Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: Analysis of 188 cases of localized disease and proposed management algorithm.

BACKGROUND: Merkel cell carcinoma (MCC) management typically includes surgery with or without adjuvant radiation therapy (aRT). Major challenges include determining surgical margin size and whether aRT is indicated. OBJECTIVE: To assess the association of aRT, surgical margin size, and MCC local recurrence. METHODS: Analysis of 188 MCC cases presenting without clinical nodal involvement. RESULTS: aRT-treated patients tended to have higher-risk tumors (larger diameter, positive microscopic margins, immunosuppression) yet had fewer local recurrences (LRs) than patients treated with surgery only (1% vs 15%; P = .001). For patients who underwent surgery alone, 7 of 35 (20%) treated with narrow margins (defined as ≤1.0 cm) developed LR, whereas 0 of 13 patients treated with surgical margins greater than 1.0 cm developed LR (P = .049). For aRT-treated patients, local control was excellent regardless of surgical margin size; only 1% experienced recurrence in each group (1 of 70 with narrow margins ≤1 cm and 1 of 70 with margins >1 cm; P = .56). LIMITATIONS: This was a retrospective study. CONCLUSIONS: Among patients treated with aRT, local control was superb even if significant risk factors were present and margins were narrow. We propose an algorithm for managing primary MCC that integrates risk factors and optimizes local control while minimizing morbidity.

Management of High-Risk Squamous Cell Carcinoma of the Skin.

OPINION STATEMENT: Non-melanoma skin cancer (NMSC) is the most common malignancy in the USA, with cutaneous squamous cell carcinomas (cSCCs) constituting approximately 20 % of all NMSC. While cSCCs typically behave in an indolent fashion and can be cured with local destructive or surgical methods, a small subset metastasizes and induces significant morbidity and mortality. Identifying and aggressively treating these "high-risk" cSCCs (HRcSCCs) is thus paramount. Recent improvements in staging cSCCs appear to offer better risk stratification than earlier staging criteria. Radiologic imaging and sentinel lymph node biopsy may be beneficial in certain cases of HRcSCC, although more studies are needed before these techniques should be uniformly incorporated into management. Surgery with complete margin control, such as that offered by the Mohs micrographic technique, represents the first-line treatment for these tumors. Radiation therapy is likely most beneficial in the adjuvant setting. Chemotherapy is typically best reserved for patients with metastatic or locally advance disease that is not controllable with surgical and/or radiation therapies. Newer targeted treatments, such as EGFR inhibitors and immunotherapies may offer greater efficacy in these settings, although further evaluation is needed.

Postoperative radiation therapy is associated with a reduced risk of local recurrence among low risk Merkel cell carcinomas of the head and neck.

PURPOSE: Merkel cell carcinoma (MCC) is a rare and often aggressive skin cancer. Typically, surgery is the primary treatment. Postoperative radiation therapy (PORT) is often recommended to improve local control. It is unclear whether PORT is indicated in patients with favorable Stage IA head and neck (HN) MCC. METHODS AND MATERIALS: We conducted a retrospective analysis of 46 low-risk HN MCC cases treated between 2006 and 2015. Inclusion criteria were defined as a primary tumor size of ≤ 2 cm, negative pathological margins, negative sentinel lymph node biopsy, and no immunosuppression. Local recurrence (LR) was defined as tumor recurrence within 2 cm of the primary surgical bed and estimated with the Kaplan-Meier method. RESULTS: Omission of PORT was offered to all 46 patients, of which 23 patients received PORT and 23 did not. No patient received adjuvant chemotherapy. There were no significant differences in surgical margins, tumor size, depth, lympho-vascular invasion status, or demographics between the two patient groups. Median follow-up for all patients was 3.7 years. Six of the 23 patients who did not receive PORT developed an LR. Compared to the group that received PORT, there was a significantly higher risk of LR in the group treated without PORT (26% vs. 0%, P = .02). Median time to LR was 11 months. All local failures were effectively salvaged. There was no difference in MCC-specific and overall survival between the 2 groups. CONCLUSIONS: For patients with HN MCC, omission of PORT was associated with a significantly higher risk of local recurrence even among those patients with the lowest-risk tumors (i.e., Stage IA without immune suppression). Thus, it is important to weigh the benefits of PORT against the side effect profile on a case-specific basis for each patient.

