purine photoproducts, are also seen. (89)

Interestingly, p53 overexpression (as an indicator of mutated p53) is already seen in actinic keratoses and clinically nonlesional sun-damaged skin, suggesting that p53 alterations are early events in carcinogenesis, and that there is a field effect with molecular abnormalities in surrounding sun-damaged skin. (130,132,133) Upon chronic UV exposure, these clones of p53 mutant cells are believed to expand owing to their selective proliferative advantage and resistance to apoptosis when compared to surrounding normal keratinocytes. (134-136)

Clonal chromosomal abnormalities and LOH at 9p, 9q, 13q, 17p, and 17q are seen in early lesions such as actinic keratoses. (137) In addition, activating UV-induced mutations at codons 12, 13, and 61 of the HRAS (Harvey rat sarcoma) and KRAS (Kirsten rat sarcoma) proto-oncogenes, as well as alterations in MYC, have been reported in cutaneous SCC and UV-irradiated keratinocytes. (138-143) More recent data have estimated that RAS mutations occur in 21% of SCCs, with HRAS mutations being the most common, followed by NRAS (neuroblastoma ras viral oncogene homolog) and KRAS. (144) HRAS mutations are also commonly seen in patients with SCC developing upon BRAF (v-raf murine sarcoma viral oncogene homolog B1) inhibitor therapy in melanoma. (145)

In addition, increased levels or activation of epidermal growth factor receptor, Src (sarcoma) family tyrosine kinases, v-myc myelocytomatosis viral oncogene homolog (Myc), and activating transcription factor 1 have been seen as early as in actinic keratosis. (146) There is more evidence for dysregulation of intracellular tyrosine and serine-threonine kinases in SCC. Src family kinases, such as Fyn, often show elevated expression levels, along with decreased expression levels of their negative regulator Srcasm in SCC. (146,147) Protein kinase C8 expression, a mediator of UV-induced apoptosis, is downregulated in SCC.

As mentioned above, cutaneous SCC is often found associated with actinic keratoses. Interestingly, LOH at CDKN2A, encoding the tumor suppressors [p16.sup.INK4a] (a cyclin-dependent kinase inhibitor) and [p14.sup.ARF] (a p53 activator), is rarely seen in actinic keratosis but more commonly in invasive SCC, suggesting a role in tumor progression. (148,149) Mutation and decreased levels of I[kappa]B kinase [alpha], an important upstream regulator of the nuclear factor [kappa]B (NF-[kappa]B) transcription factor, have been observed in SCC, suggesting it can act as a tumor suppressor in this context. (150) In addition, sun sensitivity, as determined largely by skin pigmentation through MC1R polymorphisms, is a major determinant of an individual's risk for the development of SCC. (75) Sun sensitivity, as measured by skin cancer rates, differs more than 100-fold between individuals with different degrees of skin pigmentation.

Despite intensive research, no major recurrent driver mutations have yet been defined in SCC. A recent study (151) suggests a role for NOTCH1 and NOTCH2 mutations. The Notch signaling pathway regulates many aspects of development and tissue renewal. Ligand binding to the extracellular domain of Notch on the cell surface induces a series of cleavage events, which ultimately lead to nuclear translocation of the intracellular domain of Notch. Notch then forms a transcriptional activation complex with additional molecules such as RBPJ/CSL and coactivators of the mastermind-like (MAML) family. (152) Activating Notch mutations have been found in certain hematologic malignancies, but increasing evidence points toward a role for Notch as a tumor suppressor in SCC. (153-155) Recently, NOTCH mutations (many of them predicted to be inactivating or truncating) were found in a subset of SCCs at mucosal head and neck sites. (156,157) Shortly thereafter, truncating or inactivating NOTCH1 or NOTCH2 mutations were also found in most cutaneous SCCs (as well as a subset of lung SCCs), suggesting a similar tumor suppressor role for Notch in these neoplasms. (151)

Keratoacanthoma is a clonal neoplasm that can show complex cytogenetic abnormalities such as trisomy 7; gains on 8q, 1p, and 9q; and losses at 3p, 9p, 19p, and 19q. (158,159) However, when compared to conventional SCC, genomic aberrations appear to be less common in keratoacanthoma (37.1% versus 83.7%). While loss of 9p was seen more frequently in a recent study, (160) loss of 4p and gains of 1p, 14q, 16q, and 20q were more frequently seen in conventional SCC.

ATYPICAL FIBROXANTHOMA

Clinical Features

Atypical fibroxanthoma (AFX) is a rare neoplasm that shows worrisome clinical and histologic features, but typically carries a good prognosis. (161-164) It has a relatively low tendency for local recurrence (approximately 5%-10%), and metastases occur only in exceptional cases, although questions about proper classification of metastatic lesions remain. (163,165-168) It presents on sun-damaged skin of the elderly with a male predominance and a mean age above 70 years, most often in the head and neck region, as a fast-growing, small papule or nodule. (161,163)

Histologic Features

Histologically, it is limited to the dermis without significant subcutaneous extension and is often polypoid with an epidermal collarette. The features are reminiscent of a pleomorphic sarcoma with a mixture of spindle, epithelioid, and giant cells, which show marked pleomorphism, often with bizarre forms, prominent nuclear atypia, and high mitotic activity, including atypical mitoses (Figure 5). However, lymphovascular or perineural invasion, deep subcutaneous extension, and necrosis are not seen. If present in a lesion with features of AFX, these indicate more aggressive behavior with increased likelihood of local recurrence or metastasis, according to a recent series. (169) Thus, lesions that exhibit these features with an otherwise AFX-like morphology are best termed pleomorphic dermal sarcoma. (169) Occasionally, AFX can be composed of less atypical-appearing, somewhat monomorphic spindle cells. Typically, the surrounding skin shows pronounced actinic changes with solar elastosis, telangiectasia, and sometimes actinic keratoses.

It is likely that this neoplasm is derived from a fibroblastic or myofibroblastic lineage. There are no specific positive immunohistochemical markers to identify AFX; thus, the diagnosis is one of exclusion. Staining with CD68 and CD10 is often positive, but these markers are not specific. A panel of immunostains with antibodies against cytokeratins, smooth muscle, and melanocytic antigens should be performed to rule out SCC (especially of the spindle-cell type), sarcoma, and melanoma, all of which carry a significantly worse prognosis. Recently, p63 has been proposed as an additional marker to rule out SCC, since spindle cell SCC often shows only focal and/or weak positivity for select keratins. In 2 studies, (170,171) spindle cell SCC was found to be positive for p63, while AFX was negative in 1 study with 2 cases positive in the other study.

Molecular Pathology

Atypical fibroxanthoma is thought to be a predominantly UV-induced tumor, although irradiation and immunosuppression, for example, in organ transplant patients, are also thought to play a role. (163) The predominant role of UV-induced damage in the development of AFX is supported by the observation of UV-induced photoproducts and p53 mutations with the characteristic UV signature ("C to T" transitions), and also "C to G" transitions, at dipyrimidine sites. (172,173) The presence of AFX in children with xeroderma pigmentosum, a condition characterized by deficient nucleotide excision repair and UV-induced tumors early in life (see "Squamous Cell Carcinoma" section), further supports a UV-induced pathogenesis. (174-176) Interestingly, mutations in HRAS, KRAS, and NRAS proto-oncogenes were not seen in AFX, when compared to so-called malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma). (173) Comparative genomic hybridization showed that copy number losses at 9p and 13q are commonly seen in approximately half of undifferentiated pleomorphic sarcomas and AFX alike, while other alterations, such as gains at 4q, 5p, 7q, 11p, and 12p, are only seen in undifferentiated pleomorphic sarcoma, with gains being unusual in AFX (only 9p gains were seen). (177) These findings suggest at least a partially different molecular pathogenesis between those entities.

