Anokhi Jambusaria-Pahlajani

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.

Lichenoid dermatitis in three patients with metastatic melanoma treated with anti-PD-1 therapy.

Joseph and colleagues describe the immunemediated rash, lichenoid dermatitis, in three patients treated with anti–PD-1 (MK-3475). These mild rashes are characterized by a marked T-cell infiltrate with ∼10% PD-1+ T cells. Therapies that activate the immune system through blocking the binding of programmed death ligand 1 (PD-L1) present on tumors and PD-1 (programmed death 1) present on activated immune cells are revolutionizing the care for patients with cancer. These therapies work by inhibiting negative regulators of the immune system, thereby decreasing a tumors ability to evade the immune system. The side effects of anti–PD-1/PD-L1 therapies are generally mild and as expected are related to autoimmune reactions. Two of the most common side effects of anti–PD-1/PD-L1 therapies are rash and pruritus occurring in approximately 20% of patients. Although the rash is generally recognized to be immune mediated, the exact mechanisms of the rash remain unclear. Herein, we report three cases of lichenoid dermatitis in three patients treated with MK-3475 (anti–PD-1) that were characterized with marked T-cell infiltrates with few PD-1–positive cells. The rashes in all three patients were relatively mild, allowing treatment to continue despite the rashes. Cancer Immunol Res; 3(1); 18–22. ©2014 AACR.

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.

The Sun Exposure and Behaviour Inventory (SEBI): validation of an instrument to assess sun exposure and sun protective practices

Background  Skin cancer is the most common cancer worldwide. Sun exposure is the most important risk factor for its development. The amount of exposure required to cause skin cancer has not been quantified, and the impact of sun protective practices is unknown.

Sequential Curettage, 5-Fluorouracil, and Photodynamic Therapy for Field Cancerization of the Scalp and Face in Solid Organ Transplant Recipients.

BACKGROUND Field cancerization with actinic keratoses and squamous cell carcinoma in situ (AK/SCCIS) represents a common therapeutic challenge in solid organ transplant recipients (SOTRs). These patients often show inadequate responses to methods traditionally used as monotherapy (e.g., topical chemotherapy). OBJECTIVE To describe the clinical outcomes and feasibility of a sequential approach to treatment of field cancerization in SOTRs. METHODS Four SOTRs with field cancerization of the scalp and/or face were treated using a sequential approach. Light curettage of hypertrophic lesions was followed by application of 5-fluorouracil 5% cream twice daily for 5 days and photodynamic therapy (PDT) with 1-hour incubation on day 6. Pain level during and after PDT was recorded. Photographs were obtained immediately before and after treatment and at follow-up appointments. RESULTS All 4 patients tolerated this approach well and demonstrated excellent responses to treatment with complete or near-complete clinical resolution of AK/SCCIS lesions. Patients remained free of AK/SCCIS based on clinical examination 1 to 6 months after treatment. CONCLUSION For SOTRs with field cancerization, sequential therapy represents a viable therapeutic regimen with good tolerability and durable clinical response. This approach warrants further investigation to determine which therapeutic combinations have optimal tolerability and efficacy.

Treatment of in-transit and metastatic melanoma in two patients treated with ipilimumab and topical imiquimod.

Checkpoint blockade inhibitors have revolutionized the treatment of metastatic melanoma. Despite the success of these agents in improving the overall survival of patients with metastatic melanoma, not all patients achieve clinical benefit, leaving room for improvement. The presence of cutaneous metastases in patients with metastatic melanoma provides the unique opportunity to treat the cutaneous lesions with a local modality while simultaneously treating systemic disease with systemic therapy. Herein, we describe the treatment of two patients with both in-transit and metastatic melanoma with the combination of the topical toll-like receptor 7 agonist imiquimod with systemic ipilimumab. Both patients appeared to have progressed and developed new cutaneous and systemic metastases while on single agent ipilimumab only to respond when started on topical imiquimod. Both patients tolerated the combination of imiquimod and ipilimumab without serious adverse events, and both patients had excellent clinical responses. These cases provide a proof of principle of the possibility of the combination of toll-like receptor 7 agonists with immune checkpoint blockade inhibitors.

