Basal cell carcinoma
Definition
Basal cell carcinoma (BCC) is a carcinoma derived from basal cells of the interfollicular epidermis and/or hair follicle. BCCs exhibit morphological variability but they invariably contain islands or nests of peripherally paliaded basaloid cells with hyperchromatic nuclei and scant cytoplasm.
Synonyms
Basal cell epithelioma; basalioma
Epidemiology
BCC is the most common malignancy in humans . Incidence rates are inversely related to geographical latitude and are higher in lighter-skinned populations. Rates are highest in Australia (where one in two residents develops BCC before the age of 70 years) and lowest in parts of Africa . Worldwide, the incidence of BCC is increasing everywhere except for Australia, where it seems to have reached a plateau . In the USA, the incidence rate is approximately 576 cases per 100 000 person-years {108}. The male-to-female ratio is approximately 1.5:1. Patients with two or more BCCs are at high risk of developing subsequent tumours, which are more likely to be of the superficial subtype.
Multiple BCCs disproportionately occur in men . The risk of BCC steadily increases with age. However, incidence rates are increasing faster in younger age groups, particularly among women. Exposure to indoor tanning is a risk factor for early-onset BCC .
Etiology
The finding that ultraviolet (UV) radiation exposure is the most important risk factor for BCC carcinogenesis is supported by abundant evidence , including higher incidence rates of BCC in regions closer to the equator and among individuals with relatively high sun exposure, and the tumours’ predilection for anatomical sites exposed to more sunlight. These tumours harbour many UV radiation signature mutations. Intermittent acute UV
radiation exposure, particularly during childhood, is implicated in the development of BCC. However, unlike in squamous cell carcinoma (SCC), the increase in BCC incidence peaks at approximately 30 000 hours of cumulative sun exposure and then flattens; in contrast, SCC risk increases indefinitely with increasing cumulative sun exposure . Ionizing radiation and systemic arsenic exposure are also known environmental insults
associated with BCC carcinogenesis, and organ transplant recipients may develop a risk of BCC as much as 10 times that in the general population.
Localisation
BCC is predominantly found in sun exposed skin; in one review, 64% of cases were found on the head, and 24% on the trunk . However, BCC has also been reported in the perianal and genital region, nail unit, palm, and sole. Different histological subtypes have predilections for different anatomical locations: superficial BCC occurs mainly on the trunk (overall), whereas nodular BCC is the predominant subtype of the head and neck. Superficial BCC is most common in females, in whom it is more often found on the legs than at other sites.
Clinical features
The variety of clinical presentations seen in BCC reflects the variety of the histopathological variants of these tumours. The classic feature is a pearly, telangiectatic papule, which may be eroded or ulcerated. Superficial BCC may present as an annular, mildly scaly plaque resembling tinea corporis. Sclerosing/morphoeic BCC and infiltrating BCC can have a scar-like appearance; pigmented BCC can resemble melanoma.
Genetic profile
BCC has one of the highest prevalence rates of somatic mutations of all cancers, and most of these mutations show the UV radiation signature of cytosine to thymine substitutions (C>T or CC>TT). Loss of heterozygosity of the PTCHI gene on chromosome 9q22.3 is found in 58-69% of sporadic BCCs, as well as in all BCCs in patients with naevoid BCC syndrome (NBCCS). About of the PTCHI mutations found in sporadic BCCs show the UV radiation signature. Mutations in the TP53 gene on chromosome 17p13.1 are found in 44-65% of BCCs. Loss of function of this gene is implicated in dysregulation of cell-cycle arrest, senescence, apoptosis, and DNA repair. MCIR variants are also implicated in BCC pathogenesis, and the risk is independent of skin and hair colour.
Genetic susceptibility
NBCCS is an autosomal dominant disorder characterized by multiple BCCs, odontogenic keratocysts of the jaws, palmar and/or plantar pits, and skeletal abnormalities. Patients with NBCCS develop one to more than a thousand BCCs, starting in puberty. The risk is increased following UV radiation exposure. Patients with NBCCS typically have germline mutations in the PTCHI gene, which encodes a receptor for the sonic hedgehog (SHH) protein. PTCHI mutation leads to increased release of the transmembrane protein smoothened (SMO), which leads to downstream activation of the GLII transcriptional pathway. Other genetic abnormalities that predispose individuals to BCC include xeroderma pigmentosum, Bazex—Dupré—Christol syndrome, and Rombo syndrome.
Prognosis and predictive factors
There is no formal staging system for risk stratification specific to patients with BCC. In the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, BCC is typically grouped with other cutaneous malignancies, including SCC {68}; however, TNM staging is rarely reported for this tumour, which usually remains localized. The National Comprehensive Cancer Network (NCCN) guidelines stratify the BCC variants by low versus high risk of recurrence, on the basis of clinical and pathological parameters, chiefly histological type (Table 1.01).
Nodular basal cell carcinoma
Definition
Nodular basal cell carcinoma (BCC) , the most common BCC variant is characterized by large tumour nodules in the dermis. ICD-O code 8097/3
Localisation
Nodular BCC is most common in the head and neck region.
Clinical features
Nodular BCC presents as a pearly plaque or nodule, often with telangiectasia. On dermoscopy, a pattern of arborizing vessels is seen. The cystic variant may appear as a translucent cystic nodule, and mucin-filled cystic cavities may resemble hidrocystoma. Ulceration is frequent in larger lesions, historically termed “rodent ulcers”.
Prognosis and predictive factors
Nodular BCC is considered to be a low risk variant of BCC. After adequate surgical excision (with the appropriate method determined by location and tumour size), recurrence and metastasis are exceedingly rare.
Superficial basal cell carcinoma
Definition
Superficial basal cell carcinoma (BCC) is a BCC variant with epidermal connection, confined to the papillary dermis. ICD-O code 8091/3
Synonym
Superficial multifocal basal cell Carcinoma
Clinical features
Superficial BCC is characterized by erythematous patches ranging from a few millimetres to > 10 cm in diameter. It accounts for 10-30% of BCCs and occurs most frequently on the trunk. Areas of regression appear as pale patches or fibrosis. Clinically, this is a low-risk histological subtype.
Micronodular basal cell carcinoma
Definition
Micronodular basal cell carcinoma (BCC) is a high-risk variant of BCC; it is characterized by small nests, which often extend deeply into the dermis.
Clinical features
Micronodular BCC presents as an elevated or flat, poorly defined lesion, and is most common on the head and neck. It is classified as a high-risk tumour, with the potential to recur after surgery.
