Ann Surg Oncol (2019) 26:4642–4650 https://doi.org/10.1245/s10434-019-07743-8 ORIGINAL ARTICLE – MELANOMA Squamous Cell Carcinoma with Regional Metastasis to Axilla or Groin Lymph Nodes: a Multicenter Outcome Analysis George Pang, MD1, Nicole J. Look Hong, MD, MSc2, Gabrielle Paull, MSc3, Johanna Dobransky, MHK, BSc, CCRP4, Suzana Kupper, MD5, Scott Hurton, MD6, Daniel J. Kagedan, MD2, May Lynn Quan, MD5, Lucy Helyer, MD, MSc6, Carolyn Nessim, MD, MSc4, and Frances C. Wright, MD, Med2 1Department of Surgery, Western University, London, ON, Canada; 2Department of Surgery, University of Toronto, Toronto, ON, Canada; 3Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; 4Department of Surgery, University of Ottawa, Ottawa, ON, Canada; 5Department of Surgery, University of Calgary, Calgary, AB, Canada; 6Department of Surgery, Dalhousie University, Halifax, NS, Canada ABSTRACT developed nodal and/or distant disease recurrence. Crude Background. Cutaneous squamous cell carcinoma (cSCC) mortality rate was 39.5%. Mean OS was 5.3 years [95% of the trunk/extremities with nodal metastasis represents a confidence interval (CI) 3.9–6.8 years], and 5-year OS was rare but significant clinical challenge. Treatment patterns 55.1%. Mean DFS was 4.8 years (95% CI 3.3–6.2 years), and outcomes are poorly described. and five-year DFS was 49.3%. Any recurrence was the only Patients and Methods. Patients with cSCC who devel- independent predictor of death [p = 0.036, odds ratio oped axilla/groin lymph node metastasis and underwent (OR) = 29.5], and extracapsular extension (p = 0.028, curative-intent surgery between 2005 and 2015 were OR = 189) and age (p = 0.017, OR = 0.823) were inde- identified at four Canadian academic centers. Demo- pendent predictors of recurrence. graphics, tumor characteristics, treatment patterns, Conclusions. This represents the largest contemporary recurrence rates, and mortality were described. Overall series to date of outcomes for patients with axilla/groin survival (OS) and disease-free survival (DFS) were cal- nodal metastases from cSCC. Despite aggressive treatment, culated using Kaplan–Meier analysis. Predictors of outcomes remain modest, indicating the need for a con- survival and any recurrence were explored using Cox tinued multidisciplinary approach and integration of new regression and logistic regression models, respectively. systemic agents. Results. Of 43 patients, 70% were male (median age 74 years). Median follow-up was 38 months. Median time to nodal metastasis was 11.3 months. Thirty-one and 12 Nonmelanoma skin cancer (NMSC) is the most common patients had nodal metastasis to the axilla and groin, cancer in the world. Cutaneous squamous cell carcinoma respectively. A total of 72% and 7% received adjuvant and (cSCC) accounts for 20% of all NMSC but is responsible neoadjuvant radiation, respectively, while 5% received for the majority of NMSC mortality due to its higher adjuvant chemotherapy. Following surgery, 26% patients metastatic potential.1 The incidence of cSCC is increasing in the Americas, Australia, and Europe.2 In Canada, 78,300 individuals were diagnosed with NMSC in 2015.3 In the USA, an estimated 419,000–700,000 cases of cSCC are 4,5 This paper was presented as a poster presentation at the Society of diagnosed each year. Contemporary data demonstrate an Surgical Oncology Annual Meeting in 2018 (SSO 2018). overall cSCC disease-related mortality of 2.1%.6,7 In a US study, estimated death from cSCC may be as common as Ó Society of Surgical Oncology 2019 death from renal, oropharyngeal carcinoma, and mela- 4 First Received: 19 September 2018; noma, highlighting cSCC as a significant health burden. Published Online: 22 August 2019 G. Pang, MD e-mail: [email protected] Nodal Metastatic Squamous Cell Carcinoma 4643 Generally, patients with cSCC have excellent prognosis. recurrence, regional/distant metastasis, or death, whichever The mainstay of treatment for locally isolated disease occurred first. Chi squared and Fisher’s exact tests were includes surgical excision followed by careful dermato- used to compare categorical variables, whereas Mann– logic surveillance for recurrence. Radical procedures are Whitney U tests were applied to compare continuous rarely necessary when disease is detected early. Even in the variables. Survival analysis was performed using the setting of local recurrence or primary lesion progression, Kaplan–Meier method. For OS, patients were censored at indolent growth rate offers the ability for localized treat- date of death or end of follow-up, whichever occurred first. ment with good prognosis.8 However, a small subset of Predictors of survival and any recurrence were explored cSCC patients will progress to nodal or distant metastatic using Cox regression