MERKEL CELL CARCINOMA Background

Merkel cell carcinoma (MCC; neuroendocrine carcinoma of the skin) is a rare tumor, but its incidence has rapidly increased in recent decades from 0.15 per 100 000 in 1986 to 0.44 per 100 000 in 2001. (178) It predominantly affects white patients older than 50 years with a mean age between 70 and 76 years. (179-181) Most commonly, it affects the sun-damaged skin of the head and neck region (approximately 50% of cases), followed by the extremities. (179-182) It presents as a firm, rapidly growing, usually rather small, red/pink and sometimes violaceous nodule (often less than 2 cm) with no specific clinical features. (180,182,183) The prognosis is poor owing to a high rate of regional lymph node and distant metastases. However, recent Surveillance, Epidemiology and End Results (SEER) data (179,184) suggest a modest improvement in survival, with 10-year relative survival of 64.8% in women and 50.5% in men. While localized disease carries 5-year survival rates in the 67% to 81% range, patients with regional lymph node metastases show survival rates of approximately 50%, and patients with distant metastases show rates in the 10% to 20% range. (179,184)

Histologically, MCC is predominantly based in the dermis, with some tumors showing a subcutaneous and intraepidermal component (Figure 6, A). Cytologically, it is a "small round blue cell tumor" whose cells have a high nuclear to cytoplasmic ratio, large basophilic nuclei with fine chromatin, and high mitotic activity (Figure 6, B). The cells predominantly grow in sheets or nodules, with some tumors showing a trabecular pattern. Often lymphovascular invasion is seen, consistent with MCC's high propensity to cause early lymph node metastases (Figure 6, C). Tumor thickness may correlate with outcome. (185)

The tumor cells show ultrastructural features of Merkel cells. (186,187) Merkel cells are believed to be of neuroendocrine origin and act as epidermal mechanoreceptors. (188) However, it is currently not clear if MCC is derived from epidermal Merkel cells or, alternatively, is a tumor with neuroendocrine differentiation that is derived from a common epidermal stem cell precursor. (189) Positivity for cytokeratin 20, which also is present in normal Merkel cells, is the most important diagnostic immunohistochemical marker for MCC. (190) Cytokeratin immunoreactivity is found in a "perinuclear dotlike" pattern, as seen in many neuroendocrine neoplasms (Figure 6, D). Merkel cell carcinoma often stains positively for neurofilament protein and the neuroendocrine markers chromogranin and synaptophysin. (191) In some cases it is important to perform immunostaining with thyroid transcription factor 1 to rule out a metastatic visceral small cell carcinoma, which is often positive in this entity and negative in MCC (as is cytokeratin 7 in most, but not all, cases). S100 immunostaining can be performed to rule out melanoma and, if necessary, CD99, to rule out Ewing sarcoma/peripheral neuroectodermal tumor in which it shows strong membranous reactivity. p63 expression portends a poor prognosis. (192)

Molecular Pathology

The development of MCC is associated with UV irradiation, immunosuppression, and Merkel cell polyomavirus integration, with a significantly elevated risk in patients with organ transplants, patients with chronic lymphocytic leukemia, and patients with HIV infection. (193-197) UV-associated mutations in the TP53 tumor suppressor gene are commonly seen. (198) Multiple chromosomal abnormalities such as trisomy 6, LOH at chromosome 13, and deletions and insertions of chromosome band 1p36 have been reported. (199-202) 1p36 deletion is seen in other neuroendocrine tumors and melanoma, suggesting a neural crest origin of MCC. More recently, array comparative genomic hybridization has shown a complex pattern of gains and losses, with deletions at 5q12-21 and 13q14-21 and a focal amplification at 1p34 present in 39% of MCC, that contain the MYCL1 proto-oncogene, which encodes LMyc. (203) Less genomic aberrations correlated with improved survival in this study. While mutations in the CDKN2A gene encoding the [p16.sup.INK4a] and [p14.sup.ARF] tumor suppressors are rare in MCC, promoter hypermethylation, and thus silencing of [p14.sup.ARF] expression (and less commonly [p16.sup.INK4a]), may play a role in MCC. (204)

Merkel cell carcinoma tumor cells express the c-Kit/ CD117 transmembrane receptor tyrosine kinase. (205) However, only silent or intronic, but no activating, KIT gene mutations were found in subsequent studies. (206-208) Along with those observations, an initial trial with imatinib (which targets c-Kit) proved that this drug is ineffective in MCC. (209) High c-Kit expression was recently proposed to represent an adverse prognostic factor. (206)

Alterations in the Wnt/[beta]-catenin and Ras-Raf-Erk pathways likely play no major role in MCC. (210-212) While LOH of the PTEN (phosphatase and tensin homologue) tumor suppressor gene was found in a fraction of MCCs, mutations appear to be uncommon. (213) Recent studies (214) showed that the phosphoinositide-3 kinase (PI3K)/Akt pathway, which is negatively regulated by PTEN, is activated in most MCCs. However, PI3KCA mutations were found only in a small fraction of tumors. (214,215)

Polyomaviruses, such as the SV40, BK, or JC viruses, are small double-stranded DNA viruses that have long been known to cause cancers in animal models, but their role in human carcinogenesis is not proven. Recently, clonal integration of a novel 5387-bp polyomavirus termed Merkel cell polyomavirus (MCV) was demonstrated in MCC. (194) It is still not entirely clear if it plays a causal role in tumor development. While a fusion gene of the viral large T region sequence with the human receptor tyrosine phosphatase gene PTPRG, which is supposed to act as a tumor suppressor, has lead to detection of MCV, viral DNA is randomly inserted in the genome, arguing against a causal role of this specific fusion gene. Thus, it is unclear if a role in tumor development may be due to insertional mutagenesis or due to expression of its oncoprotein, the viral large T antigen, or both. Viral T antigens transform cells by binding to tumor suppressor gene products such as p53 and Rb, and cell cycle regulatory proteins, and are involved in viral replication through their helicase/adenosine triphosphatase activity. Interestingly, inactivating mutations of the large T sequences, rendering the virus replication inactive owing to premature truncation of the transcript (but leaving a potentially transforming Rb-interacting domain intact), were found selectively in clonally integrated viruses, arguing against a secondary infection of preexisting tumors. (216)

Subsequent studies found that MCV is present in up to 88% of MCCs from European and North American patients. (217-219) However, a small fraction of other skin tumors, such as SCC, BCC, Kaposi sarcoma, or cutaneous lymphomas, are also positive for MCV. (220-223) Initial studies (224) suggest that virus-positive MCC occurs more often on the extremities, less frequently presents with nodal metastases, and is associated with a better survival rate. Virus-positive tumors were also found to show fewer genomic deletions, along with better survival, in another small series. (203) However, currently there is no consensus as to whether virus-positive tumors carry an overall better prognosis. (192,225-228)

ADNEXAL NEOPLASMS

The following selected adnexal neoplasms often occur in the head and neck region and show interesting molecular genetic findings as well as associated hereditary conditions (summarized in Table 1). Typically, they have rare malignant counterparts, which sometimes cannot be easily separated from the benign entities, and therefore are included in the discussion of the benign conditions.

Trichilemmal Neoplasms

Background.--Trichilemmoma.--Trichilemmoma is a tumor with hair follicle differentiation that can be solitary or multiple (the latter can be associated with Cowden disease and is discussed under "Hereditary Conditions" below). Solitary trichilemmoma typically presents as a single, small, skin-colored papule, either with a smooth or verrucous surface, most commonly seen on the face of older individuals. (229,230) The most common sites are the nose and eyelid, and it can also be found associated with a nevus sebaceous. (231,232) Histologically, it resembles the outer root sheath of the hair follicle with lobules of small uniform cells with regular round to oval small nuclei that appear to arise from the epidermis or hair follicles (Figure 7, A). The cytoplasm often appears clear owing to glycogen accumulation (Figure 7, B). In the periphery of the lobule, the cells show nuclear palisading and are bordered by a hyalinized rim. Hyperkeratosis and parakeratosis of the epidermal surface is typically seen. Sometimes, there can be pronounced keratinization and squamous eddy formation, resembling an irritated seborrheic keratosis, or marked verrucous changes, mimicking verruca vulgaris. Desmoplastic trichilemmoma is a variant that is not associated with Cowden disease. It shows irregular extensions of epithelial nests within a central sclerotic stroma, which can sometimes lead to problems distinguishing it from an invasive carcinoma.

Trichilemmal Carcinoma.--Trichilemmal carcinoma is rare and is also found on sun-exposed skin, especially head and neck sites. (233-235) Despite being locally aggressive, it generally shows a relatively benign course. Invasive trichilemmal carcinoma typically shows a pushing border. As opposed to trichilemmoma, the clear cells show varying degrees of pleomorphism (variation in cell size and shape), nuclear atypia, and elevated mitotic rate. Trichilemmal keratinization (ie, without a granular cell layer) is usually seen, and often there is peripheral palisading.

Hereditary Conditions.--Cowden disease (multiple hamartoma syndrome) is an autosomal dominant condition with a female predominance, which is characterized by multiple hamartomas in several organ systems. (236,237) It is characterized by a markedly elevated risk for the development of breast adenocarcinoma (men can also be affected), but patients can also develop thyroid carcinomas (most often follicular carcinomas) and other malignancies. (236,238,239) According to most recent data, estimated lifetime risks are 85.2% for breast carcinoma, 35.2% for thyroid carcinoma, 28.2% for endometrial carcinoma, 9.0% for colorectal carcinoma, 33.6% for kidney carcinoma, and 6% for melanoma. (240) Mucocutaneous manifestations are multiple facial trichilemmomas, especially surrounding the nose, mouth, and ears, as well as sclerotic fibromas, acrochordons, punctate keratoses of the palms and soles, acrokeratosis verruciformis, and oral papillomas ("scrotal tongue"). (241-243) Other associations are macrocephaly, Lhermitte-Duclos disease (a hamartomatous overgrowth of cerebellar tissue), thyroid follicular adenomas and goiter, fibrocystic breast disease, ovarian cysts, and colonic polyps. (238)

Histologically, some of the facial hamartomas may show typical features of trichilemmoma, while others may resemble an irritated seborrheic keratosis or a tumor of follicular infundibulum. (237,238,241-245) The dermal fibromas resemble storiform collagenoma with its characteristic whorled growth pattern. (243)