Comment on: The incidence and risk factors of metastasis for cutaneous squamous cell carcinoma-Implications on the t-classification system

Dear Editor, We read with great interest the recently published review article by Brougham et al. entitled “The Incidence and Risk Factors of Metastasis for Cutaneous Squamous Cell Carcinoma-Implications on the TClassification System” [1]. We commend the authors for their comprehensive review of the existing literature on this topic, discussion of the limitations of the current American Joint Committee on Cancer (AJCC) Tumor (T) Staging System, and discussion of alternative approaches to achieve improved prognostic discrimination. In the article, the authors cite an alternative T staging system (now the Brigham and Women’s Hospital [BWH] T staging) for cutaneous squamous cell carcinoma (CSCC) published by our group (Table I) [2,3]. The alternative/BWH T staging system offers improved prognostic discrimination over the current AJCC T staging system and has been validated in a 10-year cohort study of over 1,800 CSCC tumors. The staging system was built on four risk factors significantly associated with at least two CSCC outcomes of interest (local recurrence, nodal metastasis, and death from CSCC) and on multivariate analyses in our two cohort studies. We have two minor points of clarification. In table 3 of the paper by Brougham et al. [1], the authors define alternative/BWH stage T2b and T3 as having 2 and 3 risk factors, respectively; however, as shown in Table 1, T2b tumors have 2–3 risk factors and T3 have 4. In addition, the authors define tumor size greater than 2 cm in diameter as a risk factor for the alternative/BWH T staging system; however, it is tumor diameter both greater than and equal to 2 cm that are upstaged in our system. This diameter cutoff is consistent with previously published reports indicating an increased risk of recurrence and metastasis in tumors 2 cm or above [4–6], but it differs from AJCC staging, wherein the upstaging criterion is tumor diameter over (but not equal to) 2 cm. We would also like to discuss in further detail the staging system proposed in Table 5 of Brougham et al [1], which combines the results of multivariate analyses from the authors’ previously published study of 8,997 CSCC [7] with our recently published paper on the alternative/ BWH T staging system [2]. They propose a staging system based on hazard ratios (HR) from the two studies (T1 HR< 5, T2a HR> 5, T2b HR> 15, T3 HR> 25). Summing together hazard ratios, while it makes sense intuitively, it is not a statistically valid approach. Prediction models are formed by analyzing patient-level data to create a multivariate model and by using the beta coefficients from that model to develop weighted hazard ratios. The same analysis should ideally be repeated in multiple datasets from different studies to determine whether similar results can be obtained before concluding the predictionmodel is generalizable. The hazard for a patient withmultiple risk factors (for example 2.5 cm diameter and invasion of muscle) cannot mathematically be assumed to be the sum of the individual hazards reported in a given study or studies for these risk factors. From a practical perspective, another drawback of Brougham et al.’s proposed staging system is that clinicians may be unlikely to utilize a staging system based on hazard ratios because it would be cumbersome to make this calculation in real time when evaluating a patient. Clinicians would have to choose which hazards to apply from various studies reporting hazards for a given risk factor or average reported hazards for a given factor (e.g., perineural invasion). The former may imply bias regarding which studies’ hazards are chosen, and the latter,

Effect of physical activity on nonmelanoma skin cancer risk in kidney, liver, and pancreatic transplant patients.

BACKGROUND Physical activity has been associated with a lower risk of cancer, including melanoma, but the effect has not yet been assessed for nonmelanoma skin cancer (NMSC). OBJECTIVE To determine whether the risk of skin cancer differs according to physical activity level in patients at high risk for NMSC. METHODS We conducted a retrospective cohort study in kidney, liver, and pancreatic transplant patients via telephone interview. Physical activity scores were calculated for each patient using a previously validated questionnaire. Sun exposure history and skin type were also recorded. The outcome of interest was a biopsy‐proven diagnosis of at least one NMSC. RESULTS Of 142 subjects, 45 (32%) developed NMSC. There was no significant effect of physical activity on the development of NMSC. CONCLUSIONS Physical activity level may not be a major predictor of skin cancer risk in organ transplant patients. Controlled trials and population‐based studies are needed to determine whether exercise can decrease the risk of NMSC in the general population. The authors have indicated no significant interest with commercial supporters.