New Update on Squamous Cell Carcinoma, Risk Factor, Classification, Pathogenesis, Treatment

Dermatology is updated day by day here we are presenting new update on squamous cell carcinoma. Squamous cell carcinoma is a malignant tumor arising from epidermal keratinocytes or its appendages. The likelihood of developing cSCC is dependent upon exposure to risk factors (most importantly ultraviolet light) and patient-specific characteristics such as age, skin type, and ethnicity.

Epidemiology

Incidence and prevalence

Squamous cell carcinoma is the second most common skin cancer. While cSCC traditionally accounted for 20% of skin cancers, a recent study cited a 1:1 ratio between basal cell carcinoma (BCC) and SCC.

Worldwide its incidence has been increasing since 1960.  This increase may be related to higher levels of sun exposure, tanning bed use, an increase in the aging population, and improved skin cancer screening and detection.

Organ transplant recipients, who are at an increased risk due to immunosuppression, are at a 65-250 fold excess risk for developing SCC and dying from it compared with the general population.

Geographic variation

The incidence of cSCC is higher in countries closer to the equator. In Australia, for example, there are approximately 1035 and 472 cases per 100,000 for men and women, respectively. In contrast, the age-adjusted incidences for men and women in Finland are only about 6 and 4 per 100,000.

Age

The incidence of SCC increases with age. For those over 75, the incidence is approximately 5 to 10 times higher than the incidence in younger age groups and 50 to 300 times higher than for those under 45.

Sex

Males are more at risk of developing SCC, possibly due to outdoor employment and differences in sun avoidance behavior than female.

Ethnicity

Squamous cell carcinoma is predominately a disease of white populations (Fitzpatrick skin types I- III) and is especially prevalent in this group in areas of highambient sun exposure. This finding is likely related to the protective effect of epidermal melanin against the carcinogenic effects of ultraviolet light.

Factors implicated in the pathogenesis of cutaneousmalignancy in Africans and African Americans include chronic wounds, trauma,albinism, burn scars, ionizing radiation, chronic inflammationand chronic discoid lupus erythematosus.

Pathophysiology

cSCC carries more mutations than other common malignancies5 times the mutation rates in lung cancerand >4 times the mutation rates in melanoma.Through the accumulation of these mutations and other cellular changes, an area of skin (usually in response to ultraviolet light damage) can progress through increasing levels of dysplasia and transform into a cSCC.

Among them there are 4 major mutations of cSSC

• Mutation of TP53
• Caused by UVR and are frequently seen in AK and approximately 90% of SCCs.The vast majority of TP53 mutations are C→T and CC→TT tandem double transition mutations, considered the ‘mutational signature’ of UV exposure. These mutations have a strong tendency to occur at methylated cytosines and studies have shown that this methylation process increases the frequency of UVB‐induced cyclobutane pyrimidine dimer formation by 1.7 fold, confirming that methylationper se influences the probability of cell damage.
• Mutation of TP53 fails to call BAX when there is unrepairable damage to DNA such that BCl2 persists which stabilizes the mitochondrial membrane preventing leakage of cytochrome C.This enables tumor cells to resistapoptosis and expand clonally at the expense ofneighboring normal keratinocytes.
• cyclin-dependent kinaseinhibitor 2A (CDKN2A) mutations
• p16 is also a tumour suppressor protein encoded by the CDKN2Agene in the 9p21 region. It is involved in the arrest of the cell cycleat G1, suppressing the entry into the S phase. p16 mutations can also be caused by UVR. Inactivation of p16 leads to continuouscell cycling and it is thought that inactivated p16 advances AKto SCC
• Ras mutations
• 15- 30 percent of patients treated with BRAF inhibitors, such as vemurafenib and dabrafenib, develop cSCCs or keratoacanthomas. The first lesions typically appear within weeks of the start of therapy. This occurrence may be related to a paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in cells harboring preexisting RAS or receptor tyrosine kinase mutations, an event that may contribute to the proliferation and survival of cancerous cells.
• Notch homolog 1 mutation

It is a tumor suppressor gene that acts as agatekeeper event in cSCC carcinogenesis.

Somatic mutations of NOTCH receptors (NOTCH 1 andNOTCH 2) have been implicated in about 75% of SCCs. MostNOTCH mutations in SCC result from a G→A transition inducedby UVR after homozygous TP53 loss, consistent with evidence ofits role in tumor progression.