Screening, early detection, education, and trends for melanoma: current status (2007-2013) and future directions: Part I. Epidemiology, high-risk groups, clinical strategies, and diagnostic technology.

While most cancers have shown both decreased incidence and mortality over the past several decades, the incidence of melanoma has continued to grow, and mortality has only recently stabilized in the United States and in many other countries. Certain populations, such as men >60 years of age and lower socioeconomic status groups, face a greater burden from disease. For any given stage and across all ages, men have shown worse melanoma survival than women, and low socioeconomic status groups have increased levels of mortality. Novel risk factors can help identify populations at greatest risk for melanoma and can aid in targeted early detection. Risk assessment tools have been created to identify high-risk patients based on various factors, and these tools can reduce the number of patients needed to screen for melanoma detection. Diagnostic techniques, such as dermatoscopy and total body photography, and new technologies, such as multispectral imaging, may increase the accuracy and reliability of early melanoma detection.

Screening, early detection, education, and trends for melanoma: current status (2007-2013) and future directions: Part II. Screening, education, and future directions.

New evidence has accumulated over the past several years that supports improved melanoma outcomes associated with both clinician and patient screening. Population-based and workplace studies conducted in Australia and the Unites States, respectively, have shown decreases in the incidence of thick melanoma and overall melanoma mortality, and a year-long statewide screening program in Germany has shown a nearly 50% reduction in mortality 5 years after the screening ended. Current melanoma screening guidelines in the United States are inconsistent among various organizations, and therefore rates of both physician and patient skin examinations are low. As policymaking organizations update national screening recommendations in the United States, the latest research reviewed in part II of this continuing medical education article should be considered to establish the most effective recommendations. Patient and provider education will be necessary to ensure that appropriate patients receive recommended screening.

Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma.

PURPOSE: Itraconazole, a US Food and Drug Administration-approved antifungal drug, inhibits the Hedgehog (HH) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis, and reduces BCC growth in mice. We assessed the effect of itraconazole on the HH pathway and on tumor size in human BCC tumors. PATIENTS AND METHODS: Patients with ≥ one BCC tumor > 4 mm in diameter were enrolled onto two cohorts to receive oral itraconazole 200 mg twice per day for 1 month (cohort A) or 100 mg twice per day for an average of 2.3 months (cohort B). The primary end point was change in biomarkers: Ki67 tumor proliferation and HH activity (GLI1 mRNA). Secondary end points included change in tumor size in a subset of patients with multiple tumors. RESULTS: A total of 29 patients were enrolled, of whom 19 were treated with itraconazole. Itraconazole treatment was associated with two adverse events (grade 2 fatigue and grade 4 congestive heart failure). Itraconazole reduced cell proliferation by 45% (P = .04), HH pathway activity by 65% (P = .03), and reduced tumor area by 24% (95% CI, 18.2% to 30.0%). Of eight patients with multiple nonbiopsied tumors, four achieved partial response, and four had stable disease. Tumors from untreated control patients and from those previously treated with vismodegib showed no significant changes in proliferation or tumor size. CONCLUSION: Itraconazole has anti-BCC activity in humans. These results provide the basis for larger trials of longer duration to measure the clinical efficacy of itraconazole, especially relative to other HH pathway inhibitors.

Vitamin D in cutaneous carcinogenesis: part I.

Skin cancer is the most common cancer in the United States. Exposure to ultraviolet radiation is a known risk factor for skin cancer but is also the principal means by which the body obtains vitamin D. Several studies have suggested that vitamin D plays a protective role in a variety of internal malignancies. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar protective effect. These noncalcemic actions of vitamin D have called into question whether the current recommended intake of vitamin D is too low for optimal health and cancer prevention. Part I will review the role of vitamin D in the epidermis; part II will review the role of vitamin D in keratinocyte-derived tumors to help frame the discussion on the possible role of vitamin D in the prevention of skin cancer.

Vitamin D in cutaneous carcinogenesis: part II.