Infiltrating basal cell carcinoma
Definition
Infiltrating basal cell carcinoma (BCC) is a BCC variant characterized by narrow tumour cords and nests with an irregular, infiltrative growth pattern.
Synonym
Basal cell carcinoma with aggressive growth pattern
Clinical features
These tumours have a scar-like presentation, and are most frequent on the upper trunk, head, and neck. They are more common in patients aged <35 years than older patients. Biopsy should include deep reticular dermis for most accurate diagnosis. Prognosis and predictive factors This subtype has a high risk of recurrence, necessitating surgery with strict margin control. Infiltrating BCC is often admixed with low-risk subtypes (e.g. nodular BCC and superficial BCC), but the presence of infiltrative morphology defines the risk of the tumour.
Sclerosing/morphoeic basal cell carcinoma
Definition
Sclerosing/morphoeic basal cell carcinoma (BCC) is a BCC variant characterized by very thin cords of basaloid cells surrounded by abundant collagenous stroma. ICD-O code 8092/3
Synonym
Morpheaform basal cell carcinoma
Clinical features
This subtype presents as a poorly defined, scar-like plaque that rarely ulcerates or bleeds.
Prognosis and predictive factors like infiltrating BCC, micronodular BCC and basosquamous carcinoma, this variant of BCC is a high-risk subtype, prone to increased frequency of perineural invasion and local recurrence, and necessitating surgical excision with strict margin control.
Basosquamous carcinoma
Definition
Basosquamous carcinoma is considered to be an aggressive variant of basal cell carcinoma (BCC); it has features of both BCC and squamous cell carcinoma (SCC), as well as transition zones between the two.
Synonym
Metatypical basal cell carcinoma
Epidemiology
Basosquamous carcinoma arises most commonly in the sun-exposed skin of older, fair-skinned White men.
Clinical features
The lesion presents as a slowly evolving papule or nodule, which may ulcerate. Dermoscopic features include a keratin mass, surface scaling, ulceration, and white structureless areas. The lesion combines the polymorphous vascular pattern of BCC with white circles, which are also a diagnostic clue to keratoacanthoma and other SCCs (36). Basosquamous carcinoma has a metastatic rate of 5—8.4%, which is comparable to that of SCC and higher than that of conventional BCC (Prognosis and predictive factors)
This is an aggressive BCC subtype; the local recurrence rate may be as high as 4.5%, and lymph node metastasis occurs in 5% of cases. Patients with metastatic disease have a median survival of 6.5 years and an overall 5-year survival rate of 54%.
Pigmented basal cell carcinoma
Definition
Pigmented basal cell carcinoma (BCC) is a BCC variant that contains melanin pigment.
Epidemiology
Pigmented BCC has a predilection for individuals of African, Hispanic, and Asian descent
Clinical features
Pigmented BCC shows pigmentation, usually superimposed on other classic clinical BCC features (tumours without classic BCC features can be difficult to distinguish from melanoma). The pigmentation can be focal and dot-like or can involve the entire tumour. Dermoscopy can improve diagnostic accuracy. Dermoscopic features include large blue-grey ovoid nests, blue-grey globules, and leaf-like areas.
Basal cell carcinoma with sarcomatoid differentiation
Definition
Basal cell carcinoma (BCC) with sarcomatoid differentiation is a BCC variant that has a basaloid epithelial component and sarcomatous stroma, which can exhibit a variety of histologies.
Synonyms
Metaplastic carcinoma; carcinosarcomatous basal cell carcinoma; sarcomatoid basal cell carcinoma
Clinical features
These carcinomas occur predominantly in elderly men, in sun-exposed areas of the head, neck, chest, and forearms. The tumours tend to be large (averaging 2.8 cm) at presentation.
Histogenesis
A small series showed similar chromosomal changes in epithelial and mesenchymal components, divergent differentiation of the epithelial component.
Prognosis and predictive factors
The rarity of this tumour makes determination of prognosis difficult.
Basal cell carcinoma with adnexal differentiation
Definition
Basal cell carcinoma (BCC) with adnexal differentiation is a BCC variant with differentiation towards follicular, sebaceous, apocrine, or eccrine glands. ICD-O code 8090/3
Clinical features
Infundibulocystic BCC and BCC with ductal differentiation have a predilection for periocular skin.
Genetic profile
A small series of BCCs with metrical differentiation showed molecular abnormalities in CTNNBI, KIT CDKN2A, TP53, SMAD4, ERBB4, and PTCHI, providing supporting evidence that these tumours may be variants of BCC.
Genetic susceptibility
Multiple infundibulocystic BCCs can occur in the familial setting, and can also occur in naevoid BCC syndrome. BCC with sebaceous differentiation may be seen in Muir—Torre syndrome, and often has significant histological overlap with other sebaceous neoplasms.
Prognosis and predictive factors
Adnexal BCC variants do not have prognostic significance.
Fibroepithelial basal cell carcinoma
Definition
Fibroepithelial basal cell carcinoma (BCC) is a BCC variant composed of delicate, interanastomosing strands of basaloid cells surrounded by abundant fibroblastic stroma. ICD-O code 8093/3
Synonyms
Fibroepithelioma of Pinkus; Pinkus tumour
Localisation
These lesions most commonly involve the trunk, in particular the back. They are rarely multiple.
Clinical features
Fibroepithelial BCC presents as a flesh coloured nodule.
Reference:
WHO classification of skin tumours, 4th edition (2018): 26-34.
Dermatofibroma (fibrous histiocytoma) and variants
Definition
Dermatofibroma (fibrous histiocytoma) is a common benign papular or nodular skin lesion composed of variable combinations of fibroblastic cells, macrophages, and coarse collagen.
ICD-O code
Dermatofibroma (fibrous histiocytoma) 8832/0
Synonyms
Benign fibrous histiocytoma; histiocytoma (cutis); fibroma durum; subepidermal nodular fibrosis orsclerosis; sclerosing haemangioma.
Epidemiology
Dermatofibroma can arise at any age, but is most common in the third and fourth decades of life. The classic type is more common in younger females, particularly on the legs. Other variants have a more equal sex distribution.
Etiology
It has been debated whether dermatofibroma is inflammatory or neoplastic. Some lesions have shown clonality and recurrent translocations suggesting neoplasia. This entity has also been reported to arise after trauma, insect bites, or folliculitis, suggesting an inflammatory origin. More recently, gene fusions involving PRKC Band PRKCD (encoding protein kinase Cisoforms) have been noted in a subset of cases, confirming a neoplastic nature.
