Chrysalyne D. Schmults

Factors Predictive of Recurrence and Death From Cutaneous Squamous Cell Carcinoma A 10-Year, Single-Institution Cohort Study

IMPORTANCE Although most cases of cutaneous squamous cell carcinoma (CSCC) are easily cured with surgery or ablation, a subset of these tumors recur, metastasize, and cause death. We conducted the largest study of CSCC outcomes since 1968. OBJECTIVE To identify risk factors independently associated with poor outcomes in primary CSCC. DESIGN A 10-year retrospective cohort study. SETTING An academic hospital in Boston. PARTICIPANTS Nine hundred eighty-five patients with 1832 tumors. MAIN OUTCOMES AND MEASURES Subhazard ratios for local recurrence, nodal metastasis, disease-specific death, and all-cause death adjusted for presence of known prognostic risk factors. RESULTS The median follow-up was 50 (range, 2-142) months. Local recurrence occurred in 45 patients (4.6%) during the study period; 36 (3.7%) developed nodal metastases; and 21 (2.1%) died of CSCC. In multivariate competing risk analyses, independent predictors for nodal metastasis and disease-specific death were a tumor diameter of at least 2 cm (subhazard ratios, 7.0 [95% CI, 2.2-21.6] and 15.9 [4.8-52.3], respectively), poor differentiation (6.1 [2.5-14.9] and 6.7 [2.7-16.5], respectively), invasion beyond fat (9.3 [2.8-31.1] and 13.0 [4.3-40.0], respectively), and ear or temple location (3.8 [1.1-13.4] and 5.9 [1.3-26.7], respectively). Perineural invasion was also associated with disease-specific death (subhazard ratio, 3.6 [95% CI, 1.1-12.0]), as was anogenital location, but few cases were anogenital. Overall death was associated with poor differentiation (subhazard ratio, 1.3 [95% CI, 1.1-1.6]) and invasion beyond fat (1.7 [1.1-2.8]). CONCLUSIONS AND RELEVANCE Cutaneous squamous cell carcinoma carries a low but significant risk of metastasis and death. In this study, patients with CSCC had a 3.7% risk of metastasis and 2.1% risk of disease-specific death. Tumor diameter of at least 2 cm, invasion beyond fat, poor differentiation, perineural invasion, and ear, temple, or anogenital location were risk factors associated with poor outcomes. Accurate risk estimation of outcomes from population-based data and clinical trials proving the utility of disease-staging modalities and adjuvant therapy is needed.

Evaluation of AJCC Tumor Staging for Cutaneous Squamous Cell Carcinoma and a Proposed Alternative Tumor Staging System

IMPORTANCE This study proposes an alternative tumor staging system for cutaneous squamous cell carcinoma (CSCC) that more precisely defines the small subset of tumors with a high risk of metastasis and death. OBJECTIVE To identify risk factors for poor outcomes in CSCC and evaluate the 2010 American Joint Committee on Cancer (AJCC) tumor (T) staging systems ability to stratify occurrence of these outcomes. DESIGN Retrospective cohort study. SETTING A single academic hospital. PARTICIPANTS Study participants were identified via a pathology and dermatopathology database search for patients diagnosed as having high-risk CSCC. RESULTS Two hundred fifty-six primary high-risk CSCCs were included. Outcomes for AJCC tumor stages T2 to T4 were statistically indistinguishable because only 4 cases (<2% of the cohort) were AJCC stages T3 or T4, which require bone invasion. Subsequently, the bulk of poor outcomes (83% of nodal metastases, 92% of deaths from CSCC) occurred in AJCC stage T2 cases. An alternative tumor staging system was developed with the aim of better stratifying this stage T2 group. Four risk factors were found to be statistically independent prognostic factors for at least 2 outcomes of interest in multivariate modeling. These factors (poor differentiation, perineural invasion, tumor diameter ≥2 cm, invasion beyond subcutaneous fat) were incorporated in the alternative staging with 0 factors indicating T1, 1 factor indicating T2a; 2 to 3 factors, T2b; and 4 factors or bone invasion, T3. Stages T2a and T2b significantly differed in incidences of all 4 end points. Stage T2b tumors comprised only 19% of the cohort but accounted for 72% of nodal metastases and 83% of deaths from CSCC. CONCLUSIONS AND RELEVANCE The proposed alternative tumor staging system offers improved prognostic discrimination via stratification of stage T2 tumors. Validation in other cohorts is needed. Meanwhile, stage T2b tumors are responsible for most poor outcomes and may be a focus of high-risk CSCC study.

Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women's Hospital Tumor Staging for Cutaneous Squamous Cell Carcinoma

PURPOSE To compare American Joint Committee on Cancer (AJCC), International Union Against Cancer (UICC), and Brigham and Womens Hospital (BWH) tumor (T) staging systems for cutaneous squamous cell carcinoma and validate BWH staging against prior data. PATIENTS AND METHODS Primary tumors diagnosed from 2000 to 2009 at BWH (n = 1,818) were analyzed. Poor outcomes (local recurrence [LR], nodal metastasis [NM], and disease-specific death [DSD]) were analyzed by T stage with regard to each staging systems distinctiveness (outcome differences between stages), homogeneity (outcome similarity within stages), and monotonicity (outcome worsening with increasing stage). RESULTS AJCC and UICC T3 and T4 were indistinct with overlapping 95% CIs for 10-year cumulative incidences of poor outcomes, but all four BWH stages were distinct. AJCC and UICC high-stage tumors (T3/T4) were rare at 0.3% and 3% of the cohort, respectively. Most poor outcomes occurred in low stages (T1/T2; AJCC: 86% [95% CI, 77% to 91%]; UICC: 70% [61% to 79%]) resulting in heterogeneous outcomes in T1/T2. Conversely, in BWH staging, only 5% of tumors were high stage (T2b/T3), but they accounted for 60% (95% CI, 50% to 69%) of poor outcomes (70% of NMs and 83% of DSDs) indicating superior homogeneity and monotonicity as previously defined. Cumulative incidences of poor outcomes were low for BWH low-stage (T1/T2a) tumors (LR, 1.4% [95% CI, 1% to 2%]; NM, 0.6% [95% CI, 0% to 1%]; DSD, 0.2% [95% CI, 0% to 0.5%]) and higher for high-stage (T2b/T3) tumors (LR, 24% [95% CI, 16% to 34%]; NM, 24% [95% CI, 16% to 34%]; and DSD, 16% [95% CI, 10% to 25%], which validated an earlier study of an alternative staging system. CONCLUSION BWH staging offers improved distinctiveness, homogeneity, and monotonicity over AJCC and UICC staging. Population-based validation is needed. BWH T2b/T3 tumors define a high-risk group requiring further study for optimal management.

Surgical Monotherapy Versus Surgery Plus Adjuvant Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma: A Systematic Review of Outcomes

BACKGROUND Adjuvant radiotherapy (ART) has been recommended for squamous cell carcinoma (SCC) with a high risk of recurrence, particularly perineurally invasive disease. The utility of ART is unknown. This study compares reported outcomes of high‐risk SCC treated with surgical monotherapy (SM) with those of surgery plus ART (S+ART). METHODS The Medline database was searched for reports of high‐risk SCC treated with SM or S+ART that reported outcomes of interest: local recurrence, regional or distant metastasis, or disease‐specific death. RESULTS There were no controlled trials. Of the 2,449 cases of high‐risk SCC included, 91 were treated with S+ART. Tumor stage and surgical margin status before ART were generally unreported. In 74 cases of perineural invasion (PNI), outcomes were statistically similar between SM and S+ART. In 943 high‐risk SCC cases in which clear surgical margins were explicitly documented, risks of local recurrence, regional metastasis, distant metastasis, and disease‐specific death were 5%, 5%, 1%, and 1%, respectively. CONCLUSIONS High cure rates are achieved in high‐risk cutaneous SCC when clear surgical margins are obtained. Current data are insufficient to identify high‐risk features in which ART may be beneficial. In cases of PNI, the extent of nerve involvement appears to affect outcomes, with involvement of larger nerves imparting a worse prognosis. The authors have indicated no significant interest with commercial supporters.

Outcomes of Primary Cutaneous Squamous Cell Carcinoma With Perineural Invasion: An 11-Year Cohort Study

OBJECTIVE To identify factors associated with poor outcomes in perineurally invasive squamous cell carcinoma. DESIGN Retrospective cohort study. SETTING Two academic hospitals in Boston, Massachusetts. PATIENTS Adults with perineural SCC diagnosed from 1998 to 2008. MAIN OUTCOME MEASURES Hazard ratios (HRs) for local recurrence, nodal metastasis, death from disease, and overall death, adjusted for known prognostic factors. RESULTS A total of 114 cases were included, all but 2 involving unnamed nerves. Only a single local recurrence occurred in cases with no risk factors other than nerve invasion. Tumors with large nerve (≥ 0.1 mm in caliber) invasion were significantly more likely to have other risk factors, including diameters of 2 cm or greater (P<.001), invasion beyond the subcutaneous fat (P<.003), multiple nerve involvement (P<.001), infiltrative growth (P=.01), or lymphovascular invasion (P=.01). On univariate analysis, large nerve invasion was associated with increased risk of nodal metastasis (HR, 5.6 [95% CI, 1.1-27.9]) and death from disease (HR, 4.5 [95% CI, 1.2-17.0]). On multivariate analysis, tumor diameter of 2 cm or greater predicted local recurrence (HR, 4.8 [95% CI, 1.8-12.7]), >1 risk factor predicted nodal metastasis (2 factors: HR, 4.1 [95% CI, 1.0-16.6]), lymphovascular invasion predicted death from disease (HR, 15.3 [95% CI, 3.7-62.8]), and overall death (HR, 1.1 [95% CI, 1.0-1.1]). Invasion beyond subcutaneous fat also predicted overall death (HR, 2.1 [95% CI, 1.0-4.3]). CONCLUSIONS Squamous cell carcinoma involving unnamed small nerves (<0.1 mm in caliber) may have a low risk of poor outcomes in the absence of other risk factors. Large-caliber nerve invasion is associated with an elevated risk of nodal metastasis and death, but this is due in part to multiple other risk factors associated with large-caliber nerve invasion. A larger study is needed to estimate the specific prognostic impact of nerve caliber.

