Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer affecting humans. The combination of the increasing incidence and high mortality in advanced stages of the disease, defines cSCC as an emerging public health problem. Advanced disease includes metastatic and locally advanced cSCC. Metastatic disease refers to the presence of locoregional metastasis (in transit or to regional lymph nodes) or distant metastasis. Locally advanced disease has been defined as non-metastatic cSCC that is unlikely to be cured with surgery, radiotherapy, or combination treatment. While metastatic cSCC is easily diagnosed, locally advanced disease lacks consensus definition and diagnosis is made after multidisciplinary board consultation. Identifying patients with aggressive cSCC at highest risk for relapse may prevent the occurrence of advanced disease. Prognostic factors suggested by most guidelines include tumor diameter (>2 cm), localization on temple/ear/lip/area, thickness (>6 mm), or invasion beyond subcutaneous fat, poor grade of differentiation, desmoplasia, perineural invasion, bone erosion, immunosuppression, undefined borders, recurrence, growth rate, site of prior radiotherapy, and lymphatic or vascular involvement. Although risk factors associated with worse outcomes are well known, there is still a gap of knowledge on the precise risk of each factor taken individually. The aim of this review is to summarize cSCC prognostic factors and encompass the various staging systems to guide management and follow-up in cSCC patients at higher risk for local recurrence and metastasis. Finally, we describe the hallmarks of the advanced disease. Advanced cSCC diagnosis should be made by a multidisciplinary board considering patients’ performance status and disease characteristics
Cutaneous squamous cell carcinoma (cSCC) is considered the second most common non melanoma skin cancer after basal cell carcinoma (BCC). Evidence indicates however that the incidence is still underestimated. Contrary to the reported BCC:SCC ratio of 4:1, a ratio of 1:1 was observed in the US Medicare fee-for-service Population from 2006 to 2012 [ 1 ] , and an overall 263% increase in the incidence rate of SCC was observed from 1976 to 2010 in a population cohort from Minnesota [ 2 ] .
cSCC is also regarded as the second most frequent cause of death due to skin cancer after melanoma, although, on a population-based scale, the absolute number of deaths from cSCC equals that of melanoma [ 3 ] . Despite the overall favorable clinical outcome of low risk cSCC, there is a subset of cSCCs that tends to recur and metastasize exhibiting a more aggressive course. The rate of recurrence varies from 2.7% [ 4 ] to 4.6% [ 5 ] , as reported in 2 large studies including 653 and 985 patients with cSCC followed for approximately 10 years, respectively. The rate of metastases ranges from 1.2% to 4%, with 2.1% disease-specific death [ 5 ] . Because of the increasing incidence related to the aging population and the high mortality in advanced disease, cSCC is increasingly emerging as a public health problem.
The term “advanced cutaneous squamous cell carcinoma” defines cSCCs that are no longer amenable to surgery and/or radiotherapy (RT) and are eligible to anti PD-1 treatment [ 6 ] . The introduction of this class of drugs has raised awareness on advanced cSCC that was previously under-recognized and under-treated because of its poor prognosis. This draw attention towards the need for a clear and shared definition of advanced cSCC. However, the difficult management of advanced cSCCs requires that clinical and scientific efforts should be directed to prevent the occurrence of advanced disease. Risk assessment is therefore particularly important to identify the few cSCCs with a high risk of local recurrence or metastasis among all other low-risk tumors. High-risk cSCC should not turn into the advanced or metastatic form if properly managed with adequate surgery, follow-up, and adjuvant therapy. A thorough clarification of cSCC characteristics associated with poor prognosis is urgently needed, as it is crucial factor in guiding multidisciplinary discussions on an adequate management strategy.
Classification and Staging of cSCC
The WHO classification of skin tumors identifies several histologic variants of cSCC which have important implication for management and prognosis [ 7 ] . Among invasive cSCC, keratoacanthoma and verrucous SCC are considered low-grade variants as they have little, if any, metastatic potential, while acantholytic, spindle cell, adenosquamous, and clear cell SCC are characterized by a more aggressive behavior and worse prognosis [ 7 ] .
