INTRODUCTION — Cutaneous squamous cell carcinoma (cSCC) is a relatively common malignancy derived from epidermal keratinocytes. Although most patients with cSCC present with localized disease that is cured with local treatment, tumor recurrence, metastasis, and death related to this disease occasionally occur. "High-risk" cSCCs are tumors that exhibit clinical or histologic features that have been associated with increased risk for aggressive tumor behavior. The best approach to the management of high-risk cSCC is not definitively known. Mohs micrographic surgery (MMS), surgical excision with peripheral and deep en face margin assessment (PDEMA), radiation therapy, and cemiplimab are used in the management of these lesions.
The clinical and pathologic features of high-risk cSCC and the management of patients with these tumors will be reviewed here. The risk factors, prevention, and diagnosis of cSCC; the treatment of low-risk cSCC; and systemic therapy for advanced cSCC are reviewed separately.
EPIDEMIOLOGY — Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer, with more than one million tumors undergoing treatment in Medicare patients alone in the United States . It may occur in individuals of all races and ethnicities but most frequently occurs in people with lightly pigmented skin who sunburn easily. Highly curable, localized cSCC occurs most frequently; locoregional or distant metastases develop in <1 to 5 percent of cases [2-6]. In the United States, it has been estimated that approximately 5600 to 12,600 patients with cSCC develop nodal metastasis, and 4000 to 8800 patients die from cSCC annually . These figures are similar to the number of deaths from other cancers, such as melanoma, leukemia, non-Hodgkin lymphoma, renal cancer, or bladder cancer. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Epidemiology'.)
HIGH-RISK FEATURES — A wide variety of clinical and histopathologic factors have been proposed as indicators of increased risk for recurrence or metastasis of cutaneous squamous cell carcinoma (cSCC).
The National Comprehensive Cancer Network (NCCN) risk stratification and the American Joint Committee on Cancer (AJCC) staging system uniformly identify tumor diameter ≥2 cm, tumor invasion beyond subcutaneous fat or depth from the granular layer >6 mm, and perineural invasion (PNI) of nerves ≥0.1 mm in diameter as high-risk criteria (table 1) [4,8,9].
Examples of factors that have been associated with increased risk for metastasis or death on multivariate analysis in cohort studies include the three criteria identified by the NCCN and AJCC plus poor histologic differentiation, location on the ear, and immunosuppression [2,10-12]. Collectively, these may be the most significant drivers of poor outcomes in SCC. However, all major characteristics that have been associated with aggressive tumor behavior are reviewed below.
The NCCN definition of high-risk cutaneous squamous cell carcinoma — According to the 2022 National Comprehensive Cancer Network (NCCN) guidelines, the definition of high-risk cSCC based on risk factors for local recurrence, metastasis, or death is as follows :
•Lesions of any size located on the head, neck, hands, feet, pretibia, and anogenital area
•Lesions >2 to 4 cm located on the trunk or extremities (excluding pretibia, hands, and feet)
•Histopathologically acantholytic (adenoid), adenosquamous (showing mucin production), or metaplastic (carcinosarcomatous) subtypes, with PNI
●Very high-risk cSCC:
•Lesions >4 cm on any location
•Histopathologically poorly differentiated tumor, desmoplastic cSCC, >6 mm in thickness or invasion beyond the subcutaneous fat
•PNI – Tumor cells within the nerve sheath of a nerve lying deeper than the dermis or ≥0.1 mm
•Lymphatic or vascular involvement
Additional individual high-risk factors in high-risk groups (eg, organ transplant recipients, other settings of immunosuppression, genetic syndromes predisposing to the development of cSCC) include the total number of tumors and the frequency of development .
Clinical features — Clinical findings that have been used to identify high-risk cSCC include tumor location, tumor size, tumor status as primary or recurrent, and the presence of neurologic symptoms:
●Anatomic location – Certain tumor locations (eg, lips, ear, temple, cheeks) have been linked to increased risk for aggressive tumor behavior [2,5,6,14]:
•Local recurrence of cSCC is estimated to occur in 2 to 22 percent of lip tumors and in 5 to 19 percent of ear tumors. Metastasis develops in 3 to 20 percent and in 9 to 12 percent of these lesions, respectively .
•The relatively thin nature of auricular skin and the low depth of invasion required for the tumor to invade the perichondrium (approximately 2 mm) may contribute to the increased risk for local recurrence observed with tumors on the ear. In addition, the proximity of the ear to the lymph nodes of the parotid gland and neck may be an important factor for metastasis. A retrospective, cohort study of 353 patients with cSCC of the ear found that 10.5 percent of patients developed nodal metastasis, and the five-year, disease-specific survival in patients with nodal metastasis was significantly lower as compared with those without nodal metastasis (59 versus 99 percent) .
•Tumors on the cheek may also portend an increased risk for metastasis compared with tumors in some other sites. A retrospective study of approximately 9000 cases of primary cSCC found that tumors on the auricular area, lip, and cheek were more likely to metastasize than tumors on the lower leg [6,17]. While anatomic location of the lip or ear was initially included in cSCC staging systems, it is no longer considered a factor that warrants upstaging of a tumor due to improved data and refinement of these systems.
●Tumor diameter – Data from multiple studies suggest that tumors 2 cm or larger in diameter are more likely to behave aggressively than smaller tumors [4-6,18-23]. In a meta-analysis of 36 studies that included over 23,000 cSCCs in over 17,000 patients, tumors >20 mm were associated with increased risk of recurrence, metastasis, and disease-specific death (risk ratio [RR] 3.22, 95% CI 1.91-5.45; RR 6.15, 95% CI 3.56-10.65; and RR 19.10, 95% CI 5.80-62.95, respectively) .
The eighth edition of the AJCC staging system for cSCC designates a tumor size ≥2 and ≥4 cm as important for disease staging (table 1) . Tumors that reach the 2 and 4 cm thresholds are automatically upstaged from T1 to T2 and from T2 to T3, respectively.
