A new evidence-based risk stratification system for cutaneous squamous cell carcinoma into low, intermediate, and high risk groups with implications for management

REVIEW

A new evidence-based risk stratification system for cutaneous squamous cell carcinoma into low, intermediate, and high risk groups with implications for management Christian L. Baum, MS, MD,a Adam C. Wright, MD,b Juan-Carlos Martinez, MD,c Christopher J. Arpey, MD,a Jerry D. Brewer, MD,a Randall K. Roenigk, MD,a and Clark C. Otley, MDa Rochester, Minnesota; Jacksonville, Florida; and Knoxville, Tennessee Most primary cutaneous squamous cell carcinomas are cured with surgery. A subset, however, may develop local and nodal metastasis that may eventuate in disease-specific; death. This subset has been variably termed high risk. Herein, we review; an emerging body of data on the risks of these outcomes and propose an evidence-based; risk stratification for low-, intermediate-, and high-risk tumors that takes into; account both tumor and patient characteristics. Finally, we discuss a framework for; management of these tumors on the basis of data, when available, and our; recommendations when data are sparse. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2017.07.031.) Key words: cutaneous squamous cell carcinoma; immunosuppression; management; radiotherapy; risk stratification; sentinel lymph node biopsy; staging.

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utaneous squamous cell carcinoma (cSCC) has an incidence of 180,000 to 520,000 tumors per year in the United States1-3 and a metastasis rate of 2% to 5%.4-6 The prevalence of nodal metastasis (NM) from cSCC in the United States is estimated at 5604 to 12,572 cases per year,3 whereas the number of deaths is estimated at 3932 to 8791, with the upper limit of this range approximating the number of melanoma-related deaths per year.3,7 The progression of cSCC appears to be stepwise from local recurrence (LR) to regional spread and then distant metastasis.8 Most diseasespecific deaths are preceded by regional recurrence,9 and most regional recurrences involve the head and neck region.10 Furthermore, in patients treated with surgery for nodal disease, a relatively low burden of disease is correlated with lower recurrence rates and higher overall survival.9 These data indicate that controlling morbidity and mortality from cSCC is predicated on locoregional control. Therefore, From the Department of Dermatology, Mayo Clinic, Rochestera; Anderson and Rahman Dermatology, Knoxvilleb; and Department of Dermatology, Mayo Clinic, Jacksonville.c Funding sources: Dr Baum has a Career Development Award in Dermatologic Surgery from the Dermatology Foundation. Conflicts of interest: None declared. Accepted for publication July 24, 2017. Reprints not available from the authors.

Abbreviations used: ART: BWH: CLL: cSCC: CT: DSD: HRcSCC: IRcSCC: LR: LRcSCC: MMS: NM: PNI: SLNB:

adjuvant radiotherapy Brigham and Women’s Hospital chronic lymphocytic leukemia cutaneous squamous cell carcinoma computed tomography disease-specific death high-risk cutaneous squamous cell carcinoma intermediate-risk cutaneous squamous cell carcinoma local recurrence low-risk cutaneous squamous cell carcinoma Mohs micrographic surgery nodal metastasis perineural invasion sentinel lymph node biopsy

identifying cohorts with elevated and actionable risks for LR and NM may focus efforts intended to decrease cSCC-associated morbidity and mortality. Correspondence to: Christian L. Baum, MS, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, Minnesota 55905. E-mail: [email protected]. Published online September 12, 2017. 0190-9622/$36.00 Ó 2017 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2017.07.031