Molecular Pathology.--The PTEN gene on 10q23 shows germline mutations in approximately 80% of patients with Cowden disease. (246-249) PTEN is a tumor suppressor gene involved in apoptosis and cell cycle arrest. (250,251) It is a dual-specificity lipid and protein phosphatase that uses the PI3K product, phosphatidylinositol-3,4,5-triphosphate (PIP3), as a substrate and thus negatively regulates the PI3K/Akt pathway. PIP3 is required for the activation of Akt at the plasma membrane, which is a serine/threonine kinase involved in regulation of cell survival. Independently, PTEN can negatively affect the mitogen-activated protein (MAP) kinase pathway (via the Shc and Gab1 adapters) and focal adhesion kinase through its protein phosphatase activity. More than 150 frameshift, nonsense, and missense mutations have been described, and there appears to be a correlation between the presence of a PTEN mutation and breast carcinoma. (250,252,253) Seventy-six percent of the mutations lead to protein truncation, lack of protein, or a dysfunctional protein. A subset of the 20% of patients with no documented PTEN mutations likely possess loss-of-function mutations of the PTEN promoter sequence or may show inactivation of PTEN through NEDD4 (neural precursor cell expressed developmentally down-regulated protein 4) ubiquitin protein-mediated degradation, or PTEN promoter hypermethylation. (246,254) Differential expression of microRNA's miR-19a and miR-21 may also affect PTEN expression levels in patients with Cowden disease. (255) Approximately 40% of the PTEN mutations occur in the exons coding for the core phosphatase domain and the C-terminal C2 domain, which is responsible for phospholipid binding. (250) In addition, PTEN has recently been shown to exert its tumor suppressor function via ubiquitination and subsequent nuclear import, where it may help to maintain chromosome stability, and mutations have been found in ubiquitination sites in patients with Cowden disease. (256,257) Recently, PI3KCA mutations were described in a subset of patients with Cowden syndrome without PTEN mutations. (258)

In a small study using immunohistochemistry, PTEN loss was observed in most Cowden syndrome-related trichilemmomas, while most sporadic trichilemmomas showed retained expression. (259)

PTEN mutations have also been found in Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome, and it has been proposed that these disorders be classified together as "PTEN hamartoma syndromes." (252,253,260) However, an increased risk of malignancy has been demonstrated only for Cowden disease so far. (246,252)

KILLIN is a tumor suppressor gene and p53 target, which inhibits DNA synthesis through S phase arrest. (261) Interestingly, it is encoded by the PTEN locus and transcribed in the opposite direction; promoter hypermethylation in a fraction of patients with Cowden disease leads to decreased KILLIN gene expression and p53-mediated activation of killin. (262)

Cylindroma

Background.--Cylindroma is a benign tumor of sweat gland derivation and mainly affects females. (263,264) It occurs predominantly in the head and neck region with the scalp being the most common site. Solitary or multiple tumors are typically red or pink small nodules.

Histologically, cylindroma is based in the dermis and consists of multiple tumor lobules of different shapes and sizes, surrounded by a prominent periodic acid-Schiff-positive basement membrane, and arranged in a jigsaw puzzle pattern without epidermal connection (Figure 8). Usually, the cells in the periphery are smaller with a relatively high nuclear to cytoplasmic ratio and dark hyperchromatic nuclei with palisading. They surround larger cells with a paler cytoplasm and vesicular nuclei. Nodular deposits of hyaline material and ductal lumina may also be seen within lobules. Immunopositivity of ductal elements for carcinoembryonic antigen, as well as cytokeratin 7 and epithelial membrane antigen positivity, may aid in diagnosis and is suggestive of eccrine gland derivation, but apocrine derivation has also been proposed. (264-266) Malignant cylindroma very rarely arises in a preexisting benign cylindroma and shows significant potential for recurrence and metastasis. (267,268)

Hereditary Conditions.--Multiple cylindromas (socalled turban tumor) are seen in familial cylindromatosis (Brooke-Spiegler syndrome), which is inherited in an autosomal dominant fashion. (269-272) Typically, tumors start to develop in the second and third decade of life. Patients may also develop facial trichoepitheliomas, eccrine spiradenomas, and milia, with highly variable expressivity. (273-275) Patients may also develop membranous basal cell adenomas ("dermal analogue tumor") of the major salivary glands, which have a similar histologic appearance. (276-278) The development of malignant cylindromas and basal cell adenocarcinomas has been described in patients with cylindromatosis and is more common in tumors from individuals with the inherited condition than in tumors from unaffected individuals. (267,278-281)

Molecular Pathology.--The gene associated with familial cylindromatosis, CYLD1 (cylindromatosis 1), is located on 16q12-13, and is a tumor suppressor gene. (282) Tumors from patients with the syndrome show mutations in CYLD1 , usually associated with LOH or with somatic mutations of the second allele, and LOH and somatic mutations are also seen in sporadic tumors. (283-286) Loss of heterozygosity at 16q12-13 was also described in membranous basal cell adenomas of the parotid gland, (287) and CYLD mutations were found in multiple familial trichoepitheliomas, suggesting that it represents a related condition. (288,289) The mutations are located in the 3' two-thirds of the coding sequence, predominantly resulting in truncation of the protein product, due to a frameshift secondary to small insertions or deletions, creation of stop codons secondary to point mutations, or due to alteration of splice sites. (284,290-292) Somatic mutations were found both in sporadic and familial tumors and result in truncation or deletion of the encoded protein. (284) While a correlation between specific mutations and certain phenotypes has been proposed, (290) such genotype-phenotype correlations have been contested by others. (293)

CYLD1 is a 956-amino acid protein that is widely expressed. (284) It is involved in regulation of the NF-[kappa]B pathway, which is a transcription factor involved in regulation of inflammatory responses and apoptosis upon multiple cellular stimuli, including tumor necrosis factor (TNF) receptor family members. NF-[kappa]B is activated by inhibitor of [kappa]B (I[kappa]B) kinases, followed by degradation of the inhibitory I[kappa]B molecule, which then leads to release and nuclear translocation of NF-[kappa]B. (294,295) It appears that CYLD interacts with NF-[kappa]B essential modulator and TNF receptor-associated factor 2, a regulator of I[kappa]B kinase, and is capable of deubiquitinylation through its C-terminal hydrolase domain, leading to subsequent NF-[kappa]B inhibition. (296,297) In the absence of CYLD expression, NF-[kappa]B activation and decreased apoptosis are observed. (298) This inhibitory activity also results in delayed mitotic entry. (299) CYLD appears to have a negative effect on Jun kinase signaling as well. (300) More recent data point toward a broader negative regulatory effect of CYLD. For example, CYLD suppresses the Wnt/[beta]-catenin pathway through its deubiquitinylating activity. Consequently, cylindromas show hyperactive Wnt signaling. (301) In addition, the N-terminal cytoskeleton-associated protein-glycine-conserved domain of CYLD appears to be involved, together with microtubules and tubulin, in Bcl-3-mediated G1/S phase cell cycle delay and inhibition of cytokinesis in the late stages of mitosis. (302) However, no mutations in the regions coding for this domain have been found in patients with familial cylindromatosis.

Sebaceous Tumors

Background.--Sebaceous adenoma typically presents in older individuals with a female predominance. It is usually a small yellow or slightly pink nodule that is predominantly found in the head and neck region, often the face or scalp. (303,304) Histologically, sebaceous adenoma is a tumor that maintains a lobular architecture with an epidermal connection. Centrally, within the lobules are mature sebaceous cells with foamy pale cytoplasm and central indented nuclei. While these represent more than 50% of the lesion, in the periphery of the lobule basaloid immature cells ("seboblasts") with only small amounts of cytoplasm are found (Figure 9, A).

Sebaceoma is found within a similar demographic group and also most commonly presents in the head and neck region, but is typically larger than sebaceous adenoma. (304-306) Histologically, it consists of multiple dermal nodules or lobules, which often show an epidermal connection and a greater amount of basaloid cells (>50%) than in sebaceous adenoma. Typically, basaloid cells and sebaceous cells are also intermixed and lack the distinct maturation seen in sebaceous adenoma (Figure 9, B). Often, ducts can be appreciated. As opposed to sebaceous carcinoma, significant nuclear pleomorphism and stromal invasion are absent.

Sebaceous carcinoma most commonly presents in a periocular location, with the remainder of cases predominantly found in sebaceous gland-rich regions of the head and neck. (303,307) Periocular sebaceous carcinoma is estimated to represent 1.1% to 5.5% of all eyelid malignancies. It typically arises from the meibomian (tarsal) glands and is more frequently seen in the upper lid. Clinically, it presents as an indistinct slow-growing nodule that is often misdiagnosed as a chalazion or other type of tumor such as BCC. Local recurrence has been reported in 9% to 36% of cases and metastasis in 14% to 25%. (307) Extraocular tumors are erythematous or yellow nodules or plaques that can reach a significant size. Prognosis is comparable to that of periocular lesions. (307,308) Histologically, sebaceous carcinoma often shows invasion into the subcutis and skeletal muscle of the eyelid, and contains a mixture of basaloid cells and more mature-appearing sebaceous cells. Depending on the degree of differentiation, significant pleomorphism, nuclear atypia, necrosis, and atypical mitoses can be present, with only rare mature cells in some cases (Figure 9, C). Periocular lesions typically show intraepidermal pagetoid spread of tumor cells, which is less commonly seen in extraocular tumors.