However, the possibility that smaller lesions may metastasize should always be considered, particularly for lesions on the head and neck or displaying other high-risk features. In a prospective study of 266 patients with cSCC that metastasized to parotid or cervical lymph nodes, 70 percent of lesions measured ≤2 cm, indicating that factors other than tumor size likely contribute to metastatic risk . In concordance, lower size thresholds for identifying tumors on the head and neck as high-risk lesions have been proposed by some authors. (See 'The NCCN definition of high-risk cutaneous squamous cell carcinoma' above.)
●Recurrent tumors – Patients with tumors that recur locally after initial treatment are associated with an increased risk for the development of distant, metastatic disease. Between 30 and 50 percent of patients with metastatic cSCC have a history of local recurrence after surgical excision [5,23,26,27].
●Multiple tumors – Patients with multiple cSCCs have an increased risk of local recurrence or nodal metastasis. A single-institution study including 985 patients (239 patients with 2 to 9 tumors and 19 patients with ≥10 tumors) followed up for a median time of 50 months (range 2 to 142 months) found that patients with more than one tumor had a two- to fourfold increased risk of local recurrence and a three- to fourfold increased risk of nodal metastasis compared with patients with one SCC after adjusting for tumor stage . Tumor stage, but not the number of tumors, was associated with an increased risk of death from SCC.
●Location in sites of chronic wounds, scars, or ionizing radiation – Tumors that develop in sites of chronic wounds or scars have an increased likelihood for aggressive behavior [15,18,29]. The risk for metastasis for these lesions ranges from 26 to 38 percent . SCCs that arise in sites of prior radiation therapy may also be more likely to behave aggressively (table 2). In a retrospective study of patients with cSCC that arose in sites of prior radiation therapy or burns, 14 of 20 patients (70 percent) treated with prior radiation and 24 of 46 patients (52 percent) with preceding burn injuries experienced local recurrence or metastasis after surgical therapy :
•Neurologic symptoms – Nerve involvement by cSCC may present with symptoms of pain, numbness, or weakness . Deficits of cranial nerves V or VII are the most commonly detected neurologic symptoms with tumors on the head and neck [30,31]. Clinically evident invasion of named nerves may be associated with a lower likelihood for achieving local disease control than subclinical (incidentally found on histopathology) PNI [30,32-34].
A review of 12 studies, including 241 cSCCs in patients with clinical PNI and 381 cSCCs in patients with subclinical PNI, found no significant difference in the overall risk of nodal and distant metastasis by PNI classification . However, patients with clinical PNI had a higher risk of local recurrence and death from SCC compared with patients with subclinical PNI (37 versus 17 percent, and 27 versus 6 percent, respectively). (See 'Histologic features' below.)
Histologic features — Histologic features, such as the degree of tumor differentiation, histologic subtype, depth of tumor invasion, and the presence or absence of nerve involvement, influence the prognosis of cSCC. Tumors with poorly differentiated histology, deep microinvasion, or PNI are more likely to behave aggressively [14,35]:
●Histologic grade and subtype:
•Degree of differentiation – Well-differentiated tumors are less likely to exhibit aggressive behavior than less-differentiated tumors [6,18,20,36]. As an example, a retrospective study of 136 patients with invasive cSCC on the trunk or extremity treated at a tertiary care center between 1994 and 2004 found that poorly differentiated tumors were three times more likely to result in metastasis or death than well-differentiated or moderately differentiated tumors . Estimates of the risk for metastasis for poorly differentiated tumors have ranged from 33 to 58 percent .
•Desmoplastic growth pattern – Tumors with desmoplastic (infiltrative) growth patterns may also exhibit aggressive behavior [2,37,38]. Desmoplastic growth was an independent risk factor for tumor recurrence in a prospective study of 615 patients with cSCC . In another study of 1434 patients, desmoplastic growth was associated with a fourfold increase in mortality risk . In addition, a separate prospective study of 594 SCCs on the skin or lips found a 10-fold greater risk of local recurrence and a 6-fold increased risk of metastasis among tumors with desmoplastic growth (n = 44) compared with tumors without this feature .
Data are limited on the relationship between other histologic subtypes and tumor aggressiveness. A 2011 review of published data found insufficient data to support the designation of acantholytic SCC as a tumor with increased risk for aggressive behavior or metastasis , and the prognostic significance of cSCC with prominent mucin and a spindle cell component (myxoid spindle cell SCC) is unknown . At our institutions, we have observed an association between cSCC with sarcomatoid differentiation or dedifferentiation (loss of keratin staining) and aggressive tumor behavior and recurrence.
●Tumor thickness – In 2010, tumor thickness was added to the AJCC seventh edition staging system for cSCC due to the recognition of tumor thickness and depth of invasion as important prognostic factors in cSCC . Utilizing measurement tools applied to cutaneous melanoma, a Breslow depth >2 mm and a Clark level of IV or higher were classified as high-risk features based on AJCC 7. In 2017, the AJCC released the eighth edition, which included a staging system of cSCC for head and neck tumors only (table 1). The AJCC eighth edition defines "deep invasion" as invasion beyond the subcutaneous fat or >6 mm (as measured from the granular layer of adjacent, normal epidermis to the base of the tumor) . (See "Tumor, node, metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma", section on 'Primary tumor (T)'.)
The importance of tumor thickness was demonstrated by a 2016 meta-analysis of 36 observational studies including over 17,000 patients with cSCC . This study found that Breslow tumor thickness >2 mm, invasion beyond the subcutaneous fat, and thickness >6 mm were associated with a high risk of recurrence (RR 9.64, 95% CI 1.30-71.52; RR 7.61, 95% CI 4.17-13.88; and RR 7.13, 95% CI 3.04-16.72, respectively) and metastasis (RR 10.76, 95% CI 2.55-45.31; RR 11.21, 95% CI 3.59-34.97; and RR 6.93, 95% CI 4.02-11.94, respectively). Invasion beyond the subcutaneous fat was also associated with an increased risk of disease-specific death (RR 4.49, 95% CI 2.05-9.82).
