As previously mentioned, the revised AJCC staging separates eyelid carcinomas from other cutaneous squamous cell carcinomas. The TNM classification is used to stage all cell types of eyelid carcinomas, including squamous cell carcinoma. The Tx, T0, and Tis is staged similarly as for non-eyelid skin. The staging differences for eyelid skin becomes a factor for the T1 designation and higher. T1 applies to a tumor that is 5 mm or less in greatest dimension AND does not invade the tarsal plate or eyelid margin. T2a applies to a tumor that is greater than 5 mm but not greater than 10 mm in greatest dimension OR any tumor that invades the tarsal plate or eyelid margin. T2b applies to a tumor that is greater than 10 mm but not greater than 20 mm in greatest dimension OR involves the full thickness eyelid. T3a designation is applied to a tumor that meets any of the following criteria: greater than 20 mm in greatest dimension, OR any tumor that invades adjacent ocular or orbital structures, OR a tumor of any size that demonstrates perineural invasion. T3b designation is applied to a tumor that requires enucleation for complete tumor resection, exenteration, or bone resection. T4 applies to a tumor that is not resectable due to extensive invasion of either ocular, orbital, and craniofacial structures or the brain. The regional lymph node designation of Nx (regional lymph nodes cannot be assessed) is the same as for non-eyelid skin. cN0 applies to no regional lymph node metastasis based upon clinical evaluation or imaging, and pN0 applies to no regional lymph node metastasis based upon lymph node biopsy. N1 applies to regional lymph node metastasis. Distant metastasis criteria are the same for eyelid squamous cell carcinomas as non-eyelid cutaneous squamous cell carcinomas (Table 6.3) [10].

The revised staging system is more clearly defined than previous staging, including separation of eyelid squamous cell carcinomas from non-eyelid cutaneous squamous cell carcinomas and incorporation of high-risk features. However, there is concern that the current staging system requires additional updates. There have been several proposed revisions to the current staging system with concern that the current criteria defining high-risk cutaneous squamous cell carcinomas are not sufficiently accurate and thus may reduce survival and hinder management of the disease according to risk.

The first validation study of the new AJCC T staging system by using patient outcome data showed that the bulk of poor outcomes (83 % of nodal metastases and 92 % of disease-specific deaths) occurred in AJCC T2 tumors. Investigators at Brigham and Women’s Hospital proposed an alternate T staging system with the aim of better stratifying the stage T2 group into low-risk T2a and high-risk T2b categories. Four risk factors were found to be statistically independent prognostic factors, including poor differentiation, perineural invasion, tumor diameter ≥2 cm, and invasion beyond subcutaneous fat and were thus incorporated in the alternative staging with 0 factors indicating T1; 1 factor indicating T2a; 2–3 factors, T2b; and 4 factors or bone invasion, T3. Stages T2a and T2b significantly differed in incidences of all 4 end points. The high-risk T2b group contained a minority of the patients (19 % of the cohort) but the majority of poor outcomes (72 % nodal metastases and 83 % of disease-specific deaths). Therefore, this proposed staging system may offer improved outcome similarity within stages as well as worsening outcome with increasing stage [11] (Table 6.4).

This proposed staging system was further validated in a subsequent study, comparing Brigham and Women’s Hospital (BWH) tumor staging system with the AJCC staging system. The BWH staging system divides AJCC T2 tumors into two separate groups, a large low-risk T2a group and a smaller high-risk T2b group, and collapses AJCC T3/T4 (bone invasion tumors) into a single BWH T3 group, which also includes rare high-risk tumors with all four risk factors but no bone invasion. BWH T2b and T3 together account for a small fraction (5 %) of cutaneous squamous cell carcinomas but a large majority of local recurrences, nodal metastases, and disease-related deaths (47 %, 70 %, and 83 %, respectively). Conversely, BWH T2b and T3 tumors had a 21 % (95 % CI, 14–31 %) and 67 % (95 % CI, 30–90 %) risk of nodal metastases, respectively [12]. Therefore, cumulative incidences of poor outcomes were low for BWH low-stage (T1/T2a) tumors and higher for high-stage (T2b/T3) tumors, thus further validating the earlier study of an alternative staging system.