Hereditary Conditions.--Muir-Torre syndrome is a phenotypic variant of the human nonpolyposis colorectal carcinoma (HNPCC or Lynch) syndrome with mainly autosomal dominant inheritance, found in fewer than 10% of patients with this condition. (309-313) Patients with HNPCC develop internal malignancies, most commonly colorectal carcinomas with a lifetime risk of 80%, but also genitourinary and other visceral malignancies, at an earlier age than patients with sporadic tumors. Colorectal carcinomas are more commonly right sided in these patients, sometimes multiple, and generally carry a better prognosis. (314,315)

The most specific cutaneous finding in patients with Muir-Torre syndrome is sebaceous adenoma, but other sebaceous neoplasms, such as sebaceoma, sebaceous carcinoma, and occasionally also keratoacanthomas, are also seen. (316,317) The cutaneous neoplasms often precede associated internal malignancies, making early diagnosis critical. Sebaceous carcinomas also show an early onset in patients with the syndrome, when compared to patients with sporadic tumors. (318) While sebaceous neoplasms associated with Muir-Torre syndrome show certain suggestive histopathologic features such as "keratoacanthoma-like" changes, potentially a cystic architecture (although there is no agreement between studies here), and are more likely to be found on the trunk and extremities as opposed to a head and neck location, (319-323) molecular analysis is considered the gold standard (see below).

Molecular Pathology.--HNPCC and Muir-Torre syndrome show defects in mismatch-repair genes. (314) Mismatch repair is a process in which errors made by DNA polymerase, which accumulate during DNA replication in the elongation phase, are removed. The most common error is mispairing of nucleotides, but "slippage" of the DNA polymerase complex can also create errors in short repetitive DNA sequences termed microsatellites, which typically are mononucleotide or dinucleotide repeats. (314) Mismatch repair mechanisms correct these errors, but in the setting of deficient mismatch repair, these errors accumulate and create microsatellite instability (MSI). The mismatch repair system consists of human mutS homolog 2 (hMSH2), human mutS homolog 3 (hMSH3), human mutS homolog 6 (hMSH6), human mutL homolog 1 (hMLH1), and human postmeiotic segregation increased 2 (hPMS2) proteins, among others. Initially, a complex of hMSH2 and hMSH3 (or hMSH6) binds directly to the DNA segment containing the error, which then leads to recruitment of a complex of hMLH1 and hPMS2, leading to excision of the DNA sequence. (324,325) Mutations in MLH1 and MSH2 have the most severe effect, producing an "MSI-high phenotype," and are also most commonly observed in patients with HNPCC. (326,327) Accumulation of MSI in growth regulatory and tumor suppressor genes, such as the Bloom syndrome helicase gene, the proapoptotic BAX gene, PTEN, and the E2F4 transcription factor involved in cell cycle control, is then thought to drive tumorigenesis. (328)

Microsatellite instability is also seen in most patients with Muir-Torre syndrome, with the MSH2 locus more commonly affected than the MLH1 locus. (329,330) More recently, cases with loss of hMSH6 have been reported, which appears to be linked to hMSH2 loss. (323,331) Loss of hMSH2 or hMLH1 expression in sebaceous neoplasms, as demonstrated by immunohistochemistry, is suggestive of Muir-Torre syndrome. (323,331-333) The diagnosis can then be confirmed by genomic polymerase chain reaction analysis, in which certain highly unstable MSI markers are assessed for their instability by electrophoretic assessment of size distribution of amplified fragments (Figure 10, A and B). (334-337) In recent studies, (321,323) sebaceous neoplasms associated with mismatch repair deficiency were found to be more common on the extremities and trunk than head and neck, were more often benign, and showed keratoacanthoma-like features, while cystic changes were not found to be associated.

Sporadic sebaceous neoplasms do not show MSI and loss of mismatch repair gene expression. (332,333) In sporadic sebaceous carcinomas, TP53 mutations have been reported (without a UV signature at least in periocular carcinoma), and p53 accumulation is seen by immunohistochemistry in carcinoma, but not in benign sebaceous neoplasms. (338-341) In addition, the cell cycle regulator p21WAF1 is lost in some compartments in sebaceous carcinoma, but not in benign sebaceous neoplasms. (342) In Asian patients, HPV appears to play a role in tumorigenesis. (339,340)

More recent studies (343-345) have also proposed a role for the Wnt/[beta]-catenin pathway and the downstream target lymphoid enhancer binding factor 1 (Lef-1), a transcription factor, in the pathogenesis of sebaceous neoplasms (for details see next section on "Pilomatricoma"). Interestingly, LEF1 mutations were found in benign sebaceous neoplasms, irrespective of MSI status, and were shown to lead to inhibition of [beta]-catenin association and suppression of Wnt/[beta]-catenin target genes, while markers of sebaceous differentiation were upregulated in those tumors, which may explain their differentiated characteristics. (345) Mutations in the fragile histidine triad tumor suppressor gene, a repressor of [beta]-catenin transcriptional activity, have recently been found in sebaceous carcinomas irrespective of MSI status. (346,347)

Pilomatricoma and Pilomatrix Carcinoma

Background.--Pilomatricoma (pilomatrixoma) is a benign tumor of hair matrix differentiation that mainly occurs in young patients, predominantly children, although older patients, especially during late middle age, can be affected as well. (348-351) The most commonly affected site is the head and neck region, especially the cheek and neck. (156,349,351) Typically, it presents as a firm nodule or cyst that is usually less than 3 cm. A low possibility of recurrence was observed after surgical excision in some studies, but not others. (349,351,352) Pilomatricoma can be associated with Gardner syndrome, myotonic dystrophy, or rarely, Turner syndrome and Rubinstein-Taybi syndrome. (348,353-356) Pilomatrix carcinoma is a very rare tumor that usually occurs in the head and neck region in adults. It typically is larger than pilomatricoma and presents more frequently in older males, as opposed to pilomatricoma which shows a female predominance. (350,357,358) Occasionally, a preexisting benign pilomatricoma is found. (359) Metastases are relatively uncommon, but there is a significant potential for recurrence. (350,357,358)

Histologically, pilomatricoma is a well-circumscribed, dermal-based tumor, consisting of multiple lobules, and shows hair matrix differentiation. It consists of peripheral small basaloid cells with a high nuclear to cytoplasmic ratio and round nuclei, and central "ghost" or "shadow" cells with a pink cytoplasm and small pyknotic nuclei, which are lost upon further maturation (Figure 11). The basaloid cells can show striking mitotic activity, especially in early lesions, which on its own is not a feature of malignancy. Calcifications are typically seen in older lesions. Pilomatricoma, especially in adults, may occasionally show additional atypical features, such as atypical mitoses, pleomorphism, and nuclear atypia, which appear to have no clinical significance. (350,360) The presence of additional atypical features, such as large areas of tumor necrosis, infiltrative growth, lymphovascular or perineural invasion, or large tumor size, however, should raise the possibility of pilomatrix carcinoma. (357,361)

Molecular Pathology.--Pilomatricomas exhibit mutations of CTNNB1, which is the gene encoding [beta]-catenin. (362-364) [beta]-Catenin is a 92-kDa molecule involved in cellcell adhesion in adherens junctions, where it links cadherins to the actin cytoskeleton. (365) It is also an essential component of the Wnt signaling pathway. (366,367) The Wnt pathway is a ligand-activated, highly conserved pathway that regulates cell fate during embryogenesis. One of the best-characterized Wnt pathways is the canonical Wnt pathway, which specifically involves [beta]-catenin and regulates cell proliferation, differentiation, and survival. (366,367) It has been found to play a critical role in many malignancies as well as inherited diseases. (366,368) For example, activated Wnt signaling and CTNNB1 mutations have been found in colorectal carcinomas, melanomas, endometrial adenocarcinomas, and hepatocellular carcinomas. (366,367)

In the absence of Wnt, free cytoplasmic [beta]-catenin is rapidly phosphorylated at its N-terminus by the kinases GSK3[beta] (glycogen synthase kinase-3[beta]) and CK1[alpha] (casein kinase-1[alpha]), leading to its ubiquitinylation and proteasomal degradation by a "destruction complex," which is coordinated by the scaffolding protein Axin and also contains the adenomatous polyposis coli tumor suppressor gene product. (366,367,369) In activated Wnt signaling, binding of extracellular secreted Wnt glycoproteins to the Frizzled/LRP (lowdensity-lipoprotein receptor-related protein) receptor complex leads to suppression of [beta]-catenin phosphorylation. This is likely achieved by the recruitment of the scaffolding proteins Axin and Dishevelled (Dsh) to the Wnt receptor complex instead of the kinase-containing destruction complex, and consequently leads to its stabilization through decreased phosphorylation and degradation. (366,368) Accumulating [beta]-catenin then enters the nucleus in a process that involves Rac guanosine triphosphatase (GTPase) and forms a complex with the Lef/Tcf (Lef/T-cell factor) transcription factor, which displaces the Lef-associated corepressors TLE/ Groucho and histone deacetylase and converts Lef from a transcriptional repressor to a transcriptional activator. (366-368,370,371) Lef then activates proto-oncogenes such as

CMYC and CCND1 (cyclin D1). (372,373) This proposed pathogenetic mechanism is illustrated in Figure 12.