Update in Pathophysiology

Mutations in TP53 and Ras have been found in sun-damaged skin (actinic keratosis). This suggests that mutations in TP53, CDKN2A, and Ras may be early events from ultraviolet light damage that set the stage for cSCC development, but other additional mutations are likely required for tumor formation and growth.

Biomarkers in cutaneous squamous cell carcinoma

PD-L1 — The differential expression of programmed cell death ligand 1 (PD-L1) according to histologic grade and other high-risk features in cSCC has been evaluated. In a study of cSCC on the head and neck, PD-L1 expression was a significant risk factor for nodal metastasis

INPP5A — Inositol polyphosphate 5-phosphatase (INPP5A) appears to be a useful tumor marker in cSCC. In a study of 174 patients with actinic keratosis and cSCC, low expression of INPP5A was associated with a nearly fivefold higher risk of local metastasis and a nearly threefold higher risk of death.

p300 — The transcriptional coactivator p300 was found to be associated with advanced clinical stage and shown to be an independent prognostic factor of poor overall survival in a study of 165 cSCC tumors.

TERT promoter — A study of 152 cSCC lesions corroborated prior findings that patients with telomerase reverse transcriptase (TERT) gene promoter-mutated cSCC are at increased risk for local recurrence and lymph node metastases.

CD133 — The expression of cancer stem cell marker CD133 in cSCC samples from 165 patients was deemed to be an independent predictor of poor overall survival.

Epidermal growth factor receptors– Evidence in support of a relevant role of EGFR expression includes a retrospective study that found that primary cSCCs that subsequently metastasized were significantly more likely to overexpress EGFR than tumors that did not metastasize, as well as documentation of improvement of advanced or unresectablecSCC after treatment with cetuximab, an EGFR inhibitor.

Risk Factors

UV light exposure

 Ultraviolet (UV) radiation is absorbed by DNA and can result in DNA damage. Cumulative sun exposure (principally UVB radiation) is the most important environmental cause of cSCC. However UVA (present in PUVA, tanning beds) also has an etiologic role.

Ionizing radiation 

Ionizing radiation (such as that used for acne, tineacapitis, and cancer), grenz-rays (used for psoriasis and other skin diseases), and gamma rays are associated with the development of cSCC which is more aggressive, with high rates of recurrence and a 10% to 30% rate of metastasis.

Immunosuppression

Chronicimmunosuppression (eg, secondary to solid organ transplantation, human immunodeficiency virus [HIV] infection, or longterm glucocorticoid use) may increase the incidence of cSCC.Immunosuppression can play a major role incSCC, with solid organ transplant recipients(SOTRs) bearing 65 to 250 times the risk of cSCCcompared with the general population.

The risk of cSCC is determined by the age at transplantation, duration of transplant, level of immunosuppression and previous solar damage.Heart and lung transplant recipientstend to have a higher risk of cSCC than renaltransplant recipients because of the more intensive immunosuppression regimens and the older age of these patients.The risk of cSCC development is greater for SOTRs in general than it is for hematopoietic stem cell transplant recipients.

Patients with chronic lymphocytic leukemia, who lack a competent cell-mediated and humoralimmunity, also have an 8 to 10 fold increased risk for developing cSCCwhich may display a more aggressive behavior.

Chronic inflammation

There is an increased risk of cSCC in chronically inflamed skin resulting from scars, burns, chronic ulcers, sinus tracts,postradiation or inflammatory dermatoses such as lichen sclerosus et atrophicus.

Chemical carcinogens

The epidemiology of the disease has changed over the last 50 years, with a decrease in the importance of occupational exposure to chemical carcinogens and an increase in the proportion of cases caused by recreational sun exposure and an ageing population.

• Arsenic exposure — Consumption of contaminated drinking water and occupational exposure (previously used in pesticides containing lead arsenate) are associated with cSCC.

• Polycyclic aromatic hydrocarbons (tar,pitch, and soot), nitrosamines, and alkylating agents are also implicated in causing cSCC.

Family history — Individuals with a family history of cSCC may have an increased risk for developing the disorder.

Inherited disorders

Xerodermapigmentosum 

Xerodermapigmentosum (XP) is a rare disorder, in which there is an impaired ability to repair UV-induced DNA damage. In these individuals, the incidence of skin cancers prior to the age of 20 years is approximately 2000 times that seen in the general population.

Epidermolysisbullosa

Patients with recessive dystrophic EB (RDEB), and particularly those with the Hallopeau-Siemens subtype of RDEB (HS-RDEB) are at increased risk of cSCC beginning in adolescence.