The 8 th edition of the TNM classification of malignant tumor (TNM8) was published in 2017, with a version from both the American Joint Committee on Cancer (AJCC) [ 8 ] and the Union for International Cancer Control (UICC) [ 9 ] . UICC and AJCC work closely together and, in most instances, the TNM version of each organization is the same or very similar. Unexpectedly, AJCC limited its TNM8 edition to the staging system for cSCC of the head and neck and did not provide a staging system for cSCC of the trunk and limbs. In comparison, UICC TNM8 provides 2 chapters for skin carcinoma: one covering the primary sites on the head and neck and one covering the trunk and limbs. Overall, the 2 chapters in UICC 8 th and AJCC 8 th ed. for cSCC TNM of head and neck are essentially identical except for the definition of perineural involvement ( Tables 1–4 ) [ 9 , 10 ] .
TNM Clinical Classification for Skin Carcinoma (excluding eyelid, head and neck, perineal, vulva and penis) According to UICC 8th Edition
pTNM Pathological Classification for Skin Carcinoma (excluding eyelid, head and neck, perineal, vulva and penis) According to UICC 8 th Edition
TNM Clinical Classification for Skin Carcinoma of the Head and Neck According to AJCC/UICC 8 th Edition
pTNM Pathological Classification for Skin Carcinoma of the Head and Neck according to UICC 8 th Edition
The T subcategory is defined by the clinical diameter and deep invasion of the primary tumor (with thresholds of 2 and 4 cm for clinical diameter and 6 mm as limit for deep invasion) and by perineural invasion or bone erosion as parameters of upgrade to T3 or T4a/b. However, the T2 subcategory comprises a wide range of tumors, some of them associated with poor prognosis [ 6 ] . The Brigham and Women’s Hospital (BWH) classification system for the T stage was developed to better correlate higher tumor stages with poor outcomes, as an effort to more accurately separate high-risk from low-risk tumors [ 11 ] . In detail, this classification system identifies poor differentiation, perineural invasion, invasion beyond subcutaneous tissue and diameter ≥2 cm as risk factors associated with worse prognosis and provides a quantifiable risk value according to the number of identified risk factors. Thus, T2 tumors are stratified into a low-risk T2a stage (with one of the above risk factors) with 16% of these patients accounting for all SCC-related events (recurrence, nodal metastasis and/or death) and a high-risk T2b with tumors combining 2–3 risk factors and accounting for 64% of all SCC-related events. T3 stage includes tumors combining all 4 risk factors, as well as those with bone invasion.
The N subcategory is differently addressed in the 2 chapters of the UICC classification system (skin carcinoma of the head/neck and carcinoma of trunk/limbs) [ 9 ] . Unlike cSCC of trunk and limbs, cSCC of the head and neck incorporates extranodal extension and laterality into its staging criteria.
The combination of T, N, and M categories defines the stage of the tumor, with UICC and AJCC as the most widespread and used staging systems ( Table 5 ). Noteworthy, stage III in both UICC and AJCC staging systems includes cSCC, with or without nodal involvement, and stage IV includes cases with or without distant metastasis. These classifications seem to equate patients with advanced disease but with different characteristics. Likewise, both UICC and AJCC staging systems do not encompass all the potential risk factors for a worse prognosis of cSCC (eg location and differentiation) whereas a combination of prognostic factors should better guide management of cSCC in the multidisciplinary board.