Mutations in CTNNB1 are located in the exon 3 region of the gene, which encodes the N-terminal phosphorylation sites. At these sites, missense mutations cause alterations of the serine and threonine phosphorylation sites that are substrates for GSK3, thus leading to [beta]-catenin stabilization through decreased phosphorylation and degradation. (362) Accordingly, strong nuclear and cytoplasmic [beta]-catenin positivity and strong nuclear Lef-1 positivity are seen in basaloid cells in pilomatricoma by immunostaining. (362-364) The [beta]-catenin target cyclin D1 can also be detected by immunohistochemistry in pilomatricoma. (374) Similar mutations and nuclear [beta]-catenin-staining patterns can also be found in pilomatrix carcinomas. (357) The fundamental role of [beta]-catenin in hair follicle morphogenesis and development of pilomatricomas was also shown in mice expressing a stabilized truncated [beta]-catenin transgene. (375)

[beta]-Catenin expression is also found in the emerging hair matrix during human embryogenesis, supporting its role in hair follicle development and also a hair matrix origin for pilomatricoma. (368,376)

Recently, trisomy 18 was found in the basaloid component of pilomatricoma, and it was speculated that genes such as Bcl2, which is located on chromosome 18, may play a role in tumorigenesis. (377)

MELANOMA

Clinical Features

Melanoma comprises an estimated 5% of cancers in men and 4% in women according to 2010 US cancer statistics (which exclude the much more common nonmelanoma skin cancers (3)). The incidence of melanoma has been increasing with annual rates of 3% to 7% during the last decades. (378) Melanoma mainly affects middle-aged adults with a current median age of 61 years in the United States. (379) The age-adjusted incidence rate in the United States was 21.1 per 100 000 between 2006 and 2010. (379) The main environmental risk factor for the development of the more common forms of melanoma appears to be UV exposure, and thus it mainly affects fair-skinned individuals. (380-383) It is also commonly seen in patients with XP. Patients with multiple common nevi and multiple dysplastic nevi are also at increased risk. (383-385) Melanoma shows a slight male predominance, especially in the head and neck region, although overall the most common sites are the back in men and the legs in women. Most commonly, melanoma arises de novo, although a significant proportion (approximately 25%) arise in association with preexisting benign, congenital, or dysplastic nevi. (386,387) Worrisome clinical signs for melanoma are asymmetry, irregular border, dark or variegated pigmentation, a diameter greater than 6 mm, and recent change. (388,389)

The prototypic subtypes of melanoma are superficial spreading, nodular, acral lentiginous, and lentigo maligna melanoma, with lentigo maligna melanoma being relatively more common in the head and neck region. (390,391) Superficial spreading melanoma typically arises on the back or legs, presents as an irregularly pigmented macule or plaque, and is the most common variant. Nodular melanoma also prefers those anatomic sites and presents as an often ulcerated black or blue nodule.

Lentigo maligna melanoma represents approximately 10% of melanomas and typically presents as a slowly enlarging, asymmetric, brown to black macule with irregular pigmentation on sun-exposed skin. (390) It affects an older age group and is related to chronic sun exposure, while the more common types of cutaneous melanoma, such as superficial spreading melanoma, are related to acute intermittent exposure. (391-394) Desmoplastic melanoma is an uncommon form of melanoma, accounting for approximately 1% of all cases, which also affects an older age group with a median age of 66 years, from recent SEER data. (395-397) It occurs in chronically sun-damaged skin, and with 51% of all cases it predominantly affects the head and neck region. (397) While sometimes associated with lentigo maligna, it is often amelanotic and deeply infiltrative.

Recently, epidemiologic analysis led to the proposal of an "early-onset melanoma" category, which is predominantly associated with female sex, superficial spreading melanoma, and a lower extremity location, and a "late-onset melanoma" category, which is predominantly associated with male sex, lentigo maligna melanoma, and a head and neck location. (398) In this model, early and/or intermittent sun exposure may be responsible for early-onset melanomas in more susceptible individuals, and accumulated life-long sun exposure may be responsible for late-onset melanomas in less sensitive individuals.

The overall 5-year relative survival was 91.7% between 2001 and 2007 in the United States. (379) In general, adverse clinical prognostic factors are male sex, older age, ulceration, and location in the head and neck region, especially the scalp, as well as back and upper arms. (399-402) An analysis of SEER data (403) found that patients with melanoma in the head and neck region, when adjusted for other prognostic parameters, were 1.84 times more likely to die from the disease when compared to melanomas arising in other sites. However, the prognosis of lentigo maligna melanoma overall appears to be equal, or slightly better, than that of other melanoma subtypes. (404,405) Desmoplastic melanoma shows increased local recurrence rates, compared to other melanoma subtypes. By contrast, lymph node metastases are less common than in other melanoma subtypes, with fewer than 10% positive sentinel lymph node biopsy results in larger series. (396,397,406,407) Survival is better than for other melanoma types, when adjusted for other prognostic parameters such as thickness. (408-411)

Histologic Features and Immunohistochemistry

Melanoma is a malignant melanocytic neoplasm that can either exist as melanoma in situ with malignant cells being limited to the epidermis, radial growth phase melanoma with limited invasion into the superficial dermis, or vertical growth phase melanoma with tumorigenic invasive growth extending into deeper tissues or the presence of mitotic activity in the invasive component. (412) These are believed to represent sequential steps in tumor progression.

Histopathologic prognostic markers are used for various staging systems such as the TNM system (tumor characteristics, presence and characteristics of nodal metastases, and presence and sites of distant metastases), which forms the basis of the American Joint Committee on Cancer melanoma staging and classification. (413) Briefly, the most important histopathologic criteria for the primary tumor are Breslow tumor thickness, mitotic rate, and ulceration. (413) Other factors are the presence of tumor infiltrating lymphocytes, lymphovascular invasion, microsatellites, and Clark anatomic level of invasion. Tumor thickness (414) remains the most important histologic prognostic factor and is measured from the top of the granular cell layer to the deepest portion of the tumor. From the current classification, patients with T1aN0M0 melanomas (ie, melanomas with <1 mm thickness, no ulceration, and no dermal mitoses) have a 5-year survival rate of 97% and patients with locally advanced T4bN0M0 melanomas (ie, ulcerated melanomas >4 mm thickness) have a 5-year survival rate of 53%. (413) The prognosis for melanoma with distant metastases is very poor.

The histologic profile of superficial spreading melanoma consists of an asymmetric proliferation of uniformly atypical melanocytes that are found at all levels of the epidermis, with single or small aggregates of atypical melanocytes present in the stratum corneum or granulosum ("pagetoid growth"). Typically, the tumor cells both of the in situ and the invasive component are epithelioid with large amounts of cytoplasm, have atypical large vesicular nuclei with prominent nucleoli, and often contain melanin pigment. Nodular melanoma shows an absent or a less-pronounced intraepidermal component, which by definition is limited to maximally 3 epidermal rete ridges lateral to the invasive component.

Lentigo maligna in its pure form does not show pronounced pagetoid spread and consists of a contiguous proliferation of atypical melanocytes located at the lower levels of the epidermis. In contrast to the epithelioid cells with vesicular nuclei that are seen in superficial spreading melanoma, the cells show large angulated hyperchromatic nuclei and often a cytoplasmic retraction artifact (Figure 13, A). Adnexal involvement by atypical melanocytes is typically seen. Histologic signs of chronic sun damage, such as epidermal atrophy with loss of rete ridges and solar elastosis, are often present. While some authors consider that both prototypic lentigo maligna and more advanced lesions with confluent growth, pagetoid spread, and nest formation represent melanoma situ, others distinguish lentigo maligna from lentigo maligna melanoma in situ. (415) The invasive component of lentigo maligna melanoma sometimes shows spindle cells and collagen deposition that can lead to a desmoplastic appearance.