Albinism–

Individuals with albinism must protect themselves from sunlight, or they risk the early development of both cSCC and BCC.

Epidermo dysplasia verruciformis 

Epidermodysplasiaverruciformis is a rare disease characterized by extreme susceptibility to cutaneous human papillomavirus (HPV) strains 5 and 8 and cSCC.

HPV infection–

Oncogenic human papillomavirus (HPV) can be associated with cSCC, particularly periungal and anogenitalcSCC. HPV types 16 and 18 possess E6 and E7 proteins that prevent apoptosis and allow for continuous replication of viral DNA by regulating p53 and retinoblastoma (Rb), respectively. Rb normally holds E2F. If Rb is destroyed E2F floats around free which is then used by cells to move from G1 to S phase.

Squamous Cell carcinoma

Update on Risk factors

Drugs

Voriconazole 

Long-term therapy with the antifungal drug voriconazole has been associated with the development of cSCC in immunosuppressed patients, including children.

Other photosensitizing drugs-A 2018 meta-analysis of seven observational studies confirmed the association between cSCC and use of diuretics(in particular thiazide diuretics).

BRAF inhibitors — 

Between 15 and 30 percent of patients treated with BRAF inhibitors, such as vemurafenib and dabrafenib, develop cSCCs or keratoacanthomas. The first lesions typically appear within weeks of the start of therapy.

Oral contraceptives — 

Case-control studies have reported an increased risk of cSCC among women with a history of oral contraceptive use

ABO blood group

The risk of developing a cSCC was 14 percent lower among patients with A, AB, or B blood types compared with those with type O blood.

Selenium 

A double blind trial of selenium among those with a prior history of nonmelanoma skin cancer suggested that there was an increased risk of cSCC associated with dietary selenium supplementation.

Vitamin D 

Although animal and laboratory studies suggest that vitamin D may reduce the risk of skin cancerthere is insufficient evidence to make a recommendation regarding vitamin D supplementation to reduce cSCC risk.

Radon

Locations with the highest radon concentrations had an almost two-fold increase in reported cSCCs compared with areas with the lowest radon concentrationsin a study in the United Kingdom

Smoking 

Individual epidemiologic studies have yielded conflicting results about the role of smoking as a risk factor for cSCC.

Diet 

There are conflicting results about the role of diet as a risk factor for cSCC. Several prospective studies have suggested that a diet high in meat and fat significantly increases the risk of cSCC.

Other genetic syndromes 

Several other rare genetic disorders are associated with increased incidence of cSCC and younger age of onset including Fanconi’s anemia, Ferguson-Smith syndrome (keratoacanthomas), dyskeratosiscongenita, Rothmund-Thomson syndrome, Bloom syndrome, and Werner syndrome.

Associated diseases

SCCs mayalso be associated with other diseases such as hidradenitissuppurativa, morphoea, lymphoedem, Hailey–Hailey disease.

Clinical features

History

The most common sites for SCC are those most exposed to the sun like backs of the hands and forearms, the upper partof the face and, especially in males, on the lower lip and pinna.

Presentation

SCC in situ (Bowen’s disease) 

Cutaneous SCC in situ typically presents as a well-demarcated, scaly patch or plaque. Lesions are often erythematous but can also be skin colored or pigmented. SCC in situ lesions tend to grow slowly, enlarging over the course of years. Unlike the inflammatory disorders that may resemble SCC in situ, lesions are usually asymptomatic.

Erythroplasia of Queyrat 

Erythroplasia of Queyrat is a term used to describe SCC in situ involving the penis. This condition presents as a well-defined, velvety, red plaque. Patients may experience pain, bleeding, or pruritus.

Invasive SCC 

Squamous cell carcinomas often arise in photodamaged skin. The first clinical evidence of malignancyis induration. The area may be plaque‐like, verrucous, tumidor ulcerated, but in all cases the lesion feels firm when pressedbetween the finger and thumb.

The limits of the induration arenot sharp and usually extend beyond the visible margin of thelesion. The resistance to pressure is much greater than that given by an inflammatory lesion or benign epithelial hyperplasia.The tissue around the tumour is inflamed and the edge is anopaque yellowish red colour.

The better‐differentiated tumoursare usually papillomatous and are capped by a keratotic crustin the earlier stages. This may be shed later to reveal an ulcer oreroded tumour with an indurated margin and a purulent exudingsurface that bleeds rather easily.