●Perineural invasion – Perineural invasion (PNI) is associated with an increased incidence of tumor recurrence, metastasis, and death [14,20,33,35,42,43]. The local recurrence rate for tumors that exhibit this feature is estimated to be 16 to 47 percent, and metastasis is estimated to occur in 10 to 50 percent of cases [15,33].
Tumors with PNI of large nerves (diameter ≥0.1 mm) may portend a worse prognosis than tumors with smaller nerve involvement [20,33]. Moreover, tumors with PNI of large-caliber nerves are more likely to have other risk features, which may further impact the prognosis [33,35]. As an example, in a series of 1399 primary cSCCs, 21 tumors showed PNI, all of which had a desmoplastic growth pattern . PNI and desmoplasia were associated with increased rates of local recurrence, lymph node metastasis, and tumor-specific death.
Comorbidities — Comorbid conditions, such as immunodeficiency, iatrogenic immunosuppression, chronic lymphocytic leukemia (CLL), and recessive dystrophic epidermolysis bullosa (RDEB), may negatively influence the prognosis of cSCC:
●Immunosuppression – Immunosuppression due to chronic hematologic malignancy, HIV infection, and immunosuppressive therapy for organ transplantation is the strongest host risk factor for poor outcomes in patients with cSCC . In a multi-institutional series of 205 patients (138 immunocompetent patients and 67 immunosuppressed patients) treated with surgery and postoperative radiotherapy for primary or recurrent cSCC of the head and neck, locoregional recurrence-free survival and progression-free survival at two years were lower in immunosuppressed patients that in immunocompetent patients (47 versus 86 percent and 39 versus 72 percent, respectively) .
Immunosuppressed organ transplant recipients have a particularly high risk for the development of multiple and aggressive tumors. The incidence of cSCC is estimated to be 65 to 250 times greater in organ transplant recipients than in the general population [46-49]. Moreover, tumors in immunosuppressed patients may demonstrate more rapid growth, an increased likelihood for local recurrence, an increased risk for metastasis, and a poorer outcome [23,44,50-52].
The development of cSCC in iatrogenically immunosuppressed patients is a multifactorial phenomenon. The specific drug(s) administered, the medication dose, the duration of treatment, and host risk factors (eg, skin phenotype, age, and cumulative ultraviolet radiation exposure) influence the risk of tumor development. cSCC in immunosuppressed organ transplant recipients is discussed in greater detail separately. (See "Prevention and management of skin cancer in solid organ transplant recipients" and "Epidemiology and risk factors for skin cancer in solid organ transplant recipients".)
●Chronic lymphocytic leukemia – Chronic lymphocytic leukemia (CLL) impairs host immune function and may be a risk factor for recurrent and metastatic cSCC [53-57]:
•In a retrospective study of 57 tumors in 28 patients with CLL and 114 tumors in patients without CLL, all treated with Mohs surgery, tumors were seven times more likely to recur in patients with CLL than in patients without CLL (adjusted RR 7.0, 95% CI 2.1-22.8) .
•In a retrospective study that included 28 patients with CLL and 56 controls who underwent surgical excision of cSCC, 3 of the 28 patients with CLL developed metastases and died versus 0 of the 56 patients without hematologic disease .
•In another retrospective study that included 133 patients with CLL and at least one primary cSCC, Merkel cell carcinoma, or melanoma followed up for a median of 120 months, patients with advanced CLL Rai stage (III or IV) had significantly higher T stage SCC . Among these patients, the risk of death from CLL was similar to the risk of death from all three skin cancers combined (12 and 13 percent, respectively). On multivariate analysis, an advanced Rai stage at the time of the first diagnosis of SCC, Merkel cell carcinoma, or melanoma and a high T stage of SCC, Merkel cell carcinoma, or melanoma were independent predictors of poor outcomes (hazard ratio [HR] 4.5, 95% CI 2.3-8.9 and HR 4.9, 95% CI 2.2-10.8, respectively). (See "Staging and prognosis of chronic lymphocytic leukemia" and "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)
●Epidermolysis bullosa – cSCC is a common occurrence in patients with RDEB, and metastatic cSCC is the primary cause of death in these patients . Approximately 55 percent of patients die from metastatic disease by age 40 and 90 percent die from metastatic disease by age 55 [59-61]. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Epidermolysis bullosa' and "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Skin cancer'.)
Prognostic data are insufficient to estimate the risk for adverse outcomes from cSCC in other comorbidities in which the development of aggressive or metastatic cSCC has been reported. Examples include discoid lupus erythematosus [62,63], sclerodermatous disorders (systemic sclerosis, generalized morphea, and chronic graft-versus-host disease) [64,65], and hidradenitis suppurativa .
Gene expression profiling and biomarkers for risk stratification — Several studies have evaluated tumor markers in cSCC and identified associations with aggressive tumors. As the composite definition of high-risk cSCC remains unclear, the identification of reliable biomarkers is particularly promising in aiding the recognition of patients at risk for poor outcomes and guiding clinical disease management [67,68]:
●Gene expression profiling – A 40-gene expression profile test performed on formalin-embedded cSCC tissue has been developed to stratify patients with high-risk cSCC into three classes based on the three-year metastasis risk: class 1 (low risk), class 2A (high risk), and class 2B (highest risk) . In a retrospective cohort of 300 patients with high-risk cSCC according to the NCCN definition, the 40-gene expression profile classified 189 patients (63 percent) as class 1, 87 patients (29 percent) as class 2A, and 24 patients (8 percent) as class 2B . Patients stratified as class 1, 2A, and 2B had a 9, 21, and 63 percent risk for metastasis, respectively. The integration of the gene expression profile with the AJCC 8 and the Brigham and Women's Hospital (BWH) staging systems identified a subgroup of 24 patients at very high risk of metastasis (16 of whom were T1/T2 according to the AJCC 8 and 17 of whom were T1/T2a according to the BWH staging system) who would benefit from high-intensity management. Conversely, subgroups of patients classified as AJCC 8 T3/T4 or BWH T2b/T3 were assigned to class 1 based on their risk of metastasis. These patients would have been appropriately managed with low-intensity treatment.