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The term high-risk squamous cell carcinoma has lymph node biopsy (SLNB). Data from the been variably defined in prior publications.11-15 Multicenter Selective Lymphadenectomy Trial However, a unified, evidence-based definition of demonstrated that SLNB provides valuable risk high-risk cSCC (HRcSCC) is absent. Although a stratification into a low-risk, negative SLNB cohort distinction between HRcSCC and low-risk cSCC compared with the high-risk, positive SLNB cohort, (LRcSCC) provides a simple binary classification with 85% and 62% 10-year melanoma-specific system, it does not adequately account for the risk survival rates, respectively.17 These results further spectrum that reflects the refine the cohort with a 10% biology of individual tumors. or higher risk of occult CAPSULE SUMMARY In recent years, sufficient nodal disease into suboutcomes data have been groups for which focused A small subset of cutaneous squamous published to allow stratificainterventions such as intencell carcinomas are associated with local tion of cSCC along a risk sive follow-up, imaging, recurrence, nodal metastasis, and death. spectrum based on tumor therapeutic lymph node An evidence-based risk stratification staging and independent dissection, and adjuvant system that consists of tumor staging risk factors, including some systemic therapy may be and patient characteristics is proposed forms of immunosuppresconsidered. Although the for low-, intermediate-, and high-risk sion. The purpose of this rebiologic progression pattern tumors. view is to propose an of cSCC appears more preevidence-based risk stratifidictable than that of melaThis risk stratification system may cation of cSCC into LRcSCC, noma, the data for cSCC optimize patient management and lead intermediate-risk cSCC outcomes are less mature to better outcomes. (IRcSCC), and HRcSCC on than those for melanoma. the basis of the most contemTherefore, we propose that porary data. We will also an absolute risk of 20% or discuss a framework for management based on these higher for LR and NM constitutes a reasonable risk levels. action threshold for defining HRcSCC. d

d

d

WHAT ARE REASONABLE THRESHOLDS FOR RISK STRATIFCIATION OF cSCC? The risk stratification of cSCC is inherently arbitrary, although reasonable reference points exist within cutaneous oncology. Furthermore, despite its arbitrary nature, risk stratification offers value because it has the potential to incorporate data, such as immunosuppression data, that are currently absent from any staging systems. At the same time, stratification may guide management decisions that are presently based on predominantly empirical data, including considerations of the associated risks and costs of various options, as well as more unified research efforts regarding cohorts that have historically been ill defined or not defined at all. First, the risks of LR and NM for the entire cohort of patients with cSCC are each approximately 2% to 5%.4,16 Given this baseline risk for all patients with cSCC, we propose an upper limit of 5% for the LRcSCC cohort. The next level of distinction lies between the IRcSCC and HRcSCC cohorts. We believe that this threshold may be extrapolated from other cutaneous malignancies, and melanoma is the most thoroughly studied. In the case of melanoma, a 10% or higher risk for occult nodal disease is the standard accepted action threshold for consideration of a sentinel

WHAT ARE THE EVIDENCE-BASED PATIENT AND TUMOR CHARACTERISTICS THAT DEFINE LRcSCC, IRcSCC, AND HRcSCC? The Brigham and Women’s Hospital (BWH) staging system (Table I) is derived from a singleinstitution cohort of approximately 1800 tumors. Not only does the cohort represent the data set for cSCC that has most robust outcomes, but the BWH staging system also currently appears to be the most precise. BWH T2b/T3 tumors represented 5% of the cohort but the majority of NMs (70%) and diseasespecific deaths (DSDs) (83%). In contrast, NM and DSD were reported in T2a tumors, albeit at a much lower rate.16 Thus, tumors with a single risk factor have the potential to develop adverse outcomes. A recent meta-analysis analyzed more than 23,000 tumors and is the most comprehensive analysis of single risk factors for cSCC outcomes to date.18 That study quantified data that supplement BWH risk stratification of T2a tumors. The application of metaanalysis data requires consideration of relative risk and heterogeneity of data, the latter of which is quantified with the I2 statistic. Values of 0% and 100% are associated with low and high levels of heterogeneity, respectively.19 Values of 30% to 60% may represent moderate heterogeneity,20 and given

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Table I. Brigham and Women’s Hospital staging system

Table III. Follow-up recommendations

Tumor stage

Low-risk cSCC Intermediate-risk cSCC High-risk cSCC

T1 T2a T2b T3

Definition

0 risk factors 1 risk factor 2-3 risk factors $4 risk factors OR bone invasion

Risk factors are diameter of $2 cm, poorly differentiated histologic findings, perineural invasion of at least 0.1 mm, and invasion beyond subcutaneous fat. Adapted from Karia et al.16