Imiquimod Enhances IFN-γ Production and Effector Function of T Cells Infiltrating Human Squamous Cell Carcinomas of the Skin

Squamous cell carcinomas (SCCs) are sun-induced skin cancers that are particularly numerous and aggressive in patients taking T-cell immunosuppressant medications. Imiquimod is a topical immune response modifier and Toll-like receptor 7 (TLR7) agonist that induces the immunological destruction of SCC and other skin cancers. TLR7 activation by imiquimod has pleiotropic effects on innate immune cells, but its effects on T cells remain largely uncharacterized. Because tumor destruction and formation of immunological memory are ultimately T-cell-mediated effects, we studied the effects of imiquimod therapy on effector T cells infiltrating human SCC. SCC treated with imiquimod before excision contained dense T-cell infiltrates associated with tumor cell apoptosis and histological evidence of tumor regression. Effector T cells from treated SCC produced more IFN-gamma, granzyme, and perforin and less IL-10 and transforming growth factor-beta (TGF-beta) than T cells from untreated tumors. Treatment of normal human skin with imiquimod induced activation of resident T cells and reduced IL-10 production but had no effect on IFN-gamma, perforin, or granzyme, suggesting that these latter effects arise from the recruitment of distinct populations of T cells into tumors. Thus, imiquimod stimulates tumor destruction by recruiting cutaneous effector T cells from blood and by inhibiting tonic anti-inflammatory signals within the tumor.

Tumor-Specific T Cells in Human Merkel Cell Carcinomas: A Possible Role for Tregs and T-Cell Exhaustion in Reducing T-Cell Responses

Merkel cell carcinomas (MCC) are rare but highly malignant skin cancers associated with a novel polyomavirus. MCC tumors were infiltrated by T cells, including effector, central memory and regulatory T cells. Infiltrating T cells showed markedly reduced activation as evidenced by reduced expression of CD69 and CD25. Treatment of MCC tumors in vitro with IL-2 and IL-15 led to T cell activation, proliferation, enhanced cytokine production and loss of viable tumor cells from cultures. Expanded tumor-infiltrating lymphocytes showed TCR repertoire skewing and upregulation of CD137. MCC tumors implanted into immunodeficient mice failed to grow unless human T cells in the tumor grafts were depleted with denileukin diftitox, suggesting tumor-specific T cells capable of controlling tumor growth were present in MCC. Both CD4+ and CD8+ FOXP3+ regulatory T cells were frequent in MCC. 50% of non-activated T cells in MCC expressed PD-1, a marker of T-cell exhaustion, and PD-L1 and PD-L2 were expressed by a subset of tumor dendritic cells and macrophages. In summary, we observed tumor-specific T cells with suppressed activity in MCC tumors. Agents that stimulate T cell activity, block Treg function or inhibit PD-1 signaling may be effective in the treatment of this highly malignant skin cancer.

Test Characteristics of High-Resolution Ultrasound in the Preoperative Assessment of Margins of Basal Cell and Squamous Cell Carcinoma in Patients Undergoing Mohs Micrographic Surgery