●PD-L1 – Multiple studies have identified an association between increased programmed cell death ligand 1 (PD-L1) expression on tumor cells and risk for nodal metastasis in cSCC:
•In a study of 46 cSCC patients, high-intensity PD-L1 expression (defined at >50 percent in tumor cells) correlated with lymph node metastasis .
•In a study of cSCC on the head and neck, PD-L1 expression was a significant risk factor for nodal metastasis (HR 3.39) .
•Another investigation of PD-L1 expression in tumors with poor differentiation and other high-risk features, including large diameter, tumor thickness, and PNI, found 70 percent PD-L1 expression in tumor tissues and 100 percent expression in metastases .
•A retrospective analysis of 83 patients found that high-grade staining of tumor cells for PD-L1 was significantly associated with regional recurrence .
•In a meta-analysis of seven studies evaluating the protein expression between tissues from primary tumors resulting in metastasis or death versus those that did not, high primary tumor expression of PD-L1 was associated with increased risk for metastasis (odds ratio [OR] 2.34, 95% CI 1.09-5.02) .
●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 .
•Another study examining INPP5A expression of 52 primary cSCCs and 64 recurrent tumors (27 local recurrences, 32 local metastases, and 5 distant metastases) found that the INPP5A level of the recurrent and metastatic disease event tumor was predictive of overall survival (31 months for low expression versus 62 months for high expression) .
●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 .
●Long noncoding RNAs – Long noncoding RNAs (lncRNAs) are involved in cell regulation and tissue development and differentiation. One study showed that lncRNA ALINC00346 is specifically overexpressed by cSCC cells in culture and in vivo, promotes progression and metastasis of cSCC via signal transducer and activator of transcription 3 (STAT3) signaling, and is downregulated by p53 .
Epidermal growth factor receptors — Overexpression of the epidermal growth factor receptor (EGFR) has been associated with lymph node metastases and poor prognosis [82,83]. Documentation of improvement of advanced or unresectable cSCC after treatment with cetuximab, an EGFR inhibitor, provides indirect evidence in support of a role of EGFR expression [84,85]. However, a retrospective study of 56 patients with advanced cSCC on the head or neck found no association between EGFR overexpression and aggressive disease or patient survival . (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Cetuximab'.)
STAGING — The regional lymph nodes are the most common initial site of metastasis in cutaneous squamous cell carcinoma (cSCC) . A beneficial role of early detection of metastatic disease on patient outcomes is supported by the observation that patients with locally limited, operable tumors or limited nodal involvement are more likely to be cured (five-year survival of 73 percent) than patients with extensive nodal disease (five-year survival of 26 to 34 percent) [2,5].
In a prospective, cohort study of 1434 patients who underwent surgery for invasive cSCC, 40 patients died of SCC. Of those patients who died, 28 died because of tumor growth by local infiltration in the head region or infiltration into regional lymph nodes, and 12 died from visceral metastases . However, definitive guidelines for staging patients with high-risk cSCC have not been established. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".)
●The American Joint Committee on Cancer/Union for International Cancer Control staging system – In 2017, the American Joint Committee on Cancer (AJCC) released an updated staging system for cSCC based upon expert review of the available evidence . The system classifies cases by tumor burden (T), nodal involvement (N), and metastatic disease (M) (table 1). The Union for International Cancer Control (UICC), which is the AJCC's European counterpart, also updated its staging system in 2017, which parallels the AJCC staging system.
A major change in the AJCC eighth edition compared with the former AJCC seventh edition is that the cSCC staging system is limited to head and neck tumors since the system was developed within the AJCC's head and neck committee . Moreover, the AJCC eighth edition cSCC staging system expanded the criteria for upstaging to T3 and also included extranodal extension as a risk factor for upstaging of the N classification (table 1).
Further alterations to the staging system were proposed based on studies suggesting that the AJCC 7 staging system may not optimally stratify the prognostic groups for cSCC [10,87-90]. As an example, a study of 680 head and neck cSCCs comparing AJCC 7 and AJCC 8 found that 18 percent of tumors were classified as AJCC 8 T3/T4, and this small subset accounted for 70 percent of the cohort's poor outcomes (local recurrence, metastasis, and death from SCC). In contrast, fewer tumors (0.7 percent) and poor outcomes (17 percent) were classified as AJCC 7 T3/T4 .
●The Brigham and Women's Hospital Tumor Staging for cutaneous squamous cell carcinoma – The authors of this topic contributed to the development of an alternative T staging system (the Brigham and Women's Hospital [BWH] Tumor Staging for cSCC) with the aim of providing a better risk stratification for AJCC stage T2 (table 3) [10,89].
The BWH system has been shown to be superior to both AJCC 7 and AJCC 8 in its ability to stratify low-risk versus high-risk tumors [90,91].
The BWH system has also been compared with AJCC 8 in a cohort of 459 cases with 680 cSCCs of the head and neck and found to be slightly better than the AJCC 8 in identifying patients at risk for metastasis and poor outcome . In this study, 18 percent of the tumors were classified as AJCC 8 high tumor class (T3/T4) versus 9 percent of the tumors classified as BWH high tumor classes (T2b/T3). The AJCC 8 T2 and T3 included 23 percent of cases and had similar disease-specific death rates and overall survival rates, with wide overlap of the confidence intervals. In contrast, there was only slight confidence interval overlap for BWH T2b and T3. Compared with AJCC 8, the BWH system showed higher specificity and positive predictive value for identifying cases at risk for metastasis or death (93 versus 85 percent and 30 versus 17 percent, respectively) .