Staging System for Both Skin Carcinoma (excluding eyelid, head and neck, perineal, vulva and penis) and Skin Carcinoma of the Head and Neck According to AJCC/UICC 8 th Edition
Prognostic Factors in cSCC
Among the most authoritative guidelines for diagnosis and management of cSCC, EADO [ 12 ] and NCCN [ 13 ] guidelines, address the differentiation of high-risk from low-risk tumors ( Table 6 ) ( Figure 1 ). Prognostic high-risk factors proposed by EADO include tumor diameter (>2 cm), location on temple/ear/lip/area, thickness (>6 mm), or invasion beyond subcutaneous fat, poor grade of differentiation, desmoplasia, microscopic, symptomatic, or radiological perineural invasion, bone erosion, and immunosuppression. NCCN guidelines add as prognostic factors positive borders, primary vs recurrent, growth rate, site of prior radiotherapy, lymphatic, or vascular involvement and, very recently, subclassified cSCC into high-risk and very high-risk. Any high-risk factor places the patient in the high-risk category.
Figure 1 .
High-risk cutaneous squamous cell carcinoma (cSCC). (A) cSCC on the lower lip of a male aged 49, with high-risk features as location, thickness (4 mm), poor differentiation, and perineural invasion. Despite the small size, the patient developed nodal metastasis after 6 months from primary excision and adjuvant radiotherapy. (B) cSCC on the cheek of a female aged 77, defined as very high-risk according to NCCN guidelines: thickness 11.0 mm, > 4 cm in diameter, poor differentiation. (C) cSCC on the forehead of a patient aged 58, at high-risk because of poor differentiation, presence of perineural invasion, diameter > 2 cm. (D) cSCC on the nose of a patient aged 83 characterized by poor differentiation and perineural invasion.
Prognostic Factors in cSCC According to the EADO and NCCN Guidelines. Definition of High-Risk Patients (and very high-risk patients in the NCCN classification)
Risk factors associated with poor prognosis in cSCC can be classified as intrinsic (tumor-related) and extrinsic (patient- and physician-related) [ 6 ] .
Tumor-Related Prognostic Factors
Extrinsic Prognostic Factors (Patient- and Physician-Related)
The role of extrinsic risk factors is more difficult to analyze, as features such as patient’s request to limit the extent of surgery or physician’s expertise in the treatment are impossible to standardize and systematically compare. However, in clinical practice, extrinsic factors have the greatest impact on the natural history of the tumor, as they may turn an early tumor with clinical and histological low-risk features into a cSCC with a high-risk of recurrence and worse outcome, namely an advanced cSCC.
Managing Prognostic Factors - Practical Implications
Although numerous risk factors associated with worse outcomes have been identified, there is still a gap of knowledge on the precise risk of each factor individually. Combination of 2 or more factors is considered to significantly increase the risk of poor outcome. EADO guidelines recommend considering the variations of patient- and tumor-related characteristics when assessing the level of overall prognostic risk [ 6 ] . However, the decision still relies on the physician’ expertise and opinion, as neither a nomogram nor a scoring system are available yet to define which cSCC would deserve adjuvant RT or a closer follow-up program.
Adjuvant RT is offered as part of clinical practice in many medical centers for patients with high-risk cSCC, particularly for tumors with perineural invasion. However, there is still a lack of significant evidence, including randomized controlled trial data, showing a clear benefit of adjuvant RT in this setting [ 12 ] .
There is no standardized follow-up schedule for patients with cSCC due to the lack of randomized controlled trials. Patients with high-risk cSCC should be followed up every 3–6 months for the first 2 years, and every 6–12 months for years 3–5, and annually thereafter [ 13 ] . Lymph node ultrasound should be performed every 3–6 months in the first 2 years depending on risk stratification. Again, as the independent prognostic effect of high-risk factors has not been consistently defined, EADO guidelines advice individual risk assessment to guide follow-up decisions [ 12 ] .
Diagnosis of Advanced Cutaneous Squamous Cell Carcinoma
Advanced cSCC is classified as metastatic cSCC or locally advanced cSCC.