Desmoplastic melanoma is often amelanotic and often consists of a proliferation of only mildly atypical spindle cells in a fibrotic collagenous stroma, which typically invade deeply, reminiscent of a scar or a nonmelanocytic spindle cell neoplasm (Figure 13, B), thus occasionally leading to a wrong diagnosis. Sometimes a grenz zone, devoid of tumor cells, is seen in the papillary dermis. Nodular aggregates of lymphocytes are often seen, particularly at the margins of the tumor. Perineural invasion is a characteristic feature and may be associated with recurrence. Neurotropism, which is defined by some as extensive endoneural and perineural invasion, and as Schwann cell-like differentiation of tumor cells by others, can also be seen. An intraepidermal component may be lacking or, if present, may show features of lentigo maligna. Classical histologic prognostic parameters may not be good predictors of outcome in desmoplastic melanoma, but pure desmoplastic melanomas may have a better prognosis than tumors with a nondesmoplastic component. (407,409)

Melanoma is almost always positive for the immunohistochemical marker S100. However, S100 antibodies also label a broad range of other normal cells, such as Langerhans cells and other types of histiocytes, chondrocytes, or adipocytes, as well as other neoplasms such as schwannomas, neurofibromas, malignant peripheral nerve sheath tumors, and clear cell sarcomas ("melanoma of soft parts"). Carcinomas can occasionally stain with S100 as well. More specific markers that help to differentiate these--apart from clear cell sarcoma, which in difficult cases may require molecular genetic tools--are the melanoma antigens MART-1/Melan-A, the melanosomal glycoprotein HMB-45 (gp100), and microphthalmia transcription factor (MiTF). However, these markers often show negativity in invasive spindle cell and desmoplastic melanomas. Microphthalmia transcription factor also stains fibroblasts, smooth muscle, Schwann cells, and various inflammatory cells, limiting the use of these markers for these types of melanomas. In addition, they usually also stain positively in benign melanocytic lesions. Thus, an accurate differential diagnosis often relies on morphologic features, such as the identification of an in situ component, if present, and the exclusion of other entities through a panel of additional immunohistochemical markers, for example, keratins and p63 for the exclusion of spindle cell squamous cell carcinomas (although melanomas sometimes show keratin reactivity).

Hereditary Conditions

In approximately 10% of cases, melanoma is familial. Twenty percent to 30% of affected patients have mutations in the CDKN2A tumor suppressor gene at 9p21, which encodes [p16.sup.INK4a] and [p14.sup.ARF]. (416-419) As mentioned above, p16 inhibits CDK4, which, together with cyclins, regulates G1-S transition via RB phosphorylation and activation of the EF2 transcription factor. (420) CDKN2A missense mutations associated with familial melanoma render p16 catalytically inactive. (421) Mutations occur in exon 1a (affecting [p16.sup.INK4a] only), in exon 2 (affecting either [p16.sup.INK4a] or [p14.sup.ARF] or both), or in the 50 untranslated region (affecting [p16.sup.INK4a]) and most often are nucleotide exchanges. (422) Mutations that affect both [p16.sup.INK4a] and [p14.sup.ARF] result in the highest risk for development of melanoma, followed by missense mutations affecting [p16.sup.INK4a] only. (423) Typically, melanoma develops at a younger age in these patients, melanomas are sometimes multiple, atypical nevi are often present, and there is an increased risk for pancreatic carcinoma. (416,418) A very small fraction of patients with familial melanoma show mutations in the CDK4 gene itself, rendering CDK4 unable to bind to its inhibitor [p16.sup.INK4a]. (416,418) As mentioned above (see earlier section on "Basal Cell Carcinoma"), melanocortin receptor mutations affect skin pigmentation in white persons, and certain "red hair" variants carry a mildly elevated risk for the development of melanoma. (424)

Molecular Pathology

Ras/Raf/MAPK (mitogen-activated protein [MAP] kinase) Pathway.--The above described CDKN2A germline mutations occur infrequently in patients with sporadic first melanoma (12% as based on a recent study (423)). However, many melanomas show mutations in genes encoding for proteins that are part of the Ras/Raf/MAPK signaling pathway. (425) Overall, up to 80% of all melanomas show either BRAF or NRAS mutations. (426-434) These mutations lead to increased activity of the MAPK pathway. More than half of all melanomas show mutations in the BRAF protooncogene, predominantly a T to A nucleotide transversion leading to a V599E amino acid substitution within the activation segment of the Raf serine/threonine kinase gene product, increasing its catalytic activity and subsequently activating MEK (MAP kinase kinase) and ERK MAP kinases. (427,431,435)

Interestingly, a similar or even higher BRAF mutation frequency has been found in normal nevi, suggesting that additional molecular alterations are necessary for the development of melanoma. (435,436) While nevi show high levels of the [p16.sup.INK4a] tumor suppressor gene product, which may protect from progression toward melanoma by p16-driven cell cycle arrest and senescence, inactivating mutations or deletions of the encoding CDKN2A gene may account for progression in some melanomas. (435,437-439) In addition, alterations in the activation of the PI3K-Akt pathway, which promotes survival and cell cycle entry of melanoma cells, may account for progression to melanoma. Approximately 20% to 40% of melanomas show loss or altered expression of the PTEN tumor suppressor gene, which acts as an upstream inhibitor of the PI3K-Akt pathway. (429,440-442) While inactivating mutations in PTEN were thought to be uncommon, (441,443) more recent data (eg, Hodis et al (444)) show a higher rate. There appears to be a correlation between PTEN and BRAF mutations in melanoma cell lines, suggesting possible synergism between the Ras/ Raf/MAPK and PI3K-Akt pathways. (445) This has been further supported by more recent data. While BRAF V600E expression in melanocytes of mice leads to melanocytic hyperplasia, invasive and metastatic melanoma development requires additional PTEN silencing. (446) Decreased PTEN expression or increased Akt expression is seen in human melanomas associated with nevi, while both nevi and melanomas show BRAF mutations. (447) Possible synergism has also been suggested for BRAF mutations and alterations of the TP53 gene, which leads to invasive melanoma. (448,449) However, p53 is not as commonly mutated in human melanoma when compared to other malignancies. (450)

Melanomas with wild-type BRAF can show mutations in the NRAS proto-oncogene, mainly in codon 61 (approximately 15% of all melanomas (429,431,451-455)). NRAS mutations leave the molecule in its active state, which results in increased signaling via the MAPK pathway mediated through RAF molecules. (428) However, NRAS also activates the PI3K pathway. (456) In addition, a recent study (457) has shown that the NRAS-mutant melanocytes also activate RAC1, a Rho GTPase, leading to increased survival and invasion. Similar to BRAF mutations, NRAS mutations do not appear to be sufficient, requiring additional alterations for malignant transformation. (428,433,458,459) While they can be seen in normal nevi, (435) they are also often seen in congenital nevi. (460)

Interestingly, the BRAF and NRAS mutations seen in melanoma do not carry a UV signature. Melanomas with BRAF mutations are less frequently found in melanomas occurring at sites of chronic sun damage, and more frequently in melanomas occurring in skin with intermittent acute sun damage. (426,432) NRAS-mutated melanoma does not show such a clear pattern, (426) although in some studies NRAS-mutated melanoma was more frequently found on the extremities and in older patients. (452,461,462) The findings on BRAF-mutated melanoma have been further supported by data showing that BRAF mutation-positive melanomas occur in a younger age group (usually younger than 55 years), without prominent sun damage, and more often involve the trunk and lower extremities, and less frequently in chronically sun-exposed areas such as the head and neck. (463,464) With regard to clinical behavior, BRAF mutation-positive melanomas may preferentially metastasize to regional lymph nodes as opposed to other sites.4 (65,466) With regard to prognosis, many studies on primary melanomas exhibiting BRAF and NRAS mutations showed no clear difference, although a recent large prospective study (467) showed significantly decreased survival for all stages for NRAS-driven melanoma, with a trend toward decreased survival in BRAF-driven melanoma. Studies (462,467-470) showed decreased survival for both NRAS- and BRAF-mutated melanoma at advanced stages.

Histologically, BRAF mutation-positive melanomas show nest formation of intraepidermal melanocytes, pagetoid spread of melanocytes, thickening of epidermis, and sharp demarcation. (465,466) As a result, BRAF mutations are often present in superficial spreading melanomas but are relatively rare in acral and lentigo maligna melanomas (426,464) (see also Table 2 for an overview of molecular alterations associated with certain melanoma subtypes). NRAS mutation-positive melanomas do not have very distinct histologic features but tend to have little or absent pagetoid spread. (465,466) Other studies (453,455,462,464,471) have suggested that NRAS mutations are more frequently seen in nodular melanomas. In addition, there is a correlation between increased tumor thickness and NRAS mutation, which mirrors the higher percentage of NRAS mutations in nodular melanoma. (452,461,467) Pure desmoplastic melanomas usually are negative for BRAF mutations, while limited data on NRAS mutations suggest a low frequency. (472-474)

Selective BRAF inhibitors for the treatment of metastatic melanoma exhibiting the BRAF V600E genotype are currently in development, with one compound (vemurafenib/PLX4032) showing promising initial response rates with improved short-term survival (475) and gaining US Food and Drug Administration approval in 2011. However, single-agent therapy may not lead to a prolonged sustained response, and various combination regimens, for example, with BRAF and MEK inhibitors, to overcome resistance mechanisms, are also being tested (see Sullivan and Flaherty (456) for an overview). No direct drugs have been successful against mutated NRAS up to now, (428,456) but some new MEK inhibitors or combination strategies may be effective in a subset of patients. (428)

Recent next-generation sequencing efforts uncovered additional Ras/Raf/MAPK pathway alterations in a subset of melanomas. Eight percent of melanomas showed gain-of-function mutations in the MAP2K1 (encoding MEK1) and MAP2K2 (encoding MEK2) genes, (476) resulting in constitutive activation of downstream ERK MAPK. In addition, 24% of melanomas were found to exhibit MAP3K5 (MAP kinase kinase kinase 5; synonyms: ASK1, MEKK5) and MAP3K9 (MAP kinase kinase kinase 9; synonyms: MlK1, MEKK9) mutations. (477)