The AJCC 7, AJCC 8, and BWH classification systems have also been directly compared with one another in an external data set. In a nested, case-control study, the BWH system appeared to perform slightly better than AJCC 8, with both of these systems performing significantly better than AJCC 7, as evidenced by concordance (C) statistics of 0.81 (95% CI 0.75-0.88), 0.75 (95% CI 0.68-0.82), and 0.63 (95% CI 0.58-0.68) for the BWH system, AJCC 8, and AJCC 7, respectively .
The incorporation of biomarkers into staging will further improve the accuracy of cSCC staging in the future. (See 'Gene expression profiling and biomarkers for risk stratification' above.)
Tools for staging — Radiologic imaging is the diagnostic modality of choice for the assessment for bone invasion (needed for T3 or T4a/T4b staging) and for the determination of nodal and distant, metastatic involvement in patients with high-risk cSCC. Computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasound have also been utilized for disease staging. In general, CT is most appropriate in the detection of bone invasion, cartilage invasion, and nodal necrosis, while MRI is best suited to evaluate for tumor extension into soft tissue and large nerves .
A retrospective, cohort study of 108 high-stage cSCCs found that patients who did not receive imaging had a higher risk of developing nodal metastasis (30 versus 13 percent) . Additionally, imaging was independently associated with a reduced risk of disease-related outcomes (including local recurrence, nodal metastasis, and death from disease) after adjusting for tumor stage, sex, and anatomic location (subhazard ratio 0.5, 95% CI 0.2-0.9) . The more favorable disease-related outcomes in radiology groups were attributed to earlier, aggressive treatment.
Clinically detectable, enlarged lymph nodes can be evaluated via biopsy (ie, fine needle aspiration or core biopsy) or surgical excision. The evaluation for regional and distant metastases in patients with cSCC is discussed in detail separately. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".)
Sentinel lymph node biopsy — Sentinel lymph node biopsy (SLNB) is a surgical procedure utilized to detect subclinical nodal metastases in melanoma and multiple other malignancies. However, as high-quality studies evaluating the use of SLNB in high-risk cSCC are lacking and the impact of this procedure followed by completion lymph node dissection on patient survival is unclear, SLNB is not routinely recommended [9,95-98]:
●In a 2018 systematic review of 23 observational studies including 566 patients with cSCC who underwent SLNB, the pooled estimate of the prevalence of nodal metastasis was 7.9 percent (95% CI 5.2-10.6 percent) . Most of the studies included patients classified as high risk, but the definition of this risk varied from one study to another. Among 361 patients for whom follow-up data were available, 32 patients (8.9 percent) had positive SLNB, 22 patients experienced regional recurrence (9 sentinel lymph node [SLN] positive and 13 SLN negative), 11 patients developed distance metastasis (5 SLN positive and 6 SLN negative), and 12 patients died of SCC (4 SLN positive and 8 SLN negative). The false-negative rate was 3.9 percent.
●In a subsequent study of 83 patients with cSCC of the head and neck who underwent SLNB, an occult nodal metastasis was found in five cases (6 percent) . No difference was noted in the time to recurrence and time to death between patients with positive or negative SLN at the time of surgery. Moreover, no difference was in either time to recurrence and time to death between patients who received adjuvant radiation therapy (ART) and those who did not. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma", section on 'Sentinel lymph node biopsy'.)
Approach to treatment — Our approach to the treatment of high-risk cutaneous squamous cell carcinoma (cSCC) is outlined below (algorithm 1):
●Early and aggressive surgical excision is the primary modality utilized for the management of patients with localized cSCC with clinical and/or pathologic high-risk features (see 'Surgery' below). Treatment modalities that do not provide opportunities to assess the tissue margins, such as cryosurgery, electrodesiccation and curettage, topical therapies, and photodynamic therapy, are not recommended.
●Patients with locally advanced or metastatic disease that cannot be effectively managed with surgery and/or radiation are candidates for systemic immune checkpoint inhibitor therapy or chemotherapy . These patients often benefit from management by a multidisciplinary team (eg, a dermatologic surgeon, otolaryngologist, surgical oncologist, radiation oncologist, and/or medical oncologist). (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)
●Radiation therapy may also be employed as definitive or palliative therapy when complete surgical removal is not possible. (See 'Radiation therapy' below.)
●Radiation therapy is sometimes used as adjunctive, postsurgery therapy in an attempt to reduce the risk for disease recurrence. However, there is no high level of evidence to determine which patients will benefit from adjuvant radiation therapy (ART). (See 'Adjuvant radiation therapy' below.)
●Organ transplant recipients may also benefit from collaboration with transplant clinicians to assess for the need for modification of their immunosuppressive regimens. (See "Prevention and management of skin cancer in solid organ transplant recipients".)
Surgery — Surgical excision is the primary treatment modality utilized for the management of high-risk cSCC (algorithm 1). Options include Mohs micrographic surgery (MMS), surgical excision with peripheral and deep en face margin assessment (PDEMA) using permanent or frozen section analysis, and standard excision with wide margins. The National Comprehensive Cancer Network (NCCN) recommends complete margin assessment via MMS or PDEMA for high-risk SCCs, since these procedures assess complete tumor removal via the examination of 100 percent of the tissue margin .
Mohs surgery — MMS is performed under local anesthesia by a surgeon (usually a dermatologic surgeon) specifically trained in the technique. 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. The MMS technique is discussed in greater detail separately. (See "Mohs surgery".)
Although randomized trials comparing MMS with conventional surgical excision have not been performed, reports of high cure rates support the efficacy of MMS for cSCC:
●A 2013 systematic review of 10 observational studies that assessed outcomes from MMS in a total of 1572 patients with cSCC (not all high risk, inconsistent definition of "high-risk" tumor across studies) found a pooled average local recurrence rate of 3 percent (95% CI 2.2-3.9 percent) after this procedure . Similar average recurrence rates were found in seven studies with mean follow-up time of two to five years (2.8 percent, 95% CI 2.0-3.9 percent) and in two studies with mean follow-up time greater than five years (3.1 percent, 95% CI 1.4-5.4 percent).