The outline may be rounded, but is often irregular, and in pre‐malignant lesions the induration andelevation is often asymmetrical at first.

Other variants

Oral SCC — Oral SCC usually presents as an ulcer, nodule, or indurated plaque involving the oral cavity may arise in sites of erythroplakia (premalignant, persistent, red patches in the oral cavity) or leukoplakia (oral, persistent, white plaques).

Keratoacanthoma — Keratoacanthomas are keratocytic epithelial tumors that clinically and histologically resemble SCC. It is controversial whether keratoacanthomas represent a subtype of well-differentiated SCC or a separate entity.

Verrucous carcinoma — Verrucous carcinoma is a subtype of SCC that presents with well-defined, exophytic, cauliflower-like growths that resemble large warts. Lesions are subclassified according to site:

• Oral florid papillomatosis –Verrucous carcinoma of the oral mucosa
• Anogenital(also known as giant condylomaacuminatum of Buschke-Loewenstein) –Verrucous carcinoma involving the penis, scrotum, or perianal region
• Epitheliomacuniculatum – Verrucous carcinoma on the plantar foot

SCC of the lip — SCC of the lip primarily occurs on the lower lip. Lesions may present as nodules, ulcers, or indurated white plaques.

Marjolin’s ulcer — Marjolin’s ulcer is a term used to describe a rare type of SCC arising in sites of chronic wounds or scars. The malignant transformation is usually slow, with an average latency time of approximately 30 years.

Cutaneous metastases — The most frequent site of metastasis for cutaneous SCC is the regional lymph nodes; other potential sites for metastasis include the lungs, liver, brain, skin, or bone. Metastases to the skin can present with erythematous papules or nodules that resemble primary lesions of cutaneous SCC.

Differential diagnosis

1. Keratoacanthoma-have a faster rate of growth and involute to leave a scar.
2. Actinic keratosis-multiple and lack a dermal component on palpation.
3. Viral warts or seborrhoeic keratosis- not indurated and are frequently multiple.
4. Bowenoidpapulosis– Transitional state between genital warts and SCC in situ
5. Others-
6. SCC in situ-Nummular eczema, psoriasis, inflamed SK, viral warts, superficial BCC, Amelanotic melanoma, paget disease
7. Well differentiated SCC- viral warts, prurigo nodules, Merkel cell carcinoma, BCC, Atypical fibroxanthoma, amelanotic melanoma, cutaneous metastasis
8. SCC with granulomatous or verrucous lesions- Pyogenic granuloma, deep fungal infection, mycobacterial infection
9. SCC with non healing ulcer- BCC, pyodermagangrenosum, venous stasis ulcers, traumatic ulcers

Histopathology

Although clinical findings may strongly suggest a diagnosis of SCC, histopathologic examination is necessary to confirm the diagnosis.

SCC in situ — SCC in situ (Bowen’s disease) is diagnosed when histopathologic examination reveals keratinocytic dysplasia involving the full thickness of the epidermis without infiltration of atypical cells into the dermis.

The keratinocytes are pleomorphic with hyperchromatic nuclei, and numerous mitoses are present. In contrast to SCC in situ, actinic keratoses demonstrate only partial-thickness epidermal dysplasia.

Invasive SCC — Invasive SCCs have dysplastic keratinocytes involving the full thickness of the epidermis that penetrate the epidermal basement membrane to involve the dermis or deeper tissues.

Histological variants of SCC have been described: classic/no special type, acantholytic, spindle cell, desmoplastic, basaloid, verrucous,pseudovascular and follicular. The classic/no special type is the most common variant.

The cells of SCC vary from large, polygonal cells with vesicular nuclei, prominent nucleoli and an abundant cytoplasm to pleomorphic cells which provide no clear cytological evidence of their origin.

In 1921, Brodersdevised a histologic grading system for cSCC as follows:

Histologic grading	Percentage of well differentiated cells
1	>75%
2	50-75%
3	25-50%
4	<25%

In practice, many pathologistsuse the phrase well-differentiated to mean thatnearly all the cells are well-differentiated, moderatedifferentiation to indicate there are areas withoutclear keratinization, horn pearls, and other classicfeatures of cSCC, and poor differentiation to indicatethat it is difficult to determine a keratinocyte lineage

Occasionally, the keratinocytic origin of the cells can only be determined by immunohistochemical stains.