Localisation
The lesions are most commonly seen on the legs, followed by the arms and trunk. Occasional lesions are seen on the hands, feet, and head and neck. The cellular variant is the subtype most commonly involving the head and neck.
Clinical features
Most dermatofibromas asymptomatic papules are that isolated evolve rapidly and then stabilize. Early stage lesions are typically erythematous, but older ones are brown or skin-toned, often with a peripheral brown rim. The lesions are typically 1 cm in diameter but are occasionally up to 10 cm. They are typically firm, well circumscribed, and symmetrical. Most lesions are raised and dome-shaped and show a central dimple when squeezed. They may be cystic, eroded, or crusted. Occasionally several lesions are present, and rarely there can be dozens, either widely distributed or agminated. Multiple lesions may have no clinical significance, but they have been reported in conditions associated with immunosuppression and in association with immunosuppressive drugs.
Histogenesis
There is evidence of fibroblastic, myofibroblastic, and/or macrophage differentiation.
Prognosis and predictive factors
Dermatofibroma is a benign lesion. Incomplete excision may result in local non-destructive recurrence. There is conflicting evidence as to whether dermatofibroma of the face behaves more aggressively than dermatofibroma at other anatomical sites. The risk of local recurrence is higher with the cellular, atypical, and aneurysmal sub-types. Extraordinarily rare lesions have metastasized to lymph nodes and/or lung; most have been of the cellular, atypical, or aneurysmal subtype. There is some evidence suggesting that metastasizing tumours have more chromosomal aberrations than are typical of standard indolent dermatofibroma.
Reference:
WHO classification of skin tumours, 4th edition (2018): 310-312.
Dysplastic naevus
Definition
Dysplastic naevi are a subset of melanocytic naevi that are clinically atypical and characterized histologically by architectural disorder and cytological atypia, always involving their junctional component. In terms of their clinical and microscopic morphology, as well as genomic aspects, dysplastic naevi are intermediate between common acquired naevi and radial-growth-phase melanoma .
Synonyms
Atypical naevus; large atypical naevus; B-K mole; atypical mole; melanocytic dysplasia; naevus with architectural disorder and melanocytic atypia. The term “Clark naevus” is not a synonym, because its definition does not include cytological atypia or a size criterion . The term “atypical naevus” is the most commonly used synonym; however, this term encompasses a broad range of unusual lesions, unless strictly defined.
Epidemiology
Dysplastic naevi were first described in members of hereditary melanoma kindreds and later in patients with non-familial melanoma and in people unaffected by melanoma . The lesions typically develop in adolescence.The prevalence declines in older age groups, perhaps in part as a cohort effect and also because of involution . In a case—control study, one or more clinically dysplastic naevi were found in 43% of 658 patients with melanoma and in 1096 of 1009 control subjects; the most common number of naevi found was two among the patients and one among the controls. In a study of histological dysplasia, the prevalence of moderate or severe dysplasia was 24% in patients with melanoma and 12% in spouse controls.
Etiology
Like other melanocytic tumours (including melanomas), dysplastic naevi arise because of genetic, environmental, and phenotypic factors, in particular factors related to sun susceptibility and exposure. There is evidence of a genetic component to naevogenesis; genome wide association studies of naevus counts have implicated several loci, but germline susceptibility loci unique to dysplastic naevi have not been reported {908}. It is possible that stimuli from chronic ultraviolet (UV) radiation exposure and the resulting cumulative sun damage (CSD) acting on a naevus can promote the attributes of clinical and his tological atypia.
Localisation
The anatomical distribution of dysplastic naevi, like that of other naevi, only partialfy overlaps with that of melanoma, paralleling the distribution of melanoma in skin with a low degree of CSD (low CSD melanoma) rather than that of high CSD melanoma. Dysplastic naevi tend to arise in skin that is intermittently (rather than chronically) sun-exposed; the most common site is the back.
Clinical features
A widely adopted definition published by the International Agency for Research on Cancer (IARC) in 1990 (and subsequently modified) recommends the following criteria to identify atypical (dysplastic) naevi: there must be a macular component in at least one area; in addition, at least three of the following features must be present: a non—well-defined border, size > 5 mm, colour variegation, uneven peripheral contour, and erythema . The lesions almost always have a flat component (representing junctional proliferation), and there is often a central raised portion constituting a dermal component, resulting in a resemblance to a fried egg or a target. These criteria partially overlap with those for melanoma. Lesions with markedly atypical attributes, as well as new or changing lesions, should be submitted for histological evaluation to rule out melanoma. Dermoscopy and photographic follow-up and image analysis may be used to improve the specificity of clinical diagnosis.
Histogenesis
Dysplastic naevi are benign neoplasms of melanocytes. Melanocytic dysplasia may occur de novo or in association with congenital-pattern dermal naevi (defined as naevi that have a dermal component within the reticular dermis) or with common dermal naevi that are confined to the papillary dermis. It is likely that the dysplasia develops as a secondary change in relation to the pre-existing dermal naevus as a result of sequential acquisition of genetic abnormalities.
Genetic profile
Like common acquired naevi, dysplastic naevi are associated with activating mutations of an oncogene, most commonly BRAF or NRAS. A category of intermediate lesions has recently been identified that is characterized by cytological and architectural atypia and the presence of more than one genomic abnormality (in contrast to common acquired naevi, which have only a single mutated oncogene). Mutation of the TERT promoter is a frequent early event in the progression towards melanoma in situ, and there is occasionally hemizygous loss of CDKN2A . The correlation of these genetic alterations with the degree of morphological dysplasia is still unknown.
Genetic susceptibility
Dysplastic naevi are commonly found in members of hereditary melanoma kindreds. However, the transmission of dysplastic naevus does not conform to expectations of dominant Mendelian inheritance. Associations between naevi and various susceptibility genes have been identified, but these findings have little or no clinical utility at this time.
Prognosis and predictive factors
Dysplastic naevi have significance mainly in relation to melanoma, in three ways: as simulants of melanoma, as potential precursors of melanoma, and as biomarkers of increased risk for melanoma.
Their role as morphological simulants relates to the differential diagnosis of melanoma, discussed above. In various studies, remnants of a dysplastic naevus have been described in 20-30% of melanomas, and a recent prospective study found that naevus remnants (of any type) were associated with 54.2% of melanomas. Dysplastic naevi adjacent to melanomas have an increased frequency of TERT promoter mutations , indicating that they have genetically evolved beyond conventional naevi (in which such mutations are typically absent). This indicates that some dysplastic naevi represent biologically intermediate states between benign naevus and melanomas. There are currently insufficient data to determine what proportion of non—melanoma-adjacent dysplastic naevi harbor similar alterations. Dysplastic naevi are much more common than melanomas, and the risk of progression of any given lesion is very low. However, naevi that show high-grade dysplasia and/or have additional genetic alterations such as TERT promoter mutation should be considered for complete excision.