KIT.--Lentigo maligna melanoma, which typically arises in chronically sun-damaged skin, shows differences in its molecular pathology, when compared to other subtypes such as superficial spreading or nodular melanoma. As mentioned above, BRAF mutations were less frequently found in melanomas occurring at sites of chronic sun damage (such as lentigo maligna melanoma), and more frequently (81%) in melanomas occurring in skin with intermittent acute sun damage (such as superficial spreading melanoma). (426) Accordingly, 28% of melanomas arising in chronically sun-damaged skin (and comparable fractions of mucosal and acral melanomas) were found to exhibit mutations or amplifications in the KIT gene encoding for the stem cell factor receptor tyrosine kinase. (478) However, another recent study (479) suggested melanomas arising in chronically sun-damaged skin much less commonly show KIT mutations. Upon ligand binding, Kit dimerizes, leading to autophosphorylation and downstream activation of the MAPK, PI3K-Akt, and JAK-STAT (janus kinase-signal transducer and activator of transcription) pathways. (480) Most commonly, mutations affect the region coding for the juxtamembrane domain of the Kit receptor, which lead to its dimerization and constitutive activation in the absence of stem cell factor, (481) creating a target for the imatinib tyrosine kinase inhibitor and other comparable agents. (482-484) While initial trials did not show a benefit in melanoma overall, newer trials involving patients with melanomas harboring KIT alterations show some promise for response to these targeted agents. (480,485-487) In addition, melanomas arising in chronically sun-damaged skin in the absence of BRAF or NRAS mutations more often show increased copy numbers of CDK4 and CCND1 (which encodes cyclin D1 at 11q13), which are downstream effectors of the Ras-Raf-MAPK pathway. (426)

Other Molecular Alterations.--Interestingly, lentigo maligna melanoma, together with melanomas occurring on chronic sun-damaged skin in general (as evidenced by solar elastosis and a head and neck location), shows a higher rate of p53 expression than melanomas arising in patients with a high nevus density or melanomas directly associated with nevi (which more commonly are superficial spreading melanomas), also supporting a different pathogenesis. (488)

Uveal melanomas do not show BRAF or NRAS alterations. Approximately 50% exhibit mutations in GNAQ (guanine nucleotide-binding protein Q polypeptide) or GNA11 (guanine nucleotide-binding protein a 11), which link G protein-coupled receptors to the MAPK and other signaling pathways. (480,489,490)

Micropthalmia-associated transcription factor regulates the differentiation of melanocytes and the maintenance of their progenitor cells. (491-493) Despite this role in differentiation and cell cycle arrest, the finding of increased copy numbers of MITF in an aggressive subset of melanomas suggests that it may also function as an oncogene, possibly in conjunction with BRAF mutation and p16 inactivation. (383,494) Melastatin (TRPM1), which is lost in a subset of melanomas with poor prognosis, is controlled by MITF. (383,495,496) Recently, it has been proposed that the tumor suppressive activity is not mediated by melastatin itself but rather by a microRNA (miR-211) hosted within an intron of melastatin. (497)

Several recent studies involving next-generation sequencing techniques have identified multiple additional recurrently mutated somatic genes. (444,476,498-501) Most of these studies show that the majority of mutated genes carry a UV signature, with more of these mutations seen in melanomas with chronic sun exposure, although it is difficult to exclude that many may represent UV-induced passenger mutations.

Novel driver mutations identified were found in the genes for serine phosphatase PPP6C and the small Ras-related Rho family GTPase Rac1. (444,499) A small subset of melanomas was found to show an RAC1 P29S mutation, which keeps Rac1 in its active, GTP-bound state. (444,499) Both studies found a recurrent mutation with a UV signature in RAC1 (among other novel driver mutations showing UV signatures in PPP6C and STK19). In addition, some melanomas negative for NRAS and BRAF mutations show mutations with putative loss of function in NF1, (444,499) which is a negative regulator of RAS and may confer MAPK activation, (502) or sometimes show mutations in HRAS, CRAF, MAP2K1, or KIT. Hodis et al (444) also showed that 44% of BRAF-driven melanomas have PTEN alterations. Krauthammer et al (499) showed that BRAFor NRAS-mutated melanomas often have losses of PTEN and/or CDKN2A mutations, or PPP6C mutations. Hodis et al (444) also found loss-of-function mutations in CDKN2A and TP53 mutations in a subset of melanomas.

Additional potential melanoma driver mutations identified in these efforts were found in PREX2 (PIP3-dependent rac exchange factor 2), a PTEN-interacting protein with negative regulatory function, and GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) as well as TRRAP (transformation/transcription domain-associated protein). (498,501) Interestingly and very recently, mutations in a noncoding region of a gene were found in most melanomas, occurring in the promoter region of the TERT gene encoding for the catalytic subunit of telomerase, and leading to an increase in transcriptional activity. (503) Increased expression of telomerase could be involved in immortalization of melanocytes in the context of other oncogenic mutations.

Expression profiling of desmoplastic melanoma not only shows decreased expression of melanocyte differentiation antigens, consistent with the known decreased expression of these antigens by immunohistochemistry, but also upregulation of clusterin, along with neurotrophic and extracellular matrix factors, when compared to other melanoma types. (504)

Mice transgenic for the RET receptor tyrosine kinase, which binds a neurotrophic factor, develop melanomas. (505) More recently, a polymorphism in the region coding for the juxtamembrane region of the RET receptor tyrosine kinase was found in most desmoplastic melanomas, as compared to lower numbers in nondesmoplastic melanomas. (506) This polymorphism leads to increased downstream activity of the MAPK and PI3K/Akt pathways.

Diagnostic Applications

Recently, fluorescence in situ hybridization analysis with probes detecting aberrations on chromosomes 6, 7, 9, 10, and 11 was proposed as an additional diagnostic tool for melanoma. (507-509) For example, a combination of probes against 6p25 (RREB1), 6q23 (MYB), 11q13 (CCND1), and the centromeric region of chromosome 6 was reported to have a sensitivity of 83% and a specificity of 94% when compared to common nevi, dysplastic nevi, and Spitz nevi, with a 6p25 probe showing the highest specificity overall. (510) For melanoma occurring in chronically sun-damaged skin, a relative increase in 11q13 gain sensitivity to 35.7% and 41.7% was observed (versus 30.1% overall), while 6p25 gains were still the most common aberrations. The sensitivity of these fluorescence in situ hybridization probes appears to be lower for desmoplastic melanoma. (511) However, a limitation of all these studies is that they were performed on histologically unequivocal cases, and sensitivity and specificity in histologically equivocal cases may be lower. (512) Further study will be needed to establish the utility of these tests; however, it appears that the presence of multiple complex chromosomal aberrations in a histologically worrisome melanocytic lesion is highly suggestive of melanoma. For example, a study using comparative genomic hybridization found that while 96% of melanomas show at least 1 chromosomal aberration, only 13% of benign nevi do. (513) This technique has the advantage that it can be performed on paraffin-fixed tissue, although its use is currently still limited by high cost, time-consuming processing, and a requirement for relatively large amounts of tissue.

Please Note: Illustration(s) are not available due to copyright restrictions.

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Stefan Kraft, MD; Scott R. Granter, MD

Accepted for publication May 22, 2013.

From the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (Dr Kraft); and the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Dr Granter).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Stefan Kraft, MD, Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52 20246 Hamburg, Germany (e-mail: stefkraft@hotmail.com).

Caption: Figure 1. Basal cell carcinoma (BCC). A, Nodular BCC: This lesion shows classical features with lobules of basaloid tumor cells with peripheral palisading and cleft formation between lobules and the mucin-rich stroma. B, Superficial BCC: Small basaloid tumor nests are attached to the epidermis. C, Infiltrative BCC: Small irregularly shaped nests and strands of tumor cells without prominent palisading and clefting (hematoxylin-eosin, original magnifications X40 [A], X100 [B], and X400 [C]).

Caption: Figure 2. Hedgehog (HH) signaling and aberrations in basal cell nevus syndrome (BCNS) and basal cell carcinoma (BCC): Under normal conditions (left side), PTCH1 (patched 1) suppresses SMO (smoothened). In the presence of sonic hedgehog (SHH), this inhibition is relieved and SMO internalizes, relieving inhibition of GLI transcription factors by suppressor of fused (SUFU). GLI factors then translocate to the nucleus and induce transcription of target genes. In BCNS and sporadic BCC, inactivating mutations and/or loss of PTCH1, or activating mutations of SMO, lead to constitutive activation of GLI transcription factors, expression of target genes, and cellular transformation. Alterations in TP53 and CDKN2A (cyclin-dependent kinase inhibitor 2A) may play a supportive role, and alterations in pigmentation genes, such as MC1R (melanocortin receptor 1), increase the risk for these events.