●In a retrospective study that included 366 primary, intermediate-risk tumors according to the Brigham and Women's Hospital (BWH) Tumor Staging for cSCC (stage T2a, tumors with only one high-risk factor) treated with MMS (n = 240) or wide local excision (n = 126), the local recurrence rate was considerably lower in the MMS group than in the wide local excision group after a mean follow-up time of 2.8 years (1.2 versus 4 percent, respectively) . In a multivariate analysis, wide local excision was also associated with an eightfold increased risk of overall poor outcome, including any local or distant recurrence and disease-specific death (odds ratio [OR] 7.8, 95% CI 2.4-25.4).
●In a study of 647 high-risk cSCCs treated with Mohs surgery, the rates of local recurrence, nodal metastasis, distant metastasis, and disease-specific death were 2.9, 4.8, 1.1, and 1.1 percent, respectively, after an average follow-up time of 43 months . Poor differentiation and invasion beyond the subcutaneous fat were associated with local recurrence, nodal metastasis, and disease-specific death.
●In another retrospective study including 579 patients with 672 cSCCs of the head and neck (380 treated with MMS and 292 with standard excision), the recurrence rate after adjustment for tumor size and deep tumor invasion was lower with Mohs surgery than with standard excision (3 versus 8 percent, respectively) after a median follow-up of 5.7 years .
Excision with peripheral and deep en face margin assessment — Surgical excision with peripheral and deep en face margin assessment (PDEMA), also called excision with complete circumferential peripheral and deep margin assessment (CCPDMA), is an alternative to Mohs surgery. The procedure involves the examination of the entire margin of the tissue specimen by a pathologist. Histopathologic examination may be performed intraoperatively with frozen sections or with permanent sections and delayed wound closure.
Surgical excision with PDEMA is typically performed for advanced tumors that are best approached under general anesthesia due to large tumor size or great depth. PDEMA is also useful when the continuous layers of tissue removed during Mohs surgery is not ideal, such as when surgical preservation of important, deep, anatomic structures (eg, major vessels or nerves) is required.
Standard excision — In accordance with the guidelines proposed by the NCCN, standard surgical excision is not the preferred method for surgical removal of high-risk SCCs . However, if this method is used, the consensus-based guidelines of the European Dermatology Forum, the European Association of Dermato Oncology, and the European Organisation for Research and Treatment of Cancer suggest a margin of 6 to >10 mm for high-risk tumors . In addition, when performing standard excision, it is prudent to utilize a primary or delayed closure to allow for further excision with PDEMA if margins are positive.
Incomplete excision — Lesions excised with positive margins or close margins indicated on the pathology report should be re-excised with MMS or surgery with PDEMA whenever possible. Lesions excised with "close margins," which may mean tumor extending within two to three rete ridges of the margin of resection, may be followed for recurrence if re-excision will result in impaired function (eg, eyelid eversion). Depending on the anticipated loss of function, clinicians may prefer systemic treatment with programmed cell death protein 1 (PD-1) inhibitor therapy or ART (algorithm 1).
Extensive cases — The complete removal of the tumor can be challenging in patients with perineural invasion (PNI) involving large nerves or deep invasion into underlying tissues or bone. Aggressive surgical resections of named nerves and/or the skull base to achieve clear margins have been beneficial in some patients with head or neck tumors .
In cases characterized by deep or extensive local tumor involvement, MMS may be used as a preliminary step prior to deeper dissection to establish the peripheral margin and clarify the locations where deeper dissection is necessary . This approach may minimize the time required for general anesthesia. Preoperative imaging to evaluate the extent of disease is also advised [108,109].
Definitive radiation therapy — The use of radiation therapy as primary therapy is typically reserved for older patients who are not surgical candidates because of comorbidities and for those who refuse surgery (algorithm 1). The techniques, doses, and fractionation of radiation therapy for the primary treatment of cSCC are discussed elsewhere. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)", section on 'Radiation therapy'.)
Radiation therapy may also be used for the control of symptoms (eg, bleeding, pain) or as a salvage therapy for patients with incompletely resected tumors .
Adjuvant radiation therapy — In high-risk cSCC, radiation therapy is most commonly combined with surgery. Patients may receive radiation to the sites of high-risk tumors as an adjuvant, a therapeutic measure aimed at reducing the likelihood for local recurrence following a surgical excision with clear margins [27,110].
Guidelines from the NCCN, the European Dermatology Forum, the European Association of Dermato Oncology, the European Organisation for Research and Treatment of Cancer, and the American College of Radiology recommend the use of adjuvant radiation therapy (ART) for [9,111,112]:
●Tumors with positive surgical margins after excision not amenable to further surgery (see 'Incomplete excision' above)
●Tumors with clear margins that exhibit extensive PNI or large nerve involvement
We also consider the use of ART to the primary site in the following situations [20,107,113,114]:
●Patients with multiple high-risk features
●PNI of unnamed nerves >0.1 mm in diameter
●Multifocal tumor spread
●Presence of microsatellitosis
●Multiple tumor recurrences
●Lymph node involvement
●Massive local extension or intracranial invasion (see 'Tumors with skull base extension' below)
Data on the role of ART for high-risk primary cSCCs excised with clear surgical margins are limited, and there are no definitive recommendations on the indications for ART:
●In a systematic review and meta-analysis of 20 observational studies and 1 randomized trial that included 3534 patients treated for cSCC of the head and neck, ART was associated with increased overall survival and disease-free survival (hazard ratio [HR] 0.45, 95% CI 0.26-0.78 and HR 0.52, 95% CI 0.33-0.84, respectively) .
●In a phase 3, randomized trial of ART with or without concurrent chemotherapy in patients with high-risk cSCC of the head and neck, high two- and five-year rates of freedom from locoregional relapse (88 and 83 percent, respectively) were achieved in the radiation therapy alone arm .