Dysplastic naevi have been associated with increased melanoma risk in numerous clinically based case control studies; in a meta-analysis of 46 studies, the relative risk associated with the presence of 5 dysplastic/atypical naevi (vs O) was found to be 6.4. In a histological study of melanoma cases and spouse controls, moderate to severe dysplasia was associated with an increased risk of melanoma (odds ratio: 3.99, 95% Cl: 1.02—15.71), whereas mild dysplasia was not associated with an increased risk {2434}. In a subsequent study using the same database, much of the increased relative risk associated with histological dysplasia was found to be conferred by lesional size alone (>4.4 mm), which could therefore serve as a reasonable surrogate indicator of cytological and architectural atypia. In a retrospective review of pathology reports on 20 275 naevi, a personal history of melanoma was present in 5.7% of patients with mild atypia, 8.1% with moderate atypia, and 19.7% with severe atypia.
The odds ratios as a measure of association between a dysplastic naevus and a personal history of melanoma were 4.1 for severe versus mild dysplasia, 2.8 for severe versus moderate dysplasia, and 1.5 for moderate versus mild dysplasia , again suggesting that the risk associated with mild dysplasia (i.e. mild versus no dysplasia, not studied presumably because of the large numbers involved) is not significantly different from baseline.
Reference:
WHO classification of skin tumours, 4th edition (2018): 83-86.
Keratoacanthoma
Definition
Keratoacanthoma is a common, rapidly growing squamoproliferative tumour that may spontaneously regress. It is histologically indistinguishable from (and likely a variant of) well-differentiated cutaneous invasive squamous cell carcinoma, with distinct clinical behavior.
Synonyms
Welt-differentiated squamous cell carcinoma, keratoacanthoma type; keratoacanthoma-like squamous cell carcinoma
Epidemiology
Keratoacanthomas typically arise in the sun-exposed skin of older, fair-skinned individuals between the sixth and seventh decades of life and have a slight predilection for men. Rare cases occur in childhood and adolescence in association with organoid naevus or xeroderma pigmentosum .
Etiology
Ultraviolet (UV) radiation, photon radiation, trauma (e.g. at sites of a skin graft or vaccination), infections, and chemical carcinogens have been linked to the development of keratoacanthoma lesions, with solar damage being the predominant risk factor. Other factors include immunosuppression/immunodeficiency, tattoos, and BRAF inhibitors. Human polyomavirus 6 (HPyV6) DNA was recently detected in keratoacanthomas , and other serotypes (HPyV19 and HPyV48) have been isolated in giant keratoacanthomas and keratoacanthomas in HIV-infected patients.
Localisation
Keratoacanthomas most commonly occur in facial skin (in as many as 70% of cases in temperate climates); they also commonly occur on the dorsum of the hands and forearms among men and on the legs among women.
Clinical features
Solitary keratoacanthoma
This is the most common variant. It presents as a symmetrical, dome-shaped tumour, capped with keratin. It evolves rapidly and may involute over the course of several months. The size ranges from a few millimeters to 20 cm. Giant keratoacanthomas (>5 cm) have a predilection for the nose and the dorsum of the hands; they can reach up to 15 cm, with destruction of underlying tissues. Three clinical stages have been observed: a proliferative stage (a rapidly enlarging erythematous papule or nodule with a smooth surface), a mature stage (a central whitish-yellow nodule with a crateriform keratotic core), and a regressing stage (a keratotic nodule that progressively flattens in association with elimination of the central keratotic plug, sometimes followed by the formation of a hypopigmented scar).
Multiple keratoacanthomas
These rare tumours can be sporadic or familial. Sporadic multiple keratoacanthomas may be associated with prurigo nodularis, usually on the sun-damaged lower legs of elderly women.
Multiple familial keratoacanthomas of Ferguson-Smith type
These keratoacanthomas, also known as multiple self-healing squamous epithelioma, were first described in Scottish families with an autosomal dominant inheritance pattern with variable penetrance. Patients may have hundreds of keratoacanthomas, each with characteristics similar to those seen in solitary keratoacanthoma.
Multiple keratoacanthoma centrifugum marginatum
Theses rare skin tumours show persistent growth with an annular, coral reef— like appearance. The lesions involve the back of the hands and can become very large, approaching 20 cm.
Generalized eruptive keratoacanthomas of Grzybowski
Affected patients have a generalized eruption of hundreds to thousands of small, well-demarcated papules (some with keratotic centres), predominantly in unexposed skin. The condition is exceedingly rare, and familial clustering has been described.
Subungual keratoacanthoma
This rapidly growing and locally destructive tumour originates in the distal nail bed, separating it from the nail plate. The thumb, middle finger, and big toe are most commonly involved.
Histogenesis
Most examples of keratoacanthoma affect hair-bearing skin, and are most likely to be derived from follicular infundibular/isthmus keratinocytes. Rare tumours located on glabrous skin and mucous membranes are probably derived from epithelial keratinocytes.
Genetic profile
The MAP3K8 (TPL2) oncogene may be a driver common to the development of both keratoacanthoma and squamous cell carcinoma. Patients with multiple familial keratoacanthomas of Ferguson-Smith type have DNA repair failures associated with Muir—Torre syndrome and xeroderma pigmentosum. Disease-specific mutations in TGFBRI have also been identified in patients with multiple familial keratoacanthomas of Ferguson-Smith type . There is a possible role of TP53in the development of some keratoacanthomas; mutant p53 oncoproteins are found in about 10% of tested lesions.
Genetic susceptibility
Rarely, there is a genetic predisposition to developing keratoacanthomas, in particular multiple familial keratoacanthomas of Ferguson-Smith type. Muir—Torre syndrome is commonly associated with keratoacanthoma lesions, suggesting that the genetic defect (or defects) that causes the syndrome also plays an etiological role in keratoacanthoma.
Prognosis and predictive factors
Many (if not most) keratoacanthomas eventually undergo resolution, but central facial giant keratoacanthoma and subungual keratoacanthoma may be locally aggressive. It is impossible to predict with certainty the behaviour of a well differentiated squamoproliferative lesion on the basis of a partial biopsy, or when margins are involved.
Reference:
WHO classification of skin tumours, 4th edition (2018): 36-38.
