Squamous cell carcinoma (SCC)
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 estab-1ish, but data on non-melanoma skin cancer suggest that there were an estimated701 000 SCC tumours affecting 430 500people 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.
Localisation
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.