Pritesh S. Karia

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.

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.

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.

A quantitative systematic review of the efficacy of imiquimod monotherapy for lentigo maligna and an analysis of factors that affect tumor clearance

BACKGROUND The reported efficacy of imiquimod for lentigo maligna varies widely, without consensus on tumor or treatment factors that can impact tumor clearance. OBJECTIVE We sought to provide a more precise estimate of clearance rates in patients with lentigo maligna who are treated with imiquimod and to analyze factors that can impact tumor clearance. METHODS We performed a literature search for biopsy-proven lentigo maligna treated with imiquimod monotherapy, linked treatment and outcome data to individual tumors, calculated histologic and clinical clearance rates with 95% confidence intervals (CIs), and analyzed the impact of tumor and treatment factors on tumor clearance using logistic regression. RESULTS Based on 347 tumors from 45 studies, histologic and clinical clearance rates were 76.2% (95% CI, 71.4-81.0%) and 78.3% (95% CI, 73.6-82.9%), respectively. The incidence of clinical recurrence was 2.3% (95% CI, 0.5-4.2%), with a mean follow-up of 34.2 ± 11.8 months. Treatment with >60 total applications, or with >5 applications per week was associated with a higher likelihood of histologic clearance (odds ratio, 8.4 [95% CI, 2.9-24.1] and odds ratio, 6.0 [95% CI, 2.4-14.7], respectively). LIMITATIONS Our limitations included the accuracy and scope of published data, variable follow-up times, potential patient selection, and publication bias related to case series/cohort designs of previous studies. CONCLUSION Imiquimod offers a 76% histologic and 78% clinical clearance rate for lentigo maligna. Both cumulative dose and treatment intensity affect tumor clearance.

Association of Advanced Leukemic Stage and Skin Cancer Tumor Stage With Poor Skin Cancer Outcomes in Patients With Chronic Lymphocytic Leukemia

IMPORTANCE Although it has been well established that patients with chronic lymphocytic leukemia (CLL) have an increased risk of developing skin cancer, few studies have investigated the effect of CLL stage on the risk of poor skin cancer outcomes. The present study of CLL staging assesses outcomes of melanoma, squamous cell carcinoma, and Merkel cell carcinoma in this high-risk population. OBJECTIVE To determine if progression of CLL measured by advanced Rai stage (III or IV) is associated with worse skin cancer outcomes. DESIGN, SETTING, AND PARTICIPANTS Twenty-year retrospective study at 2 academic centers in Boston, Massachusetts, of adults with CLL and either melanoma, squamous cell carcinoma, or Merkel cell carcinoma. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) for the development of poor skin cancer outcomes (local recurrence, nodal metastasis, distant metastasis, or death from skin cancer). RESULTS In total, 133 patients with 377 primary skin cancers and a median follow-up of 41 months were included. Squamous cell carcinoma predominated (92.0%). The risk of death from skin cancer was equivalent to the risk of death from CLL (13.5%). On multivariate analysis, advanced Rai stage (III or IV) at the time of the first skin cancer diagnosis (HR, 4.5; 95% CI, 2.3-8.9) and a high skin cancer tumor (T) stage (HR, 4.9; 95% CI, 2.2-10.8) were associated with poor skin cancer outcomes. Those with both a low skin cancer T stage and a low Rai stage (n = 265) had a low risk (5.3%; 95% CI, 3.2%-8.7%) of poor skin cancer outcomes. Those with a low T stage and a high Rai stage (n = 89) had a significantly higher risk of poor skin cancer outcomes (16.9%; 95% CI, 10.9%-26.0%). The 23 patients with a high T stage had high risks of poor outcomes regardless of CLL status (27.3% if a low Rai stage and 50.0% if a high Rai stage, with wide 95% CIs). CONCLUSIONS AND RELEVANCE In patients with CLL and non-basal cell carcinoma skin cancer, mortality is as high from skin cancer as from CLL. The Rai stage and skin cancer T stage should be considered when risk-stratifying patients with skin cancer. Regular communication between dermatologists and oncologists will help facilitate the identification of patients with CLL who are at high risk of having poor skin cancer outcomes.

Association of Sirolimus Use With Risk for Skin Cancer in a Mixed-Organ Cohort of Solid-Organ Transplant Recipients With a History of Cancer