Junctional, compound, and dermal naevi
Definition
Junctional, compound, and dermal naevi are benign localized neoplastic proliferations of naevus cells (a type of melanocyte). Like all melanocytic naevi, these lesions are defined by the presence of nests of melanocytes.
Synonyms
Common acquired naevi; banal naevi
Epidemiology
Acquired naevi appear during childhood and reach maximum number in adolescence, declining in number thereafter in cross-sectional studies. This finding may be due to a cohort effect, a process of senescence and disappearance over time, or both.
Etiology
The prevalence of naevi in various populations depends on phenotypic factors (in particular sun susceptibility), sun expo-sure patterns, and genetic susceptibility, resulting in mutations of a single oncogene in a single cell, which expands to form a clone.
Localisation
Naevi are widely distributed over the body, with the most frequent site being the trunk.
Clinical features
These are localized, generally symmetrical and uniformly pigmented lesions, typically <5 mm in diameter They have been assumed to evolve from initial junctional proliferations to compound and then dermal naevi with accompanying development of a papular component, loss of the junctional component, and loss of pigment; however, a more complex model of separate evolution has been proposed.
Histogenesis
These lesions are thought to evolve as junctional proliferations of melanocytes, related to the mutation of a single oncogene as a driver mutation in actinically altered skin {2390}, and to evolve through the stages of compound and dermal naevi as described above.
Genetic profile
Most acquired naevi have activating mutations of the oncogene BRAF (typically BRAF p.V600E) and less often mutations of NRAS. Different mutations are associated with distinct forms of naevi of other types, discussed in the respective sections. BAPI-inactivated melanocytic lesions must be distinguished from Spitz naevi and atypical Spitz tumours, and are more akin to naevi with partial transformation by a second genomic event (i.e. BAPI loss).They usually lack epidermal hyperplasia, are usually epithelioid rather than spindled, often include a second naevus cell component, lack BAPI expression, and are usually BRAF-mutant.
Genetic susceptibility
Several so-called naevus susceptibility genes have been described, but this information has not yet been translated into clinical practice. Prognosis and predictive factors Naevi have medical significance in relation to melanoma, as simulants, potential precursors, and risk markers (discussed in the sections on dysplastic naevi and melanomas). Briefly, individuals with an increased total number of naevi or an increased number of large naevi are at increased risk of melanoma as deter-mined in case—control and prospective cohort studies. It has been shown that about one third of melanomas arise in compound naevi. Although many melanomas are associated with precursor naevi , the risk of progression for individual lesions is very low.
Reference:
WHO classification of skin tumours, 4th edition (2018): 80-81.
Seborrhoeic keratosis
Definition
Seborrhoeic keratosis is a benign intraepidermal neoplasm that most commonly occurs in ageing skin.
Synonyms
Senile wart; seborrhoeic wart
Epidemiology
These lesions are very common. In an Australian population, seborrhoeic keratoses were present in 12% of people aged 15—25 years, 79% of people aged 26—50 years, and 100% of people aged years. The lesions increase in number with age and are found less commonly in more-pigmented skin. There is no apparent sex predilection.
Etiology
Ultraviolet (UV) radiation exposure is related to the etiology of some seborrheic keratoses. Other possible causes under investigation include genetic and metabolic factors.
Localisation
Seborrhoeic keratoses have a predilection for the trunk, head, and neck, but can occur on any skin surface other than the palms, soles, and mucosal surfaces. They tend to group together in skin creases, such as under the breast or in the groin.
Clinical features
Seborrhoeic keratoses typically present as solitary or multiple flat-based papules or plaques with a filiform surface. A brown or black appearance is typical, but some lesions are pale or Grey. Macular seborrhoeic keratoses remain thin, with subtle scale. Stucco keratoses, which are considered a variant of seborrhoeic keratosis, form distinctive small keratoses that are largely restricted to the lower limbs. Dermoscopy reveals multiple brown or white clods, representing plugs of keratin, and thick ridges imparta cerebriform pattern. The acute appearance of multiple seborrhoeic keratoses associated with an internal malignancy is called the Leser Trélat sign.
Histogenesis
Seborrhoeic keratoses arise from epidermal keratinocytes. They have an increased proliferation rate and decreased apoptosis compared with normal keratinocytes.
Genetic profile
Somatic mutations are seen in FGFR3,PIK3CA, the TERT promoter, the DPH3promoter, BRAS, KRAS, EGER, and AKTI.
Prognosis and predictive factors
Seborrhoeic keratoses are benign, but a search for internal malignancy should be performed in response to the sudden appearance of multiple lesions.
Reference:
WHO classification of skin tumours, 4th edition (2018): 57-60.
Actinic keratosis
Definition
Actinic keratosis (AK) is an intraepithelial neoplastic lesion that may progress into invasive squamous cell carcinoma (SCC) or may spontaneously regress.
ICD-O code
8070/0
Synonyms
Solar keratosis; keratinocytic intraepithelial neoplasia: senile keratosis
Epidemiology
AKS occur more commonly in more sun exposed regions, in people with fair skin, and in males; their incidence increases with advancing age.
Etiology
Risk factors include cumulative intermittent sun exposure, chronic immunosuppression, arsenic exposure, PUVA therapy, and chronic cutaneous inflammation. Exposure to ultraviolet (UV) radiation (UVB and to a lesser extent UVA radiation) plays the major role in carcinogenesis .
Localisation
The lesions occur on sun-exposed areas such as the face, lower lip (actinic cheilitis), bald scalp, lateral neck, forearms, and dorsal hands, as well as on the lower legs and trunk.
Clinical features
AK commonly presents as an asymptomatic scaly erythematous patch or plaque, usually 2—10 mm in diameter, surmounted with a rough adherent scale often resembling sandpaper. There are often multiple lesions, flesh-coloured and confluent, with a background of chronic sun damage.
Genetic profile
TP53 mutations are the most common genetic alteration in AK. Other mutations include mutations
of CDKN2A on chromosome 9p21 — the gene encoding p16 (p161NK4a) and p14ARF — and mutations of CDKN2B — the gene encoding p15 (p151NK4b). Loss of heterozygosity has been documented in as many as four loci and several chromosomes.
Genetic susceptibility
The genetic factors associated with an increased risk for the development of AK are those that result in constitutional sensitivity to sunlight, such as childhood freckling, blue eyes, and blond or red hair.
Oculocutaneous albinism; Rothmund Thomson, Cockayne, and Bloom syndromes; and xeroderma pigmentosum are associated with the development of AKs in earlier life.