●In a series of 349 patients with advanced head and neck cSCC treated with surgical resection with or without ART, ART was associated with improved overall survival (HR 0.59, 95% CI 0.38-0.90). For patients with PNI, ART was associated with improved overall survival as well as disease-free survival (HR 0.44, 95% CI 0.24-0.86 and HR 0.47, 95% CI 0.23-0.93, respectively) .
Tumors with skull base extension — Complete tumor resection is not always possible without introducing an unacceptable level of morbidity, such as some cases of widespread skull base invasion or advanced intracranial extension. In such cases, ART is administered in an attempt to control surgically inaccessible tumor remnants [9,112]. The efficacy of radiation therapy in this setting has not been evaluated in randomized trials or prospective studies. In a systematic review that included 19 studies with 956 tumors treated with a combination of primary radiation, surgery, and ART/salvage radiation therapy, the pooled local recurrence rate was 17 percent, and the pooled disease-specific death rate was 9.3 percent . However, these results must be interpreted with caution because most studies did not differentiate between ART and salvage radiation therapy.
Chemoradiation — Cisplatin and carboplatin have been used as chemosensitizing agents in conjunction with radiation therapy for patients with SCC arising in noncutaneous sites. However, an additional benefit with these agents has not been demonstrated in patients with high-risk cSCC. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)
A phase 3, randomized trial compared ART versus adjuvant chemoradiotherapy in high-risk head and neck cSCCs, defined as primary lesion >5 cm, involvement of muscle/cartilage/bone, the presence of in-transit disease, or high-risk nodal disease (>3 cm in size, two or more involved nodes or extranodal spread) . In this trial, 321 patients were randomized to postoperative radiation therapy (60 to 66 Gy in 30 to 33 fractions) or postoperative radiation therapy plus six cycles of weekly carboplatin. After a median follow-up of 60 months, no significant benefit with the addition of carboplatin was noted. The two- and five-year freedom from locoregional relapse rates were 88 and 83 percent, respectively, in the radiation therapy alone group and 89 and 87 percent, respectively, in the chemoradiation group. Severe late toxicities (grade 3 or 4) were infrequent .
Systemic therapies — Anti-programmed cell death protein 1 (PD-1) antibodies cemiplimab and pembrolizumab have shown high efficacy in the treatment of locally advanced and metastatic SCC in phase 1/2 trials [100,119-121]. Alternative treatments include conventional chemotherapy agents (carboplatin plus paclitaxel) or cetuximab. The use of systemic immunotherapy and chemotherapy in patients with advanced cSCC not amenable to local treatments, including surgery, radiation, and chemoradiation, is discussed in detail separately. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Cutaneous squamous cell carcinoma'.)
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 [122,123]. A six-month, randomized trial in which patients were given a combination of oral 13-cis-retinoic acid (isotretinoin) 1 mg/kg per day and interferon alfa 3 million units three times per week or no adjuvant therapy failed to find a reduction in the risk for tumor recurrence in patients treated with this regimen . Because of the lack of evidence to support the efficacy of oral retinoids for the prevention of tumor recurrence or metastasis in patients with high-risk cSCC, we cannot recommend the routine use of oral retinoids for this indication.
However, patients with a history of SCCs are at risk for developing subsequent SCCs. Therefore, oral retinoids can be considered in patients with high-risk SCCs and in immunosuppressed patients at high risk of developing multiple cSCCs. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Chemoprevention for SCC' and "Cutaneous squamous cell carcinoma: Primary and secondary prevention", section on 'Chemoprevention'.)
Immunosuppressed patients — Immunosuppressed patients, such as solid organ transplant recipients and patients with chronic lymphocytic leukemia (CLL), are at high risk of developing multiple and aggressive cSCCs. The prevention and management of cSCC in organ transplant recipients is reviewed separately. (See "Prevention and management of skin cancer in solid organ transplant recipients".)
In patients with CLL, particularly those with Rai stage III or IV, treatment of the underlying CLL should be considered for high-risk SCCs to improve the immune status of the patient and decrease the risk of recurrence.
MANAGEMENT OF NODAL DISEASE — Aggressive surgical resection of the nodal basins is the primary treatment modality for clinical lymph node involvement following histologic confirmation. For two or more positive lymph nodes, one node >3 cm with no extracapsular extension, any node with extracapsular extension, or incompletely excised nodal disease, the National Comprehensive Cancer Network (NCCN) recommends adjuvant radiation therapy (ART) . This indication is supported by the results of two retrospective studies where surgery in combination with ART improved disease-free survival in patients with a single involved lymph node [125,126].
The administration of ART following resection has improved locoregional disease control in patients with involvement of parotid and cervical nodes . In a prospective study of 87 patients with high-risk cutaneous squamous cell carcinoma (cSCC) metastatic to the parotid gland followed for a minimum of two years, multivariate analysis demonstrated that failure to have postoperative radiation was an independent predictor of reduced disease control in the parotid region . In addition, a retrospective review of 167 immunocompetent patients with cSCC metastatic to the lymph nodes found a lower rate of recurrence in patients who received lymphadenectomy and ART compared with patients treated with lymphadenectomy alone (20 versus 43 percent) . (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)
FOLLOW-UP — Approximately 70 to 80 percent of recurrences or metastases of cutaneous squamous cell carcinoma (cSCC) occur within two years after therapy, and approximately 95 percent occur within five years . Thus, close follow-up is indicated.
Clinical — Specific guidelines for the frequency and duration of follow-up for patients with a history of high-risk cSCC have not been established. We agree with the general guidelines proposed by the National Comprehensive Cancer Network (NCCN) for patients with cSCC, which recommend performing a full skin examination and a regional lymph node examination according to the following schedule :
●Patients with local disease – Every three to six months for two years, then every 6 to 12 months for three years, then annually for life
●Patients with regional disease – Every one to three months for one year, then every two to four months for one year, then every four to six months for three years, then every 6 to 12 months for life
The optimal frequency of follow-up may vary from the above, based upon the clinician's assessment of the risk for recurrence. At follow-up appointments, patients should be questioned about symptoms of pain, focal weakness, and numbness in the region of the tumor, and patients with head and neck tumors should receive a basic cranial nerve examination. (See "The detailed neurologic examination in adults".)