IMPORTANCE Solid-organ transplant recipients (OTRs) are at an increased risk for skin cancer. Prior studies have demonstrated a reduced incidence of skin cancer in renal OTRs treated with sirolimus. However, little information exists on the use of sirolimus for the prevention of skin cancer in nonrenal OTRs or those already diagnosed as having a posttransplant cancer. OBJECTIVE To compare subsequent skin cancer formation in a mixed-organ cohort of OTRs who were or were not treated with sirolimus after developing a posttransplant index cancer of any type. DESIGN, SETTING, AND PARTICIPANTS A 9-year retrospective cohort study at 2 academic tertiary care centers. Electronic medical records were reviewed for OTRs diagnosed as having a posttransplant cancer of any type to determine the type of organ transplanted, pretransplant and posttransplant cancer, and immunosuppressive medications. Patients underwent transplant from January 1, 2000, to December 31, 2008. Data were collected from July 30, 2011, to December 31, 2012, when follow-up was completed, and analyzed from April 28, 2013, to October 4, 2014. MAIN OUTCOMES AND MEASURES Factors associated with subsequent skin cancer development were evaluated via multivariate Cox regression analysis. RESULTS Of 329 OTRs with an index posttransplant cancer (100 women and 229 men; mean [SD] age, 56 [19] years), 177 (53.8%) underwent renal transplant; 58 (17.6%), heart transplant; 54 (16.4%), lung transplant; 34 (10.3%), liver transplant; and 6 (1.8%), mixed-organ transplant. Ninety-seven OTRs (29.5%) underwent conversion to sirolimus therapy after diagnosis. One hundred thirty OTRs (39.5%) developed second posttransplant cancers, of which 115 cases (88.5%) were skin cancers. An 11.6% reduction in skin cancer risk was observed in the sirolimus-treated vs non-sirolimus-treated groups overall (26 of 97 [26.8%] vs 89 of 232 [38.4%]; P = .045) and among nonrenal OTRs only (8 of 34 [23.5%] vs 44 of 112 [39.3%], respectively), although the latter difference was not significant (P = .09). Independent predictors of skin cancer formation after the index posttransplant cancer were history of pretransplant skin cancer (subhazard ratio, 2.1; 95% CI, 1.2-3.7), skin cancer as the index posttransplant cancer (subhazard ratio, 5.5; 95% CI, 2.5-6.4), and sirolimus treatment (subhazard ratio, 0.6; 95% CI, 0.4-0.9). These same risk factors were associated with skin cancer formation when the analysis was limited to nonrenal OTRs. No difference was found in allograft rejection or death between sirolimus-treated and non-sirolimus-treated groups. CONCLUSIONS AND RELEVANCE In this mixed-organ cohort of OTRs, patients taking sirolimus after developing posttransplant cancer had a lower risk of developing subsequent skin cancer, with no increased risk for overall mortality. Thus, conversion to sirolimus therapy may be considered in OTRs who develop cancer if the risk for skin cancer is of concern. Larger studies are needed to quantify sirolimus-associated risk reduction for other cancer types.

Outcomes of Patients With Multiple Cutaneous Squamous Cell Carcinomas A 10-Year Single-Institution Cohort Study

IMPORTANCE Patients with multiple cutaneous squamous cell carcinomas (CSCCs) pose a management challenge for physicians, but their prognosis is unknown because outcomes have not been compared between patients who form single vs multiple CSCCs. OBJECTIVE To compare outcomes in patients with 1 vs multiple CSCCs. DESIGN, SETTING, AND PARTICIPANTS A 10-year retrospective single-institution cohort study at an academic tertiary care center of patients with dermally invasive (non-in situ) primary CSCC diagnosed from January 1, 2000, through December 31, 2009. MAIN OUTCOMES AND MEASURES Electronic medical records were reviewed to determine the tumor stage (Brigham and Womens Hospital tumor stage) and outcomes (local recurrence [LR], nodal metastases [NM], and death due to CSCC). Outcomes were compared between patients with 1 vs more than 1 CSCC via multivariable competing-risk regression adjusted for other significant cofactors. RESULTS Of 985 patients with CSCC, 727 had 1 CSCC, 239 had 2 to 9 CSCCs, and 19 had 10 or more CSCCs. Most patients with 10 or more CSCCs were immunosuppressed (15 of 19 [78.9%]). The median follow-up time was 50 months (range, 2-142 months). Patients with more than 1 CSCC had a higher risk of LR (subhazard ratio for 2-9 CSCCs, 1.8; 95% CI, 1.1-4.3; and for ≥10 CSCCs, 3.8; 95% CI, 1.4-10.0) and NM (subhazard ratio for 2-9 CSCCs, 3.0; 95% CI, 1.4-6.5; and for ≥10 CSCCs, 4.2; 95% CI, 1.4-10.4) compared with patients with 1 CSCC, adjusted for Brigham and Womens Hospital tumor stage. The 10-year cumulative incidence of LR and NM was higher in patients with 2 to 9 CSCCs and markedly higher in those with 10 or more CSCCs compared with patients who had 1 CSCC (10-year cumulative incidence for 1 CSCC: LR, 3.0%; 95% CI, 2.0%-4.5%; and NM, 2.3%; 95% CI, 1.5%-3.8%; for 2-9 CSCCs: LR, 6.7%; 95% CI, 4.2%-10.6%; and NM, 5.9%; 95% CI, 3.5%-9.6%; and for ≥10 CSCCs: LR, 36.8%; 95% CI, 19.2%-59.0%; and NM, 26.3%; 95% CI, 11.8%-48.8%). CONCLUSIONS AND RELEVANCE Patients with multiple CSCCs warrant frequent follow-up because they have an elevated risk of LR and NM. In particular, patients with 10 or more CSCCs have markedly elevated risks of recurrence and metastasis.

The positive impact of radiologic imaging on high-stage cutaneous squamous cell carcinoma management

Background: There is limited evidence on the utility of radiologic imaging for prognostic staging of cutaneous squamous cell carcinoma (CSCC). Objective: Review utilization of radiologic imaging of high‐stage CSCCs to evaluate whether imaging impacted management and outcomes. Methods: Tumors classified as Brigham and Womens Hospital (BWH) tumor (T) stage T2B or T3 over a 13‐year period were reviewed to identify whether imaging was performed and whether results affected treatment. Disease‐related outcomes (DRO: local recurrence, nodal metastasis, death from disease) were compared between patients by type of imaging used. Results: 108 high‐stage CSCCs in 98 patients were included. Imaging (mostly computed tomography, 79%) was utilized in 45 (46%) patients and management was altered in 16 (33%) patients who underwent imaging. Patients that received no imaging were at higher risk of developing nodal metastases (nonimaging, 30%; imaging, 13%; P = .041) and any DRO (nonimaging, 42%; imaging, 20%; P = .028) compared to the imaging group. Imaging was associated with a lower risk for DRO (subhazard ratio, 0.5; 95% CI 0.2‐0.9; P = .046) adjusted for BWH T stage, sex, and location. Limitations: Single institution retrospective design and changes in technology overtime. Conclusions: Radiologic imaging of high‐stage CSCC may influence management and appears to positively impact outcomes. Further prospective studies are needed to establish which patients benefit from imaging.