Prognosis and predictive factors
AK may regress spontaneously, remain stable, or progress to invasive SCC; cases in which there are >5 AKS have an increased risk of progression. The annual rate of malignant transformation is usually cited as < 1 per 1 000 cases, but transformation rates are higher among the higher-risk cases.
Reference:
WHO classification of skin tumours, 4th edition (2018): 51-52.
Squamous cell carcinoma
Definition
Cutaneous squamous cell carcinoma (SCC) is a malignancy of epidermal keratinocytes that exhibits various degrees of differentiation that partially recapitulate the cytology of squamous cells of the epidermal stratum spinosum. The lesions can be in situ or invasive with the potential for metastasis.
ICD-O code
Squamous cell carcinoma NOS 8070/3
Epidemiology
The incidence of SCC is difficult to establish, but data on non-melanoma skin cancer suggest that there were an estimated 701 000 SCC tumours affecting 430 500 people in the USA in 2006 (assuming that of tumours are SCC). SCC is the second most common form of skin cancer (after basal cell carcinoma) and is more common in men than in women. Most cases occur in sun-exposed skin of elderly individuals, most commonly individuals with lighter skin pigmentation.
Etiology
In addition to ultraviolet (UV) radiation, other factors that have been implicated in the etiology of SCC include chronic immunosuppression, other forms of radiation, topical carcinogens, burn scars, chronic inflammation, sinus tracts, HPV infection, arsenic, and coal tar. Cutaneous SCC was the first occupational cancer to be identified, described in the scrotal skin of British chimney sweeps in1775 by Percivall Pott.
Localisation
The sites most often affected are chronically sun-exposed areas, including the face and lips, ears, balding scalp, arms, trunk, and (particularly in women) legs. More widespread sites may be affected in those who have used indoor tanning. In rare lesions associated with HPV infection or immunosuppression, the genitalia and distal digits (particularly the subungual region) are commonly involved.
Clinical features
SCC in situ may appear as roughened hyperkeratotic lesions mimicking benign keratoses, dermatoses (e.g. psoriasis), or lichen simplex chronicus. With invasion and progressive growth, hyperkeratotic nodules may develop ulceration. The well differentiated keratoacanthoma variant of SCC forms crateriform lesions with central keratin plugs. Less well differentiated tumours produce irregular, erythematous scaling nodules and plaques. Lesions with perineural spread may produce pain or paraesthesias. Lymph node spread is the primary route of metastasis. When visceral lesions develop, they most commonly affect the lung, followed by the bone, CNS, and liver.
Histogenesis
Most UV radiation—related cutaneous SCCs appear to develop through a multistep process in actinic keratoses or infields of squamous dysplasia. Common mutations involve tumour suppressor genes such as TP53, NOTCHI, and NOTCH2 {1800). Activating mutations in genes such as HRAS and KRAS are also frequently involved. UV radiation—induced TP53 mutations likely occur early on in the process. Advanced age, immunosuppression, and environmentally determined defects in the epigenome appear to contribute to impaired elimination of precursors of malignant transformation. Cutaneous SCC probably arises from an epidermal or follicular stem cell.
Genetic profile
Recent genetic expression profile studies suggest that the differentially expressed genes CXCL8 (IL-8), MMPI, HIFIA,ITGA6, and ITGA2 are promising diagnostic and therapeutic targets .
Genetic susceptibility
Patients with xeroderma pigmentosum, vitiligo, and albinism are at increased risk of SCC. A recent two-stage genome-wide association study of a large number of SCCs revealed 11 susceptibility loci. Of these, 7 are related to pigmentation: MCIR, AS/R TYR, SLC45A2 OCA2,IRF4, and BNC2. The other 4 are involved in tumour immune evasion, apoptosis inhibition, or other oncogenic pathways:liq23.3 (CADMI), 2p22.3, 7p21.1 (AHR),and 9q34.3 (SEC16A).
Prognosis and predictive factors
Confirmed high-risk prognostic features are tumour thickness > 2 mm, Clark level IV or V invasion, perineural invasion, primary site on the ear or lip, and poor differentiation. Perineural invasion of nerves >0.1 mm in diameter correlates with higher disease-specific death rates.
Acantholytic squamous cell carcinoma
Definition
Acantholytic squamous cell carcinoma (SCC) is a histological variant of invasive SCC characterized by impaired intercellular adhesion that may result in the formation of pseudo glandular spaces.
ICD-O code
8075/3
Synonyms
Adenoid squamous cell carcinoma; pseudo glandular squamous cell carcinoma
Epidemiology
The acantholytic variant accounts for< 5% of all SCCs, although the criteria for this designation (focal versus wide-spread acantholysis) are not well established. Older male patients are most frequently affected, and an increased incidence has been reported in organ transplant recipients.
Etiology
Given that most acantholytic SCCs occur in chronically sun-exposed sites, ultra-violet (UV) radiation—induced damage is likely a causative factor. The known association with chronic immunosuppression implies a role for defective immunosurveillance.
Localisation
The lesions often involve skin of the head, neck, face, and ears. Other sun-exposed sites can also be involved. In one review, about 60% of lesions involved the head and neck, and 40% involved the trunk and extremities .
Clinical features
The clinical appearance of acantholytic invasive SCC is the same as that of its non acantholytic counterpart (SCC-NOS).
Histogenesis
The histogenetic factors are most often the same genomic, molecular, and causative factors that are applicable to ordinary invasive SCC. Compared with non-acantholytic SCCs, the acantholytic variant has been shown to have decreased expression of desmoglein 3 and E-cadherin. Defective desmosomal protein expression has been confirmed and is probably largely responsible for the acantholytic pattern observed histologically. The genetic pro-file of and potential susceptibility loci for acantholytic SCC are not yet understood.
Prognosis and predictive factors
It has been suggested that acantholytic SCC is a more aggressive variant of SCC , with a mortality rate at follow-up of 19%, although more-recent data conflict with this interpretation. Histological attributes that may confer aggressive behaviour have recently been comparatively evaluated for acantholytic versus non-acantholytic SCC; these included microscopic tumour diameter, depth of invasion, degree of differentiation, and presence of perineural invasion. No significant differences between acantholytic and non-acantholytic ordinary SCCs were identified; overall, the notion that acantholytic SCC is a biologically and clinically more aggressive variant of SCC has not been substantiated.
Spindle cell squamous cell carcinoma
Definition
Spindle ceil squamous cell carcinoma (SCC) is a rare, poorly differentiated variant of SCC; it is composed predominantly of spindled tumour cells with partial or complete loss of morphological squamous differentiation.