Table II. Risk stratification of primary cSCC and associated absolute risks for outcomes Risk category and risk factors

Low-risk cSCC BWH T1 BWH T2a Intermediate-risk cSCC BWH T2a with diameter [2 cm BWH T2a with depth beyond SC fat High-risk cSCC BWH T2b/T3 BWH T2a with depth beyond SC fat BWH T2a AND CLL with Rai stage III or IV

Absolute risk for LR

0.6% 5%

Absolute risk for NM

0.1% 3%

6%

12%

14%

d

21% d

67% 22%

25%

37%

BWH, Brigham and Women’s Hospital; CLL, chronic lymphocytic leukemia; cSCC, cutaneous squamous cell carcinoma; LR, local recurrence; NM, nodal metastasis; SC, subcutaneous. Adapted from Thompson et al,18 Karia et al,16 and Velez et al.25

the heterogeneous nature of cSCC data, an upper limit of 60% for I2 is a reasonable cutoff. When a relative risk of 5 or higher (as discussed earlier) and an I2 less than 60% are applied to cSCC, the 2 risk factors that qualify are tumor invasion beyond subcutaneous fat and diameter larger than 2 cm. Current staging systems for cSCC do not include immunosuppression as an independent risk factor.16,21,22 There is a paucity of outcomes data that adjust for staging of primary cSCC across the various types of immunosuppression. A recent study of 205 patients, including 58% with recurrent tumors, demonstrated an increased risk of locoregional recurrence (hazard ratio, 5.0; P = .0025) in a heterogeneous group of immunosuppressed patients (including organ transplant recipients, patients with hematologic malignancies, and patients with HIV) compared with immunocompetent patients treated with surgery and

Risk category

Follow-up frequency

Annually 6-12 mo for 2 y, then annually 2-4 mo for 2 y, then annually; consider repeating imaging yearly for 2 y

cSCC, Cutaneous squamous cell carcinoma.

adjuvant radiation for cSCC.10 Currently, the immunosuppressed population with the most robust outcomes data is the cohort with chronic lymphocytic leukemia (CLL) or non-Hodgkin’s lymphoma. Not only do they have an increased risk for cSCC, but also the LR rates after Mohs micrographic surgery (MMS) are reported at 13.4%.23 Furthermore, 1 study, which included 377 tumors in 133 patients, demonstrated that Rai stage24 (low stage, I-II; high stage, III-IV) is an independent risk factor in cSCC outcomes stratified by BWH staging.25 Specifically, BWH T1/T2a tumors with a high Rai stage had a higher rate (16.9%) of LR, NM, and DSD than BWH T1/T2a tumors with a low Rai stage (5.3%). For patients with BWH T2/T3 tumors, LR, NM, and DSD were increased for patients with a low (27.3%) or high (50%) Rai stage. Therefore, we believe that another significant and welldocumented prognostic factor is CLL with Rai stage III or IV. On the basis of the best available current data, we propose that the criteria outlined in Table II16,18,25 be used to define primary LRcSCC, IRcSCC, and HRcSCC for the outcomes of LR and NM.

A FRAMEWORK FOR MANAGEMENT OF HRcSCC As the risk for tumors increases, so too should consideration of a multidisciplinary approach. All patients with cSCC should be educated on self-examination, encouraged to follow sun-protective measures, and educated on the importance of recommended follow-up. There are no data on the correlation between follow-up times and outcomes. However, we recommend that follow-up intervals be based on the risk stratification of the tumor (Table III) and that each follow-up visit include a thorough palpation and visualization for cutaneous and nodal recurrence. Radiologic and surgical staging for occult nodal metastases All patients with cSCC should have a thorough examination of the draining nodal beds at the time of definitive treatment for the tumor. Additional staging is not recommended for LRcSCC. For IRcSCC and

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Table IV. Considerations for staging options and adjuvant therapy for HRcSCC BWH stage