Caption: Figure 3. Invasive squamous cell carcinoma. Nests of large keratinizing cells with eosinophilic cytoplasm, nuclear atypia, and mitotic activity (hematoxylin-eosin, original magnification X400).

Caption: Figure 4. Actinic keratosis. Predominantly basally located atypical keratinocytes with large, irregular, hyperchromatic nuclei (hematoxylineosin, original magnification X400).

Caption: Figure 5. Atypical fibroxanthoma. Pleomorphic and multinucleated tumor cells (hematoxylin-eosin, original magnification X400).

Caption: Figure 6. Merkel cell carcinoma. A, Predominantly dermal nodule consisting of small round blue cells. B, The cells have a high nuclear to cytoplasmic ratio and watery, pale chromatin with nuclear molding. C, Lymphovascular invasion is a common feature. D, Perinuclear dotlike reactivity for CK20 is characteristic (hematoxylin-eosin, original magnifications X20 [A], X400 [B], X100 [C], and X200 [D]).

Caption: Figure 7. Trichilemmoma. A, Lobules of small uniform cells with peripheral palisading. B, The bland-appearing cells exhibit a clear cytoplasm owing to glycogen accumulation (hematoxylin-eosin, original magnifications X40 [A] and X400 [B]).

Caption: Figure 8. Cylindroma. Tumor lobules with a prominent basement membrane are arranged in a jigsaw pattern (hematoxylin-eosin, original magnification X100).

Caption: Figure 9. Sebaceous neoplasms. A, Sebaceous adenoma: The periphery of the lobule shows immature basaloid cells and the center, mature sebaceous cells. B, Sebaceoma. Basaloid cells are more prominent and intermixed with sebaceous cells. C, Sebaceous carcinoma. There is significant pleomorphism and mitotic activity (hematoxylin-eosin, original magnifications X200 [A], X100 [B], and X400 [C]).

Caption: Figure 10. Microsatellite instability assessed by polymerase chain reaction (PCR) and capillary electrophoresis for the genomic marker BAT 26. A, Product from normal tissue (1 arrow). B, Amplification of tumor DNA yields a novel PCR product indicating microsatellite instability (2 arrows).

Caption: Figure 11. Pilomatricoma. Transition from peripheral basaloid cells to central "ghost cells" (hematoxylin-eosin, original magnification X200).

Caption: Figure 12. Wnt (Wingless and INT-1)/[beta]-catenin pathway. Left panel: Under inactive conditions, cytoplasmic [beta]-catenin ([beta] Cat) is recruited to a "destruction complex" organized by axin. N-terminal phosphorylation of [beta] Cat by casein kinase (CK) and glycogen synthase kinase (GSK) leads to ubiquitinylation and proteasomal degradation of [beta] Cat. Lef-1 (lymphoid enhancer-binding factor 1) acts as a transcriptional repressor in the presence of TLE (Groucho) and histone deacetylase (HDAC). Middle panel: Extracellular Wnt ligands bind to LRP5/6 and Frizzled, leading to recruitment of Dishevelled (DSH), which then recruits axin and the destruction complex, followed by its degradation. [beta]-Catenin accumulates in the cytoplasm and translocates to the nucleus where it activates Lef-1-mediated transcription of genes. Right panel: In pilomatricoma, point mutations alter the N-terminal phosphorylation sites in p Cat, which then cannot be phosphorylated, inhibiting its degradation and leading to accumulation in the cytoplasm. [beta]-Catenin and Lef-1-mediated transcription of target genes includes cyclin D1. Abbreviations: APC, adenomatous polyposis coli; LRP, low-density-lipoprotein receptor-related protein.

Caption: Figure 13. Melanoma subtypes more common on sun-exposed skin of the head and neck. A, Lentigo maligna melanoma in situ. The cells show a cytoplasmic retraction artifact and large angulated nuclei. B, Desmoplastic melanoma. Atypical spindle cells in a dense fibrocollagenous stroma (hematoxylin-eosin, original magnifications X400 [A] and X200 [B]).
Table 1. Genetic Abnormalities in Adnexal Tumors

Gene                  Location           Associated Condition

CTNNB1                3p21               *  Pilomatricoma
([beta]-catenin)                         *  Pilomatrix carcinoma

CYLD                  16q12-13           * Familial cylindromatosis
                                         * Cylindroma

FHIT (fragile         3p14               * Sebaceous carcinoma
histidine triad)

KLLN (killin)         10q23              * Cowden syndrome
                                         (multiple
                                         trichilemmomas)

LEF1                  4q23-25            * Differentiated sporadic
                                         sebaceous neoplasms

MSH2, MLH1, MSH6      2p21, 3p21, 2p16   * Muir-Torre syndrome
                                         (multiple sebaceous
                                         neoplasms)

PTEN (phosphatase     10q23              * Cowden syndrome (multiple
and tensin homolog)                      trichilemmomas)

TP53                  17p13              * Sporadic sebaceous
                                         carcinoma

Gene                  Gene Function

CTNNB1                * Proto-oncogene in Wnt signaling
([beta]-catenin)      * Activates Lef-1 transcription factor

CYLD                  * Tumor suppressor
                      * Deubiquitinylation
                      * NF-[kappa]B inhibition
                      * Wnt/[beta]-catenin inhibition

FHIT (fragile         * Tumor suppressor
histidine triad)      * Inhibits Wnt/[beta]-catenin

KLLN (killin)         * Tumor suppressor
                      * p53 target
                      * Inhibits DNA replication (S-phase arrest)

LEF1                  * Proto-oncogene
                      * Transcription factor in Wnt pathway
                      * Hair follicle morphogenesis

MSH2, MLH1, MSH6      * DNA mismatch repair

PTEN (phosphatase     * Tumor suppressor
and tensin homolog)   * Phosphatase
                      * Inhibits PI3K/Akt pathway
                      * Inhibits MAPK pathway

TP53                  * Tumor suppressor
                      * Inhibits cell cycle progression
                      * Proapoptotic
                      * Induces DNA repair

Gene                  Common Genetic Abnormalities

CTNNB1                Mutations in regions encoding phosphorylation
([beta]-catenin)      sites lead to stabilization

CYLD                  Mutations lead to truncated product

FHIT (fragile         Intragenic deletion and promoter methylation
histidine triad)

KLLN (killin)         Promoter hypermethylation

LEF1                  Double nucleotide substitutions impair Lef-1
                      binding to [beta]-catenin and transcriptional
                      function

MSH2, MLH1, MSH6      Germline mutations lead to truncated product,
                      subsequent microsatellite instability

PTEN (phosphatase     Frameshift, nonsense, and missense mutations;
and tensin homolog)   less commonly, promoter hypermethylation

TP53                  Point mutations; likely no "UV signature"

Abbreviations: LEF-1, lymphoid enhancer-binding factor 1; MAPK,
mitogen-activated protein kinase; NF-[kappa]B, nuclear factor
[kappa]B; PI3K, phosphoinositide-3 kinase; Wnt, Wingless and INT-1.

Table 2. Genetic Abnormalities in Melanoma

Gene              Location      Clinical/Histologic Characteristics

BRAF              7q34          * Most common alteration in melanoma
                                * Often sites of acute intermittent
                                  sun exposure
                                  (superficial spreading,
                                  nodular melanomas)
GNAQ and GNA11    9q21, 19p13   * Uveal melanoma
                                * Blue nevi
KIT               4q11-12       * Mucosal melanoma
                                * Acral melanoma
                                * Some melanomas in chronically sun-
                                  damaged skin (some lentigo maligna
                                  melanomas)
NRAS              1p13          * BRAF-wild-type melanomas
                                * More nodular melanomas, but also
                                  superficial spreading
                                * Slight relative increase in
                                  extremity location
RET               10q11         * Desmoplastic melanoma
                                * Lower frequency in cutaneous
                                  nondesmoplastic melanoma

Gene              Gene Function

BRAF              * Proto-oncogene in Ras-Raf-MAPK cascade
                  * Activates MEK

GNAQ and GNA11    * Proto-oncogenes
                  * Guanine nucleotide-binding proteins
KIT               * Proto-oncogene
                  * Receptor tyrosine kinase for stem cell factor
                  * Broad effect on downstream pathways

NRAS              * Proto-oncogene in Ras-Raf-MAPK cascade

RET               * Proto-oncogene
                  * Receptor tryosine kinase
                  * Bound by glial cell line-derived neutrotrophic
                    factor

Gene              Common Genetic Abnormalities

BRAF              Point mutation leading to V599E substitution in
                    activation segment; leads to
                    increased enzymatic
                    activity

GNAQ and GNA11    Mutations in codons 183 and 209 lead to
                    constitutive activation
KIT               Mutations in region coding for juxtamembrane
                    domain; constitutive activation of kinase

NRAS              Activating mutations in codon 61

RET               Polymorphism (G691S) leads to increased
                    downstream activity of MAPK and PI3K/Akt
                    pathways

Abbreviations: MAPK, mitogen-activated protein (MAP) kinase; MEK, MAP
kinase kinase; PI3K, phosphoinositide-3 kinase.
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Author:Kraft, Stefan; Granter, Scott R.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jun 1, 2014
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