BACKGROUND Noninvasive techniques to assess subclinical spread of nonmelanoma skin cancer (NMSC) may improve surgical precision. High-resolution ultrasound has shown promise in evaluating the extent of NMSC. OBJECTIVES To determine the accuracy of high-resolution ultrasound to assess the margins of basal cell (BCC) and squamous cell carcinomas (SCC) before Mohs micrographic surgery (MMS). METHODS We enrolled 100 patients with invasive SCC or BCC. Before the first stage of MMS, a Mohs surgeon delineated the intended surgical margin. Subsequently, a trained ultrasound technologist independently evaluated disease extent using the EPISCAN I-200 to evaluate tumor extent beyond this margin. The accuracy of high-resolution ultrasound was subsequently tested by comparison with pathology from frozen sections. RESULTS The test characteristics of the high-resolution ultrasound were sensitivity=32%, specificity=88%, positive predictive value=47%, and negative predictive value=79%. Subgroup analyses demonstrated better test characteristics for tumors larger than the median (area>1.74 cm2). Qualitative analyses showed that high-resolution ultrasound was less likely to identify extension from tumors with subtle areas of extension, such as small foci of dermal invasion from infiltrative SCC and micronodular BCC. CONCLUSION High-resolution ultrasound requires additional refinements to improve the preoperative determination of tumor extent before surgical treatment of NMSC.

Nitric Oxide–Producing Myeloid-Derived Suppressor Cells Inhibit Vascular E-Selectin Expression in Human Squamous Cell Carcinomas

Squamous cell carcinomas (SCC) are sun-induced skin cancers that are particularly numerous and aggressive in immunosuppressed individuals. SCC evade immune detection at least in part by down-regulating E-selectin on tumor vessels, thereby restricting entry of skin homing T cells into tumors. We find that nitric oxide potently suppresses E-selectin expression on human endothelial cells and that SCC are infiltrated by nitric oxide-producing iNOS+ CD11b+ CD33+ CD11c− HLA-DR− myeloid-derived suppressor cells (MDSC). MDSC from SCC produced NO, TGFβ and arginase and inhibited endothelial E-selectin expression in vitro. MDSC from SCC expressed the chemokine receptor CCR2 and tumors expressed the CCR2 ligand HBD3, suggesting CCR2-HBD3 interactions may contribute to MDSC recruitment to SCC. Treatment of SCC in vitro with the iNOS inhibitor L-NNA induced E-selectin expression at levels comparable to imiquimod-treated SCC undergoing immunologic destruction. Our results suggest that local production of NO in SCC may impair vascular E-selectin expression. We show that MDSC are critical producers of NO in SCC and that NO inhibition restores vascular E-selectin expression, potentially enhancing T cell recruitment. iNOS inhibitors and other therapies that reduce NO production may therefore be effective in the treatment of SCC and their premalignant precursor lesions actinic keratoses.

Incidence of and Risk Factors for Skin Cancer in Organ Transplant Recipients in the United States

Importance Skin cancer is the most common malignancy occurring after organ transplantation. Although previous research has reported an increased risk of skin cancer in solid organ transplant recipients (OTRs), no study has estimated the posttransplant population–based incidence in the United States. Objective To determine the incidence and evaluate the risk factors for posttransplant skin cancer, including squamous cell carcinoma (SCC), melanoma (MM), and Merkel cell carcinoma (MCC) in a cohort of US OTRs receiving a primary organ transplant in 2003 or 2008. Design, Setting, and Participants This multicenter retrospective cohort study examined 10 649 adult recipients of a primary transplant performed at 26 centers across the United States in the Transplant Skin Cancer Network during 1 of 2 calendar years (either 2003 or 2008) identified through the Organ Procurement and Transplantation Network (OPTN) database. Recipients of all organs except intestine were included, and the follow-up periods were 5 and 10 years. Main Outcomes and Measures Incident skin cancer was determined through detailed medical record review. Data on predictors were obtained from the OPTN database. The incidence rates for posttransplant skin cancer overall and for SCC, MM, and MCC were calculated per 100 000 person-years. Potential risk factors for posttransplant skin cancer were tested using multivariate Cox regression analysis to yield adjusted hazard ratios (HR). Results Overall, 10 649 organ transplant recipients (mean [SD] age, 51 [12] years; 3873 women [36%] and 6776 men [64%]) contributed 59 923 years of follow-up. The incidence rates for posttransplant skin cancer was 1437 per 100 000 person-years. Specific subtype rates for SCC, MM, and MCC were 812, 75, and 2 per 100 000 person-years, respectively. Statistically significant risk factors for posttransplant skin cancer included pretransplant skin cancer (HR, 4.69; 95% CI, 3.26-6.73), male sex (HR, 1.56; 95% CI, 1.34-1.81), white race (HR, 9.04; 95% CI, 6.20-13.18), age at transplant 50 years or older (HR, 2.77; 95% CI, 2.20-3.48), and being transplanted in 2008 vs 2003 (HR, 1.53; 95% CI, 1.22-1.94). Conclusions and Relevance Posttransplant skin cancer is common, with elevated risk imparted by increased age, white race, male sex, and thoracic organ transplantation. A temporal cohort effect was present. Understanding the risk factors and trends in posttransplant skin cancer is fundamental to targeted screening and prevention in this population.