It has also been suggested that while anatomic location and lack of perineural invasion are good prognostic predictors, the subjectivity of tumor differentiation and the importance of the Clark level are not as well defined. Furthermore the differentiation between low-risk and high-risk cutaneous squamous cell carcinomas is currently defined by the cutoff of 2 mm for the depth of tumor invasion. It has been suggested that this is a poor marker given that a significant number of cutaneous SCCs are thicker than 2 mm. Thus, the current depth cutoff allows for higher sensitivity but decreased specificity in terms of predicting risk [13].

Additionally, although the new AJCC staging system includes several “high-risk” factors, there are several other factors that have been proposed to be included in the staging system. Immunosuppression has been demonstrated to negatively contribute to prognosis and thus has been proposed to be reflected in the staging system. The current TNM criteria exclude clinical risk factors in staging, including immunosuppression [14].

Furthermore, recurrent cutaneous squamous cell carcinomas have been shown to be associated with a higher rate of lymph node metastases. A comparative analysis of lymph node metastasis in recurrent versus primary cutaneous squamous cell carcinomas was 15 % and 2 %, respectively (P < .001) [15]. Cutaneous squamous cell carcinoma recurrence has also been correlated to tumor size, with larger tumors associated with a significantly higher rate of recurrence. Finally, recurrent lesions have been associated with a higher rate of perineural invasion, lymphovascular invasion, and subcutaneous tissue invasion [16]. As tumor recurrence has been demonstrated to be an important risk factor in cutaneous squamous cell carcinoma, it has been proposed that tumor recurrence should be included in the high-risk classification [15].

Other factors that have been proposed as possible prognostic factors in cutaneous squamous cell carcinoma are peritumoral actinic keratoses, various Clark levels, desmoplasia, and Ki67 expression [1, 17]. The true prognostic value of these factors still needs to be further elucidated by additional studies.

High-risk cutaneous SCCs are those tumors associated with a high risk of subclinical metastasis and thus adverse events including local recurrence, nodal metastases, and disease-specific death [13]. As previously mentioned, immunosuppression adversely affects outcomes in transplant patients with SCC, and lack of sufficient prospective data in these patients makes establishing high-risk criteria difficult [13, 14]. Risk factors often occur together, and studies with sufficient subjects to calculate outcomes with multivariate (as opposed to univariate) modeling to control for this coexistence are limited [2]. Proposed “high-risk” factors will be discussed independently, as several consensus guidelines have been published but with differing definitions [18], and criticism that important factors are excluded, or are overly sensitive as to include many low-risk tumors [13]. With no universally accepted standard definition of high-risk features, these are often defined on a study-by-study basis, with some using the terms “high risk” and “very high risk.” [19]. Immunosuppression itself is considered high risk in some guidelines (National Comprehensive Cancer Network, NCCN) but not others (American Joint Committee on Cancer, AJCC). As always, prospective multicenter studies looking into transplant patients in particular are needed to better define “high risk” in an already high-risk population. Clinical and histologic factors are the most studied indicators of high risk, but recent work on molecular factors will likely become relevant with more research.

According to the American Cancer Society, many of the millions of skin cancers diagnosed annually are preventable [39]. In immunosuppressed OTRs, reducing morbidity from increased tumor burden and mortality from high-risk squamous cell carcinomas can be challenging. The basic idea of chemoprevention hinges upon the stepwise progression of carcinogenesis and the understanding that there are many steps between sun exposure and the development of a skin cancer [6, 40–42]. Chemoprevention differs from standard preventative strategies. Standard prevention is always necessary, especially in OTRs, and it includes various sun protection behaviors, clothing, sunscreen, and education [43]. Conversely, chemoprevention is defined as the use of natural, synthetic, or biologic agents to reverse, suppress, or prevent the stepwise carcinogenic progression [7, 42, 44]. Chemopreventive agents should be both effective and safe, causing minimal toxicity to normal cells [6, 44]. Chemoprevention is indicated in patients who are at a high risk for the development of many skin cancers or metastases; thus, OTRs automatically fit this indication [45]. Although the risk of cutaneous carcinoma development varies based on the type of organ transplant, OTRs remain the major target for chemoprevention [44, 46, 47]. When determining if a patient should be placed on a chemopreventive agent, several factors may be considered: the age of the individual at transplantation, prior history of sun exposure and skin cancers, the number of new skin cancers the patient is developing per year, the level of immunosuppression, and the patient’s skin phototype [48–50].