Update in Histopathology

• Histologically, verrucous carcinomas have an endophytic component with well-differentiated squamous epithelium and pushing borders.
• Some histologic subtypes of cSCC bear a poor prognosis. DesmoplasticcSCC is highly infiltrative, recurs 10 times more frequently, and metastasizes 6times more frequently than other cSCC variants.The adenosquamous variant, characterized by secretory tubular structures,is another subtype reported to have a high risk of local recurrence, metastasis, and death.

Factors associated with local recurrence and metastases

Diameter

A tumor diameter >2.0 cm doubles the risk of cSCC recurrence and triples the rate ofmetastasis compared to lesions<2 cm in diameter.

Depth–

The risk factor most highly associated with recurrence and metastasis is tumor depth, with tumors of Breslow thickness>2mm having a 10-fold higher risk of local recurrence and tumors extending beyond subcutaneous fat (into deeper layers, such as the fascia, muscle, perichondrium, and periosteum) having an 11-fold higher risk of metastasis compared with more superficial tumors.

Perineural involvement–

The overall incidence of perineural involvement in cSCC is 2% to 14%.Perineural invasion of large-caliber nerves (involvednerves measuring >0.1 mm) is associated with increased nodal metastases, disease-specificmortality, local recurrence and metastatis.

Histologic differentiation–

The presence of poor differentiation indicates a poorer prognosis with high local recurrenceand a metastatic risk than that of well-differentiated cSCCs.

Previously treated/recurrent cSCC-

Once a cSCC has recurred, it has a much worse prognosis, with risk of spread to regional lymph nodes and distant metastases.

Site-cSCC of the ear and lip has a reported higher recurrence risk.

cSCC arising in scar-cSCCs arising from a leg ulcer, burn scar, radiation dermatitis, discoid lupus, and other chronic wounds have a reported metastatic risk of 26%.

Immunosuppression-cSCCs in immunosuppressed patients may display more rapid growth, recur locally in 13% of patients,and have a 5-8% risk of metastasis, usually in the second year after excision.Prognosis is usually worse for older patients with tumors located on head and neck skin, when multiple tumors are present, and when there is a history of high exposure to the sun.

Classification Schemes

Brigham and Women’s Hospital Tumor classification system

The Brigham and Women’s Hospital (BWH) staging system, proposed in 2013, offers an alternative tumor (T) classification system but does notinclude N or M staging criteria.

Two studies consisting of a total of 2074 cSCCs showed the BWH T classification to have improved prognostic discrimination over AJCC-7 with BWH T2b cSCCs carrying an elevated risk of nodal metastases (24% and 37%)and disease-specific death (16% and 20%) because of cSCC. However it should ideally becompared against the new AJCC-8 T classification in a larger population-based cohort.

Update on classification of Squamous cell carcinoma

Update on Classification

AJCC-8 staging system

The new AJCC-8 staging system (2016) is based on multiple studies published since AJCC-7 (2010), which show the most relevant prognostic risk factors for cSCC. The low number of cases meeting T3 and T4 criteria had been a criticismof AJCC-7. The expansion of the T3 category in AJCC-8 will likely lead to more cases and more poor outcomes occurring in this category. The N category currently reflects the evidence-based data showing decreased survival with increasing node size, increased number of nodes, and extracapsular extension.However given that this staging system has recently been introduced, its prognostic accuracy has yet to be validated.

American Joint Committee on cancer cutaneous SCC staging system of tumor of head and neck

National Comprehensive Cancer Network(NCCN)

Current National Comprehensive Cancer Network (NCCN) clinical practice guidelines for cSCC provide an approach to stratifying high-risk and low-risktumors.This stratification takes both clinical andpathologic parameters into account and is based on acombination of available evidence and expert opinion. The NCCN risk stratification is primarilyintended to provide health care providers with practical clinical guidance on how to treat cSCCrather than to provide accurate prognostication and assess outcome as the BWH system does.

Complications and co‐morbidities

Surgery to excise the tumour may resultin large scars or skin grafts on cosmetically visual sites. In somepatients, multiple or large tumours may develop requiring extensivesurgery.

Disease course and prognosis

Squamous cell carcinomas, in the absence of high‐risk features,carry an excellent prognosis. SCCs with high‐risk features, have a greater potentialfor local invasion and to develop metastases.

Investigations

Biopsy

Although clinical findings may strongly suggest a diagnosis of SCC, histopathologic examination is necessary to confirm the diagnosis, assess for perineural invasion, tumor differentiation, and tumor depth.The recommended biopsy techniques for cSCC are punch biopsy, shave biopsy, and excisional biopsy.