Disease-specific death rate, %

T1 T2a

0 1

0.6 5

T2b

10

21

T3

100

67

Nodal metastasis rate, %

Adjuvant therapy for local recurrence: ‘‘safety margin,’’ immunostains, radiotherapy

Local recurrence rate, %

None Consider ‘‘safety margin’’ and/ or immunostains if PNI or poor tumor differentiation Encourage ‘‘safety margin’’ and/or immunostains; consider radiotherapy to primary site especially if PNI or poor tumor differentiation Encourage ‘‘safety margin’’ excision, immunostaining, and radiotherapy

0.1 3

Positive SLNB rate, %

0 7

Adjuvant therapy for nodal metastasis: SLNB, imaging, and radiotherapy

None None

21

29

Consider imaging; consider SLNB or radiotherapy to nodal basin

67

50

Recommend imaging; encourage SLNB or radiotherapy to nodal basin

Data derived from Karia et al,16 Thompson et al,18 and Schmitt et al.26 BWH, Brigham and Women’s Hospital; HRcSCC, high-risk cutaneous squamous cell carcinoma; PNI, perineural invasion; SLNB, sentinel lymph node biopsy.

Table V. Advantages and disadvantages of staging options and adjuvant therapy, stratified by type of recurrence SO or AT

Local recurrence ‘‘Safety margin’’ (AT) Immunostains (AT) Radiotherapy to primary site (AT) Nodal metastasis Imaging (SO) Sentinel lymph node biopsy (SO) Radiotherapy to nodal basin (AT)

Advantage

Disadvantage

Removal of discontiguous tumor Detection of subtle tumor Destruction of discontiguous tumor

Tissue loss; complexity of repair Time (h); technical expertise Time (wk); morbidity, logistics

Noninvasive; detection of subclinical nodal disease Early detection of microscopic disease and removal of metastasis Destruction of micrometastatic tumor

Relatively low sensitivity General anesthesia; surgical morbidity Time (wk); high morbidity

AT, Adjuvant therapy; SO, staging option.

HRcSCC, however, additional staging may be considered. A summary of the staging recommendations, considerations, advantages, and disadvantages is presented in Table IV16,18,26 and Table V. The purpose of staging for occult nodal metastases in these cohorts is to decrease the morbidity and mortality related to macroscopic nodal disease. Ultrasonography has been suggested in the evaluation of clinically node-negative patients with oral squamous cell carcinoma,27,28 as well as for patients with melanoma and occult NM.29,30 Although ultrasonography is an intriguing option, we are unaware of any data related to detection of occult nodal disease from cSCC. Other forms of imaging, especially computed tomography (CT), have been more extensively analyzed. In the largest retrospective study to date (N = 98), patients with BWH T2b/T3 tumors and imaging (79% had CT) had 50% fewer disease-related outcomes (LR, NM, or

DSD) compared with those who did not have imaging. The authors attributed these results to earlier intervention of advanced disease.31 Positron emission tomographyeCT, although not as well described, has demonstrated particular utility in patients with cSCC and CLL and may be attributable to more intense uptake from cSCC than background nodal involvement of CLL.32 There are no prospective studies describing the sensitivity, specificity, or survival benefit of radiologic staging for cSCC. SLNB is also an option for staging cSCC. SLNB is a safe14 and feasible15 method for identifying a sentinel lymph node in cSCC, including tumors of the head and neck. A 2014 meta-analysis reported that BWH T2b and T3 tumors are associated with positive SLNB rates of 29.4% and 50%, respectively.26 Subsequent studies have demonstrated a positive SLNB rate in variably defined cohorts ranging from

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12.3%14 to 15.1%15 and negative predictive values of 98% after a median follow-up of 19.4 months (range, 2.4-41).14 Recent data have emphasized the importance of serial step sectioning of lymph node specimens with immunohistochemical staining to minimize false-negative results.15 Although the impact of SLNB on outcomes of cSCC requires further study, current data suggest that SLNB may be considered in practice and should be studied further in comparison with imaging modalities in properly selected, high-risk populations, such as the HRcSCC cohort. Within a multidisciplinary approach, we consider SLNB for all BWH T2b/T3 tumors and T2a tumors that are larger than 2 cm in diameter. If SLNB is not performed, then either CT or positron emission tomographyeCT is recommended. Rigorous clinical follow-up remains a critical component in all patients with HRcSCC and may be a reasonable strategy alone for patients who will reliably return to the clinic.