Metastatic disease includes locoregional metastasis (in transit or to regional lymph nodes) or distant metastasis which are easily diagnosed by imaging (stage III and IV according to AJCC/UICC 8 th ed.]. Noteworthy, the 8 th ed. of AJCC/UICC staging system does not include the presence of in-transit metastases. The prognostic role of satellite and in transit metastasis in cSCC has been recently investigated by Xu et al [ 29 ] who found a significant association with worse overall survival.
Locally advanced cSCC has been defined as non-metastatic cSCC that is unlikely to be cured with surgery, radiotherapy, or combination treatment (surgery and radiotherapy) ( Figure 2 ). However, locally advanced disease lacks consensus definition and diagnosis is made after multidisciplinary board consultation. Thus, the diagnosis of locally advanced cSCC is influenced by the expertise of each center. The need for standardized definition criteria of locally advanced cSCC is high in the clinical trial setting.
Figure 2 .
Locally advanced cutaneous squamous cell carcinoma (cSCC). (A) cSCC in a 83-year-old male patient, located on the right parietal region, no previous treatment, late diagnosis. (B) cSCC in a 77-year-old male patient on the left shoulder, recurrent to surgery. (C) cSCC on the leg of a 61-year-old immunosuppressed male, no previous treatment. (D) cSCC on the scalp of a 89-year-old male patient, recurrent after radiotherapy.
In phase 2 trial of cemiplimab for advanced cSCC, locally advanced cSCC patients were included if they experienced recurrence after 2 or more surgical procedures with subsequent unlikely curative resection, if the tumor already reached substantial local invasion precluding complete resection, or if surgical treatment would lead to substantial complications or deformity. Acceptable reasons for RT to be considered inappropriate were: previous RT with further RT exceeding the threshold of an acceptable cumulative dose, judgment of the radiation oncologist that the tumor was unlikely to respond to RT, or a risk–benefit assessment that RT was contraindicated for the patient [ 30 ] .
Clinical progression of cSCC into the advanced form seems to be associated not only to the intrinsic aggressiveness of cSCC, but also to patient characteristics that may impact on clinician decision and incomplete tumor initial management.
Regarding real-life profile of advanced cSCC patients, a retrospective study by Hillen et al [ 3 ] , analyzed 190 patients with advanced cSCC. Patients presented a median age of 78 years, an ECOG status 0–1, and location of the primary tumor most frequently on the head and neck, including high-risk locations such as ears or lips. Despite nonmalignant comorbidities influenced the decision for cSCC-specific therapy in only 21% of patients, the authors highlighted the fact that many clinicians might be unaware that locally advanced cSCC can lead to death. Eigentler et al [ 31 ] , showed that in a cohort of 1,434 patients who excised a cSCC between 2005 and 2015 and were followed-up for a median period of 36.5 months, a higher number of patients died due to local infiltration in the head region or regional infiltration into neck lymph nodes, compared to death due to visceral metastases.
Concerning pitfalls of initial management of cSCC, a retrospective study by Deilhes et al [ 32 ] , in a cohort of 109 patients with advanced cSCC, showed that 63% of patients had a delay of more than 3 months between the lesion’s first observation and biopsy, 62% of patients had incomplete histological examinations, and only 35% of patients completed all the procedures required for optimal management of the disease. Moreover, the authors highlighted that 75% of their patients’ cohort were living in rural areas and the decreased availability of dermatologists might have impacted mismanagement of the disease.
The clinician’s goal should be the recognition and appropriate treatment of cSCC at higher risk for recurrence and/or for progressing into advanced disease. However, it should be acknowledged that diagnosis, management, and follow-up of high-risk cSCC are still not straightforward. More studies are needed to standardize the relevance of each risk/prognostic factor, to explore the risk estimation of outcomes, and to prove the utility of disease-staging modalities. The adjuvant setting should be further explored to prevent progression of the disease. Currently, diagnosis and management of high-risk and advanced cSCC rely on a multidisciplinary approach that favors the most suitable therapeutic option based on the characteristics of the patient and of the disease.
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