The biopsy technique used will depend on the characteristics of the suspected malignancy (morphology, location, etc.) and the judgment of the physician. The biopsy size and depth should be adequate(extend at least into the mid-reticular dermis). Repeat biopsy may be considered if the initial biopsy specimen is inadequate for accurate diagnosis.

While reporting features like degree of differentiation and, whenpossible and appropriate, any features that would classify the lesion as high risk, including aggressive histologic subtypes (acantholytic, adenosquamous,and carcinosarcomatous), depth greater than 2 mm (measured from the granular layer of the adjacent intact epidermis), Clark level IV or greater, andpresence of perineural and/or angiolymphatic invasion should be mentioned.

The presence of prognostically favorable features, such as histopathologic subtype, including verrucous carcinoma and keratoacanthomatous SCC, may be clinically useful.

Imaging

Imaging to evaluate for nodal involvement may be considered forhigh-risk tumors (eg. BWH category >=T2b). Imaging may also be considered to assess for deep structural involvement with extensive localized disease.

Computed tomography and magnetic resonance imaging —

. CT and MRI are the most common initial radiologic tests used in the assessment of patients with cutaneous SCC. Although conventional CT and MRI scans add little to the clinical examination of a node‐negative region they are useful for evaluating tumor extent for preoperative planning and staging in patients with large or deeply invasive lesions.

 CT is superior to MRI for the evaluation of skull base invasion, involvement of cartilage, and bone erosion or destruction, while MRI is more useful for detecting perineural invasion, providing soft tissue contrast, defining tissue planes, and identifying bone marrow infiltration in the absence of significant osseous destruction.

Positron emission tomography 

The use of PET in the setting of malignancy has risen with increasing test availability and decreasing test cost. PET functions through the detection of the accelerated uptake of intravenously administered fluorodeoxyglucose that occurs in tumor cells.

A beneficial feature of PET is its ability to detect metastases in sites of fibrosis, necrosis, and dense scarring related to radiotherapy, areas that may be difficult to assess with other studies. However, false-positive results are common with PET due to the incidental detection of metabolically active inflammatory, infectious, or other lesions.

Another, less favorable feature of PET is the poor spatial resolution attained with this study. The integration of PET and CT (PET/CT) has addressed this issue through providing improved anatomic correlation.

Ultrasound and ultrasound-guided fine needle aspiration cytology

USG spares the radiation exposure associated with CT, but the utility of this procedure may be compromised by operator-dependent accuracy, difficulty in following specific lesions over time, and reduced ability to detect metastases to deep lymph nodes.

The last item may be less of a concern in cutaneous SCC, which typically metastasizes to superficial lymph nodes. In cases where an SCC is deemed very high risk, particularly when drainage is to the parotid nodes, ultrasound has been shown to be a sensitive and accessible method of evaluating the lymph nodes especially when combined with a guided fine needle aspiration (FNA) or core biopsy.

Update on Investigations

Dermoscopic clues

Dermoscopy can help to establish the diagnosis of cSCC. cSCC is characterized under dermoscopy by 2 vascular patterns: small dotted vessels andglomerular vessels. Pigmented cSCC in situ can also have small brown globules and a gray-brown homogenous pigmentation on dermoscopic examination. Invasive cSCC tends to have looped/hairpin and serpentine vessels.

Sentinel lymph node biopsy

The role of SLN biopsy in the management and outcome of patients with high-risk cutaneous SCC has not been evaluated in randomized trials. Data from observational studies are insufficient to determine whether early detection of microscopic metastatic disease has a beneficial effect on patient survival.

Nuclear morphometry 

A retrospective case series of 40 patients evaluated the utility of nuclear morphometry (karyometry) for differentiating between aggressive and nonaggressive SCCs. Investigators found that karyometric classification scores correlated with tumor behavior.

Others

A number of new techniques such as reflectance confocal microscopy and highresolutionoptical coherence tomography are currently being evaluated but image quality is variable due to hyperkeratosis seen in SCC, thickness of the tumourand illumination not adequately reaching deeper structures resulting in unreliable images.

Management

Patients should be given a thorough explanation of the diagnosisand signs to observe should any future tumors arise. Ideally, they should be reviewed by the clinical nurse specialist, who can provide sun avoidance information, detailed information about their tumor and self‐examination of the skin and lymph nodes.