The presence of neurologic symptoms may be indicative of tumor recurrence involving the nerves. Some patients experience postsurgical sensory defects that may or may not slowly improve over time. Worsening signs or symptoms of neurologic dysfunction should raise concern for a recurrent tumor.
Any palpable lymphadenopathy at follow-up warrants tissue evaluation via fine needle aspiration or excisional biopsy.
Imaging surveillance — Clear guidelines regarding indications for baseline and follow-up imaging as surveillance for perineural and nodal metastases in the absence of clinical signs of advanced disease have not been defined. Additionally, recommendations for specific imaging modalities vary widely and include ultrasound, computed tomography (CT) with contrast, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI):
●In a single-institution, retrospective, cohort study of patients with high-risk primary cSCC who underwent either structural and/or functional baseline or surveillance imaging (CT, PET-CT, MRI, or ultrasound), 30 percent of patients demonstrated metastatic disease, 69 percent of which was not detected on physical examination. Notably, a majority of these studies with positive findings were performed during two years of surveillance imaging .
●Another retrospective, single-center study found that high-stage cSCCs (Brigham and Women's Hospital [BWH] stage T2b/T3) that did not undergo diagnostic imaging at the time of diagnosis were twice as likely to develop a nodal metastasis or a poor outcome compared with tumors that did receive imaging . This risk difference was attributed to earlier identification and management of recurrences.
●A small study evaluated the utility of PET-CT in detecting nodal metastases at the time of diagnosis in 30 lymph nodes from 26 patients with primary cSCC . The definition of a standardized uptake value (SUV) maximum >2.5 as malignant on imaging yielded a sensitivity of 100 percent and a specificity of 81 percent.
●A large study of over 1800 patients with primary cSCC reported that those with BWH stage T2b/T3 disease accounted for 70 percent of nodal metastases and 83 percent of disease-specific deaths, revealing that this group is at especially high risk for poor outcomes . Based on the results of this study, many clinicians agree that baseline CT with contrast and MRI is indicated for patients with BWH stage T2b/T3 and that surveillance imaging via biannual CT with contrast is judicious in this population .
Some authors have recommended the routine use of ultrasonography for the detection of nonpalpable lymph node involvement, but the value of routinely performing this procedure requires further study .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonmelanoma skin cancer" and "Society guideline links: Mohs surgery" and "Society guideline links: Cutaneous squamous cell carcinoma".)
SUMMARY AND RECOMMENDATIONS
●Definition of high-risk cutaneous squamous cell carcinoma – Multiple clinical and pathologic features are considered indicators of increased risk for local recurrence, metastasis, or death. According to the 2022 National Comprehensive Cancer Network (NCCN) guidelines, high-risk and very high-risk cutaneous squamous cell carcinomas (cSCCs) include (see 'High-risk features' above):
•Tumors of any size located on the head, neck, hands, feet, pretibia, and genitalia
•Tumors 2 to 4 cm on the trunk or extremities (excluding hands, feet, pretibia)
•Tumors >4 cm on any location (very high risk)
•Certain histopathologic subtypes (acantholytic/adenoid, adenosquamous, metaplastic)
•Tumors >6 mm in thickness
•Tumors with perineural, lymphatic, or vascular invasion
●Staging – The management of patients with high-risk cSCC begins with an assessment of the extent of the disease, based upon clinical, pathologic, and radiologic features (table 1). Radiologic imaging with computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasound have been utilized for the assessment for bone invasion and determination of nodal and distant, metastatic involvement in patients with high-risk cSCC. As high-quality studies evaluating the use of sentinel lymph node biopsy (SLNB) in the staging and management of high-risk cSCC are lacking and the impact of SLNB followed by completion lymph node dissection on patient survival is unclear, SLNB is not routinely performed in these patients. (See 'Staging' above and "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".)
●Management – Our approach to the management of high-risk cSCC is illustrated in the algorithm (algorithm 1):
•Patients with resectable tumors – For patients with surgically resectable tumors, we suggest treatment with Mohs micrographic surgery (MMS) or surgical excision with peripheral and deep en face margin assessment (PDEMA), if available, rather than standard excision (Grade 2C). If standard excision is used, margins of 6 to 10 mm are considered acceptable in most cases (see 'Surgery' above):
-Tumors excised with positive margins – We suggest re-excision, if feasible (Grade 2C), rather than adjuvant radiation therapy (ART) or systemic therapy. However, if additional surgery is not feasible due to anatomic constraints, alternative options include ART and/or systemic treatment with programmed cell death protein 1 (PD-1) inhibitors. (See 'Incomplete excision' above.)
-Adjuvant radiation therapy for tumors excised with clear margins – The indications for ART following the attainment of clear surgical margins are unclear. We suggest ART for patients with tumors that exhibit extensive perineural or large nerve involvement (Grade 2C). We also offer ART to patients with cSCC showing highly infiltrative growth and/or poor differentiation or multiple high-risk features, in which surgical margins are uncertain, but this practice is not uniform among clinicians. (See 'Radiation therapy' above.)
•Locally advanced tumors/nonsurgical candidates – We prefer immunotherapy with PD-1 inhibitors for the treatment of high-risk cSCC in patients who are poor surgical candidates and in patients with locally advanced tumors. Alternative approaches include definitive radiation therapy and conventional chemotherapy. The use of systemic therapies for the treatment of advanced cSCC is discussed separately. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies" and "General principles of radiation therapy for head and neck cancer".)
●Follow-up – Patients with high-risk cSCC require frequent clinical follow-up to evaluate for signs of disease recurrence or development of new skin cancer. We typically see these patients every three to six months. A total body skin examination, palpation of regional lymph nodes, and evaluation for neurologic symptoms should be performed at every follow-up visit. (See 'Follow-up' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Chrysalyne D Schmults, MD, MSCE, who contributed to an earlier version of this topic review.