and logistic regression models, disease. Regional lymph nodes are the most common site respectively. Before variables were included in the Cox of metastasis, reportedly occurring in 2.0–12.5%.4,9,10 regression models, bivariate comparisons were completed Most cases of cSCC occur in the sun-exposed head and using Chi square and log-rank (Mantel–Cox) tests. All p- neck region, where the corresponding treatment of nodal values of 0.300 and lower were included in the Cox metastases is well documented.11 cSCC originating in the regression model. A similar stepwise approach was trunk and extremities with metastases to the axilla/groin implemented to yield logistic regression model with high r2 lymph nodes has received less attention. Few studies value. Analyses were conducted using SPSS 21.0 (IBM describe outcomes for this patient group, with most being Corp., Armonk, NY). small single-center case series,4,6,7,12,13 and 5-year overall survival (OS) rates vary from 34.4% to 48.0%.8,14 RESULTS Multimodality treatment has been used inconsistently with varying efficacy. While SCCs are often thought to be Patient Characteristics radiation sensitive, widespread application to cSCC with lymph node metastases remains a topic of investigation. Table 1 presents patient, primary lesion, nodal disease, The aim of this study is to retrospectively examine and treatment characteristics. Of 43 consecutive patients, clinical outcomes of patients with cSCC of the trunk/ex- median age was 74 years and 70% were male. Four tremity with documented regional metastases to the patients had history of immunosuppression [fingolimod for axilla/groin nodal basins treated at four Canadian tertiary multiple sclerosis (MS), prednisone for rheumatoid arthritis cancer centers. (RA), Crohn’s disease, chronic lymphocytic leukemia (CLL) treatment]. Four patients had history of chronic PATIENTS AND METHODS lesions at the primary site (1 Marjolin’s ulcer, 2 burn scars, 1 venous ulcer) prior to development of nodal cSCC. In four Canadian tertiary centers (Toronto, Ottawa, Median follow-up time was 38 months (3.2 years). Calgary, and Halifax), consecutive patients with cSCC of the trunk/extremities with axilla/groin nodal metastasis Primary Lesion Characteristics surgically treated from 1 January 2005 to 31 December 2015 were retrospectively identified from prospectively A primary lesion was identified in 93% of patients. Six kept institutional databases. All patients had a confirmed patients had multiple primary lesions. All known primary clinical and pathological diagnosis of nodal metastasis and lesions were excised prior to nodal surgery, except for one underwent curative-intent nodal dissection. Patients with patient who declined digital amputation. Of primary lesions primary mucosal cSCC (e.g., anogenital), cervical nodal with available pathology data, median diameter and depth metastases, head and neck primary lesions, and nodal were 3.0 and 1.1 cm, respectively. Perineural (PNI) and metastases documented only on microscopic examination lymphovascular (LVI) invasion were present in two (5%) of sentinel lymph node biopsy were excluded. This study and four (9%) patients, respectively (Table 1). was approved by each institution’s Research Ethics Board. Descriptive statistics describe patient, disease, and Presentation and Treatment of Nodal Metastatic treatment characteristics. Continuous variables are sum- Disease marized using mean, median, and range, while categorical variables are reported as proportions and percentages. The At time of diagnosis, 36 (84%) patients presented with primary outcome was 5-year OS, defined as time from clinically palpable nodes [median nodal size 5.5 cm with nodal dissection to death from any cause. Secondary out- 42% having extracapsular extension (ECE)] and 42% come was disease-free survival (DFS), defined as time required skin resection with the dissection. A total of 31 from nodal dissection to occurrence of any local (72%) and 12 (28%) patients had axillary and groin 4644 G. Pang et al. TABLE 1 Patient, primary lesion, nodal disease, nodal treatment, TABLE 1 continued and recurrence characteristics (n = 43) n (%) n (%) Fine-needle aspirate (FNA) 18 (42%) Patient characteristics Excisional biopsy 9 (21%) History of transplant, predisposing 0 Location of nodal disease congenital diseasea Axilla 31 (72%) Previous or concurrent malignancy 15 (35%) Groin 12 (28%) Primary lesion(s) Treatment of nodal disease Location of primary cutaneous lesion Surgery Hand, arm 17 (39%) Lymph nodes resectedc Foot, leg 9 (21%) Total number of lymph nodes in Median 17 (range 0–41) Back, chest, abdomen 12 (28%) axillary dissection Pelvis/buttock, genitalia (nonmucosal) 2 (4%) Positive lymph nodes in axillary Median 2 (range 0–18) No primary