A treatment plan that considers recurrence rate, preservation of function, patient expectations, and potential adverse effects is recommended.

Surgical treatment

On the basis of the limited available data and consensus opinion, for low risk cSCCNCCN guidelines recommend 4 to 6 mm clinical margins to a depth of the mid-subcutaneous adipose tissue.Standard excision may be considered for selected high-risk tumors.

However, strong caution is advised when selecting a treatment modality for high-risk tumors without a complete margin assessment.The completeness of the procedure must be evaluated through histologic assessment of the specimen’s margins. For incompletely excised SCC, further excision with circumferential histologic margin control or Mohs micrographic surgery should be advised.

Mohs Micrographic surgery (MMS)

Mohs surgery, a specialized tissue-sparing procedure that involves histologic assessment of 100 percent of the excised tumor margins. During the procedure, frozen sections encompassing 100 percent of the tissue margin are examined by the surgeon, allowing for confirmation of the removal of the tumor prior to wound closure.

MMS is recommended for high-risk cSCC and tumors in cosmetically or functionally sensitive areas where excision with a 4 to 6 mm margin may lead to significant cosmetic, anatomic, or functional distortion. Asymmetric subclinical extensionbeyond the clinically visible tumor, and perineural involvement in cSCCsupport the importance of meticulous and complete margin assessment with MMS.

However, aggressive histopathologic growth patterns poorly visualizedwith frozen sections (eg, sarcomatoid/spindle cell or single cell infiltrative cSCC) may limit the utility of MMS under certain circumstances. An additionallimitation is that tissue blocks from MMS layers are not available for molecular testing or further evaluation of high-risk or unusual features by usingparaffin sections.

To overcome this challenge, the tumor debulk specimen may be submitted for paraffin sections to document high-risk features and obtain ancillary molecular studies, if indicated, without compromising the integrity of the MMS procedure.

Curettage and electrodessication

C&E is regularly used in daily practice for the treatment of low-risk cSCC. The limited available data suggest that C&E is aneffective treatment modality for properly selectedtumors, although results are highly operator dependent.

C&E may be considered for small, low-risk primary cSCC. Lesions on terminal hair bearing skin (the scalp, pubic, axillary regions, and the beard area in men) should be excluded from treatment with C&E because of potential follicular extension of tumor.

Moreover, C&E may be associated with a longerhealing time and inferior cosmetic outcome compared with standard excision and is best avoidedin cosmetically sensitive areas.

Nonsurgical Treatment

Radiation therapy

Primary radiation therapy can be used in special situations in which surgery is not feasible, contraindicated, or not preferred by the patient after a discussion of risks and benefits. Several different types of radiotherapy can be used to treat cSCC, including superficial radiation therapy, isotope-based brachytherapy (interstitial or topical contact), or external electron beam radiation.

Primary or adjuvant radiation therapy is an effective treatment option for selected patients with cSCC, resulting in good tumor control and cosmesis,with the understanding that the cure rates may be lower. Smaller and thinner tumors may be more responsive to radiation therapy.

Primary cSCC with concerning perineural invasion or otherwise at high risk for regional or distant metastasis may be considered for adjuvant radiation therapy to the local tumor site following surgical treatment. High-level evidence about the effectiveness of this approach is lacking.

Cryosurgery

Given the lack of histologic margin control with this approach, as well as the known risk for subclinical extension of cSCC, cryosurgery should be considered only for low-risk lesions, when more effective therapies are contraindicated or impractical.

The objective of cryosurgery, interchangeably referred to as cryotherapy, in the treatment of cSCC is to cause selective destruction of the same volume of tissue that would have been removed with standard excision. Although cryosurgery is frequently used for the treatment of precursor lesions (ie, actinic keratoses), limited data are available on its use forcSCC.

Update on treatment

Photodynamic therapy (PDT)

Photodynamic therapy (PDT) is a 2-part treatment consisting of topical application of a photosensitizer, either 5-aminolevulinic acid (ALA) or methylaminolevulinate (MAL), followed by 1 to several hours of incubation by light irradiation, typically with a blue, red, or broadband light source.

Limited case report and case series data suggest that PDT may be used as an adjuvant modality in combination with curettage and surgery for invasive cSCC in high-risk patients such as solid organ transplant recipients (SOTRs) and potentially to spare tissue, but the specific contribution of PDT to observed outcomes in such combination approaches is uncertain.