ICD-O code
8074/3
Synonyms
Pseudosarcomatous squamous cell carcinoma; sarcomatoid squamous cell carcinoma
Epidemiology
These skin tumours arise most commonly in elderly White men, and rarely in Asian populations. The incidence is highest among individuals aged > 70 years. The reported age range for penile tumours is broad (28—81 years).
Etiology
Ultraviolet (UV) radiation exposure, iatrogenic ionizing irradiation, scarring burns, solid-organ transplantation, and immunosuppression predispose individuals to this variant. Penile tumours are frequently associated with high- or low-grade squamous intraepithelial dysplasia or lichen sclerosus.
Localisation
Spindle cell SCC typically arises in the sun-exposed skin of the face and head, neck, chest, and upper extremities. Simi-lar tumours are found in mucocutaneous regions of the head and neck (e.g. the larynx, hypopharynx, oropharynx, and nasal cavity), as well as within the urogenital tract, and are well described on the distal penis (e.g. the glans/pre-puce and foreskin).
Clinical features
Spindle cell SCC is typically a raised orexophytic plaque, nodule, or tumour, and is indistinguishable from classic SCC. It is often about 2 cm in largest dimension, and can reach up to 10 cm. Patients often present with bleeding or ulceration, and may report a history of rapid tumour growth.
Histogenesis
A monoclonal origin for these tumours is the currently accepted theory. Themorphological changes have been postulated to be caused by epithelial—mesenchymal transition, in which the precursor squamous cells lose polarity and cohesiveness and transform into spindle-shaped cells, acquiring increased motility and invasiveness.
Prognosis and predictive factors
Spindle cell morphology itself may be a predictor of poor prognosis. Depth of invasion (particularly invasion into bone or muscle), as well as origination at the site of a burn or radiation damage (including sun damage) may be associated with worse outcome or death. Positive margins are associated with significantly higher rates of recurrence and metastasis, and with significantly poorer survival. Penile variants have a high rate of metastasis and are associated with a high rate of death due to metastatic dis-ease.
Verrucous squamous cell carcinoma
Definition
Verrucous squamous cell carcinoma (SCC) is a rare, well-differentiated variant of cutaneous SCC; it has a characteristically undulant architecture and often exhibits locally aggressive behaviour, yet has low potential for metastasis. Similar lesions also affect mucosal surfaces.
ICD-O code
8051/3
Synonyms
Oral florid papillomatosis; Ackerman tumour {338,488}; epithelioma cuniculatum; Buschke—Löwenstein tumour; giant condyloma acuminatum; papillomatosis cutis carcinoides
Epidemiology
Verrucous SCC is predominantly a tumour of older men, with 75% of patients aged 2 60 years.
Etiology
Chronic irritation, inflammation, HPV infection, and impaired immunity have been proposed as possible etiological factors. As with other forms of cutaneous SCC, chemical carcinogens and environmental exposures have also been implicated. However, the precise inciting factors responsible for this uncommon variant remain unknown.
Localisation
Verrucous SCC can affect both oral mucosa and skin. The mucosal site of predilection is the oral cavity (Ackermantumour); cutaneous lesions most often involve the palms, soles (epithelioma cuniculatum), distal digits, and genital region (Buschke—Löwenstein tumour), but isolated reports indicate that verrucous SCC can arise at virtually any cutaneous site, including the skin of the scalp, face, back, and extremities, some-times in association with chronic ulcers and scars, such as in the pretibial variant (papillomatosis cutis carcinoides).
Clinical features
The clinical appearance of cutaneous verrucous SCC varies according to its site of occurrence. Palmoplantar lesions tend to grow and evolve slowly, forming hyper-keratotic plaques that may be confused with verrucae or callosities. Anogenital lesions form exophytic, condylomatoid excrescences that may be deeply invasive and difficult to eradicate, particularly in the setting of immunocompromise. Occasionally, tumours can have a more nodular clinical appearance.
Histogenesis
Verrucous SCC has been described in association with a variety of reactive and inflammatory conditions, including vulvar lichen planus, although the precise histogenesis remains unclear. The role of HPV is controversial, in part because of diagnostic confusion between condylomatous and hyperplastic lesions and true verrucous SCC. An analysis of13 rigorously defined verrucous SCCs from head and neck, anogenital, and extragenital skin using PCR-based HPV detection failed to implicate a causal role for HPV. However, there is a clear association between certain oncogenic HPV types and cutaneous SCC, particularly in the setting of immunosuppression, and the potential role of HPV in verrucous SCC warrants further investigation.
Genetic profile
Overexpression of MDM2, a negative regulator of p53, has been implicated.
Prognosis and predictive factors
Incompletely excised lesions have a high recurrence rate, and recurrences can be more aggressive than the initial tumour. Metastasis generally does not occur, although transformation to more-aggressive forms of SCC has been described inpatients who had received irradiation or chemotherapy.
Adenosquamous carcinoma
Definition
Adenosquamous carcinoma is a rare squamous cell carcinoma (SCC) variant that exhibits mixed squamous and glandular differentiation and aggressive clinical behaviour.
ICD-O code
8560/3
Etiology
Although this is considered to be a variant of SCC with divergent glandular differentiation, the pathogenesis is unknown. Malignant transformation from epithelial stem cells differentiating into both squamous and glandular-like cells is a plausible explanation.
Clinical features
These tumours occur mostly in the head and neck of elderly patients, most frequently in men. Clinically, they can be indistinguishable from typical SCC, presenting as an indurated keratotic plaque. The incidence is likely higher among immunosuppressed patients.
Prognosis and predictive factors
This variant has been associated with an aggressive clinical course, with a high rate of recurrence and metastasis. Because of the relative frequency of nerve involvement and subclinical extension, meticulous examination of all resection margins to assess the adequacy of excision is required.
Clear cell squamous cell carcinoma
Definition
Clear cell squamous cell carcinoma (SCC) is a histological variant of SCC that microscopically shows abundant clear cytoplasm. There is no consensus on the required proportion of clear cells for the definition of clear cell SCC, but > 25%has been suggested. The tumours may be invasive or in situ.
ICD-O code
8084/3
Epidemiology
This rare SCC variant often occurs on sun-damaged skin of older men.
Etiology
The risk factors appear to be similar to those for conventional SCC.
Localisation
The head and neck are affected most frequently. Similar tumours on the glans penis may behave aggressively.