Locoregional disease control LRcSCC can be effectively and efficiently managed by a variety of options, such as superficial destruction, wide local excision, and MMS. The primary intervention for locoregional control of IRcSCC and HRcSCC is surgery with negative margins. The efficacy of MMS was demonstrated in 260 patients with cSCC with multiple risk factors ($1 of the following: tumor [2 cm, perineural invasion [PNI], ear/lip location, temple location in elderly men, and immunosuppression). After a mean follow-up of 3.9 years, the LR was 1.2% and the metastasis rate was 2.3%.11 An LR rate of 13.4% has been reported after MMS for SCC in patients with CLL, which may be attributed, in part, to the significant subclinical extension of tumors in these patients.23 To optimize peripheral margin control and to immediately characterize residual tumor, we recommend MMS as the preferred primary surgical intervention for IRcSCC and HRcSCC. Multikeratin immunostains may be included during MMS, and if there is uncertainty in interpretation of the histology or if the tumor appears discontiguous, an additional margin (ie, ‘‘safety margin’’) of normal tissue may be resected and submitted for review of paraffin-embedded formalin-fixed tissue. Currently, there are no data on the efficacy of a safety margin or immunostains, although such data would be highly desirable. The risks and benefits of multicytokeratin immunostains and safety margins are reviewed in Table V. A prospective study is under way in our institution to evaluate the utility of multikeratin immunostains for detection of occult

cSCC in negative surgical margins in patients with cSCC and CLL or non-Hodgkin’s lymphoma. Despite meticulous surgical technique and microscopic scrutiny of margins, LR may occur after margins are interpreted as negative.11,16,23 Data on adjuvant options for HRcSCC in this setting are sparse, and adjuvant radiotherapy (ART) is the most commonly described option. Generally, reports of radiotherapy for cSCC are retrospective; are underpowered; describe concomitant chemotherapy; are frequently missing data regarding surgical margin status; and are enriched for patients with recurrent disease, perineural invasion, and/or NM.10,33,34 To date, it appears that radiotherapy after surgery may offer improved rates of locoregional recurrence in immunocompetent patients compared with in immunosuppressed patients10 and improved local disease control in patients with PNI,35,36 particularly in those with extensive microscopic PNI but not in those with focal microscopic PNI.37 There are no prospective studies to date on the safety and efficacy of ART after negative surgical margins for HRcSCC. We conducted a retrospective analysis of 32 patients treated with ART to the primary site after negative MMS margins. After a median follow-up time of 3.9 years,38 the LR rate was 3.8% for BWH T2b/T3 tumors (n = 26) and the NM rates were 0% for BWH T2b tumors (n = 20) and 17% for BWH T3 tumors (n = 6). Because the morbidity of radiotherapy is higher than that of any other option considered in this discussion, we reserve consideration of ART to the primary site after negative surgical margins only for HRcSCC.

CONCLUSION In this manuscript we have attempted to define thresholds for LRcSCC, IRcSCC, and HRcSCC in the context of existing data and the risk factors that constitute each risk level. We expect that this three-tiered stratification will be refined in the future and that the associated management should continue to evolve. We look forward to well-designed prospective efforts in this evolution that will ultimately lead to improved patient outcomes. REFERENCES 1. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-287. 2. Muzic JG, Schmitt AR, Wright AC, et al. Incidence and trends of basal cell carcinoma and cutaneous squamous cell carcinoma: a population-based study in Olmsted County, Minnesota, 2000 to 2010. Mayo Clin Proc. 2017;92(6):890-898. 3. Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis,

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