Topical therapies

The available data do not currently support the use of topical modalities for the treatment of cSCC. Published studies investigating the use of topical imiquimod or 5-fluorouracil (5-FU) for cSCC (excluding SCC in situ) are limited to case reports for imiquimod and 2 small case series for 5-FU.

Variable lengths of follow-up and histologic clearance limit the strength of these data. Because use of 5-FU typically results in marked erythema, erosions, and crust lasting for a month or longer, decreased patient compliance with treatment regimens mayresult in diminished effectiveness.

Similarly, imiquimod dosing for cSCC is complicated by the resultant tissue effects, including erythema, edema and erosions, ulceration and crust, that are not consistent from one individual to the next. In addition, imiquimod use for larger surface areas may be associated with systemic symptoms, including fatigue, influenza-like symptoms, myalgia, and headache.

Laser treatment

Treatment of cSCC by a Nd:YAG laser has been reported in a single retrospective study, with this extremely limited experience precluding the recommendation of laser for this indication.

Systemic Treatment

Treatment targeting the EGFR pathway 

Monoclonal antibodies (cetuximab, panitumumab) and oral agents (gefitinib, erlotinib) that target the epidermal growth factor receptor (EGFR) have antitumor activity in patients with advanced squamous cell carcinoma of the skin, as initially suggested by case reports and small studies.

Systemic chemotherapy 

There are only limited data on the role of systemic chemotherapy in the treatment of advanced cutaneous squamous cell carcinoma. Cisplatin-based combinations appear to be the most active regimens and have been adapted from those used for squamous cell cancers arising in other sites.

Anti-programmed cell death 1 protein (PD-1) antibody

Cemiplimab is a US Food and Drug Administration (FDA)-approved systemic therapy for locally advanced and unresectable and metastatic cSCC cases. Other anti-PD-1 and PD-L1 antagonists, such aspembrolizumab, have also been utilized in cases of locally advanced or unresectablecSCC unresponsive to other treatments.

Oral retinoids 

Although oral retinoids may reduce the development of new primary cSCCs, they have not been shown to impact the recurrence of aggressive SCCs.

Recommendations for management of locally advanced or metastatic SCC

• Surgical resection, with or without adjuvant radiation therapy and possible systemic therapy are recommended for regional lymph node metastases.
• Combination chemoradiation therapy should be considered for inoperable disease.
• Patients with advanced disease should be provided with or referred for best supportive and palliative care to optimize symptom management and maximize quality of life.

Recommendations for the follow-up

• After diagnosis of a first SCC, screening for new keratinocyte cancers (BCC or cSCC) and for melanoma should be performed on at least an annual basis.
• Patients with a history of cSCC should be counseled onskin self-examination and sun protection.
• Topical and oral retinoidsshould not be prescribed to reduce theincidence of keratinocyte cancers in those with a historyof cSCC, unless they are SOTRs. In the situation of SOTRs,only acitretin may be beneficial.

References:

1. Rook’s Textbook of Dermatology, 2016
2. Fundamentals of Pathology, Husain A. Sattar
3. SyrilKeenaT.Que, Fiona O. Zwald, Chrysalyne D. Schmults Cutaneous squamous cell carcinoma- Incidence, risk factors, diagnosis, and staging (2018) Journal of the American Academy of Dermatology Volume 78, Issue 2, Pages 237–247
4. Alam M., Armstrong A., Baum C., Bordeaux J.S., Brown M., Busam K.J., Eisen D.B. Guidelines of care for the management of cutaneous squamous cell carcinoma (2018)  Journal of the American Academy of Dermatology,  78  (3) , pp. 560-578
5. Migden MR, Rischin D, Schmults CD et al., PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2018;379(4):341. Epub 2018 Jun 4Cumsky HJL, Costello CM, Zhang N et al., The prognostic value of inositol polyphosphate 5-phosphatase in cutaneous squamous cell carcinoma, J Am AcadDermatol. 2019;80(3):626. Epub 2018 Oct 22. 
6. Giacchero D, Barrière J, Benezery K et al., Efficacy of cetuximab for unresectable or advanced cutaneous squamous cell carcinoma–a report of eight cases. ClinOncol (R CollRadiol). 2011 Dec;23(10):716-8. Epub 2011 Aug 9.
7. Cowen EW, Nguyen JC, Miller DD et al., Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole, J Am AcadDermatol. 2010;62(1):31. Epub 2009 Nov 6.
8. Su F, Viros A, Milagre C, Trunzer K et al., RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors, N Engl J Med. 2012;366(3):207.