Clinical features
These tumours, which often present in elderly men, have no clinical features to distinguish them from conventional SCC. The presence of ducts, highlighted by staining for CEA and EMA (epithelial membrane antigen), helps to identify porocarcinoma, hidradenocarcinoma, and dermal duct tumours. In clear cell cytokeratin fibroxanthoma, atypical staining is negative and keratinization is absent {1899}. Clear cell and balloon cell melanomas stain for melanocyte markers. If there is no evidence of epidermal origin, metastatic carcinomas should be considered, especially from the kidney (PAX8-positive).
Genetic susceptibility
The genetic susceptibilities are unknown beyond those associated with conventional SCC.
Prognosis and predictive factors
The prognosis of clear cell SCC is comparable to that of other SCC types.
Other (uncommon) variants
Definition
The other variants of cutaneous squamous cell carcinoma (SCC) are a poorly defined group of uncommon tumours that exhibit differentiation characterisation stromal responses that result in diagnostic ambiguity.
ICD-O codes
Squamous cell carcinoma with sarcomatoid differentiation 8074/3
Lymphoepithelioma-like carcinoma 8082/3
Pseudovascular squamous cell carcinoma 8074/3
Squamous cell carcinoma with osteoclast-like giant cells 8035/3
Synonyms
For SCC with sarcomatoid differentiation: carcinosarcoma; metaplastic carcinoma; pseudosarcomatous squamous cell carcinoma; sarcomatoid squamous cell carcinoma; For pseudovascular SCC: pseudoangiosarcomatous squamous cell carcinoma; pseudovascular adenoidsquamous cell carcinoma;pseudo angiomatous squamous cell carcinoma {1410}
Epidemiology
These SCC variants are exceedingly rare.
Etiology
The etiology is similar to that of common forms of SCC.
Localization
SCC with sarcomatoid differentiation typically involves sun-exposed skin of the face and head, neck, chest, and upper Lymphoepithelioma-like extremities. Carcinoma (LELC) of the skin typically involves sun-exposed skin, most often of the head and neck. Pseudovascular SCC affects ultraviolet (UV) radiation—damaged skin of the head and scalp, and typically occurs in elderly individuals. SCC with osteoclast-like giant cells (SCC-OGC) generally involves the head and neck of elderly individuals.
Clinical features
These rare variants of SCC typically show rapid growth but have no individually characteristic features.
Histogenesis
The rarity of these uncommon variants precludes definitive data regarding histogenetic pathways. Although LELC of the skin histologically resembles undifferentiated nasopharyngeal carcinoma(lymphoepithelioma), a strong association with EBV has not been demonstrated, which facilitates this variant’s distinction from lymphoepithelioma.
Prognosis and predictive factors
Some pseudo vascular SCCs and SCC OGCs demonstrate more-aggressive biological behaviour than do other SCC variants.
Reference:
WHO classification of skin tumours, 4th edition (2018): 35-45.
Squamous cell carcinoma in situ (Bowen disease)
Definition
Squamous cell carcinoma (SCC) in situ, also known as Bowen disease, is SCC confined to the epidermis and superficial adnexal epithelium, further characterised by full-thickness involvement of the epidermis by dysplastic squamous cells. The term “Bowen disease” was originally used specifically to describe SCC in-situ in sun-protected skin as a harbinger of internal malignancy, but the terms “Bowen disease” and “SCC in situ” are now used interchangeably to describe epidermal SCC in situ of both sun-dam-aged and sun-protected skin.
Synonyms
Intraepidermal carcinoma; Bowenoid papulosis; keratinocytic intraepidermal neoplasia (KIN Ill) Vulvar intraepithelial neoplasia (VIN Ill), penile intraepithelial neoplasia (PelN Ill), erythroplasia of Queyrat, and anal intraepithelial neoplasia (AIN Ill) are discussed in the relevant WHO classifications of tumours of the corresponding organ systems.
Epidemiology
Most cases present in the sun exposed skin of elderly White patients with higher cumulative sun exposure, with a median age of presentation > 60 years. Specific populations at higher risk of SCC in situ include organ transplant recipients on immunosuppressive regimens and populations with long-term exposure to high levels of arsenic in drinking-water. Ultra-violet (UV) radiation exposure from tanning beds has resulted in an increased number of young people presenting with SCC in situ, but the finding of SCC in situ in a young person with minimal sun damage should prompt consideration of arsenic exposure.
Etiology
Most cases of SCC in situ (Bowen dis-ease) are caused by UV radiation expo-sure, including UVB and UVA radiation exposure from sunlight or tanning beds. Radiotherapy and photo chemotherapy are also etiological. High-risk (alphagenus) HPV infection is the major cause of SCC in situ involving the peri-ungual region and genital skin. The terms “VIN Ill” and “PelN Ill” are used for genital lesions. Beta genus papilloma viruses may have synergistic effects with UV radiation in the setting of immunosuppression due to organ transplant or HIV infection in causing some cutaneous SCCs in situ. Arsenic ingestion can play a role in SCC in situ in non sun exposed skin.
Localisation
SCC in situ predominantly involves sun-exposed skin, but also occurs in non sun exposed skin. Typical sites of involvement include the lower limbs, head, neck, and hands. Less commonly affected regions include subungual, periungual, genital (VIN Ill, PelN Ill, and erythroplasia of Queyrat), and perianal (AIN Ill) sites.
Clinical features
SCC in situ usually presents as a solitary, slow-growing, scaly, erythematous patch or plaque, which can remain unchanged for many years. Clinical features include crusting, pigmentation, and a verrucous appearance. Dermoscopic features include scale, glomerular vessels, yellow crust, haemorrhage, hypopigmentation, and linear irregular vessels.
Histogenesis
UV radiation—induced mutations of TP53play a role in the development of many SCCs. SCC in situ in the context of arsenic exposure arises from oxidative stress, depletion of natural antioxidants, immune dysfunction, genotoxicity, impaired DNA repair, and disrupted signal transduction{1155}.
Genetic profile
UV radiation—induced mutations of the gene encoding p53, which is centrally involved in cellular apoptosis, proliferation, and DNA repair, are present in 40%of SCC in situ cases. Amplification and activating mutations of HRAS, NRAS, and KRAS, likely due to UVB radiation exposure, are common. Molecular and cytogenetic studies pro-vide supporting evidence that SCC in situ and actinic keratoses are precursors of invasive SCCs.
Prognosis and predictive factors
Approximately 3—5% of all SCC in situ lesions progress to invasive SCC; among erythroplasia of Queyrat lesions specifically, the proportion is 10%.
Reference:
WHO classification of skin tumours, 4th edition (2018): 46-47.