The role of vitamin D in health maintenance and disease prevention in fields ranging from bone metabolism to cancer is currently under intensive investigation. A number of epidemiologic studies have suggested that vitamin D may have a protective effect on cancer risk and cancer-associated mortality. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar risk reducing effect. Potential mechanisms of action include inhibition of the hedgehog signaling pathway and upregulation of nucleotide excision repair enzymes. The key factor complicating the association between vitamin D and skin cancer is ultraviolet B radiation. The same spectrum of ultraviolet B radiation that catalyzes the production of vitamin D in the skin also causes DNA damage that can lead to epidermal malignancies. Part II of this continuing medical education article will summarize the literature on vitamin D and skin cancer to identify evidence-based optimal serum levels of vitamin D and to recommend ways of achieving those levels while minimizing the risk of skin cancer.

Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the women's health initiative randomized controlled trial.

PURPOSE: In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial. METHODS: Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication. RESULTS: Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC. CONCLUSION: Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.

Hat, shade, long sleeves, or sunscreen? Rethinking US sun protection messages based on their relative effectiveness.

BACKGROUND: Sun protection messages in the United States emphasize sunscreen use, although its efficacy in skin cancer prevention remains controversial. METHODS: We used data from NHANES 2003-2006, restricted to adult whites (n = 3,052) to evaluate how Americans protect themselves from the sun. Participants completed questionnaires on the frequency with which they used sunscreen, wore a hat, long sleeves, or stayed in the shade, in addition to the number of sunburns in the past year. RESULTS: Although using sunscreen is the most common sun protective behavior (30%), frequent sunscreen use was not associated with fewer sunburns. However, the odds of multiple sunburns were significantly lower in individuals who frequently avoided the sun by seeking shade (OR = 0.70, p < 0.001) or wearing long sleeves (OR = 0.73, p = 0.01). CONCLUSIONS: Our findings suggest that shade and protective clothing may be more effective than sunscreen, as typically used by Americans.

Genotype-phenotype correlations among pachyonychia congenita patients with K16 mutations.

Pachyonychia congenita (PC) is a rare, autosomal dominant keratin disorder caused by mutations in four genes (KRT6A, KRT6B, KRT16, or KRT17). The International PC Research Registry is a database with information on patients' symptoms as well as genotypes. We sought to describe the heterogeneity of clinical symptoms and to investigate possible genotype-phenotype correlations in patients with two types of K16 mutations, p.Asn125 and p.Arg127, causing the PC-16 subtype of PC. We found that clinical symptoms depended on the type of amino-acid substitution. Patients with p.Asn125Asp and p.Arg127Pro mutations exhibited more severe disease than patients carrying p.Asn125Ser and p.Arg127Cys mutations in terms of age of onset of symptoms, extent of nail involvement, and impact on daily quality of life. We speculate that amino-acid substitutions causing larger, more disruptive changes to the K16 protein structure, such as a change in amino-acid charge in the p.Asn125Asp mutation or a bulky proline substitution in the p.Arg127Pro mutation, may also lead to more severe disease phenotypes. The variation in phenotypes seen with different substitutions at the same mutation site suggests a genotype-phenotype correlation. Knowledge of the exact gene defect is likely to assist in predicting disease prognosis and clinical management.

Association of facial skin aging and vitamin D levels in middle-aged white women.

To investigate the relationship between UV-induced skin photodamage and 25(OH) vitamin D levels, we performed a cross-sectional study in 45 female subjects aged >40. Menopausal status, smoking status, skin cancer history, oral supplement use, and season of blood draw were recorded and serum 25(OH)D measured. A single-blinded, dermatologist evaluated standardized digital facial images for overall photodamage, erythema/telangiectasias, hyperpigmentation, number of lentigines, and wrinkling. Adjusting for age and season of blood collection, women with lower photodamage scores were associated with a 5-fold increased odds of being vitamin D insufficient (OR 5.0, 95% CI: 1.1, 23). Low scores for specific photodamage parameters including erythema/telangiectasias, hyperpigmentation, and wrinkling were also significantly associated with vitamin D insufficiency. Our results suggest an association between skin aging and 25(OH)D levels.

Reduced expression of biomarkers associated with the implantation window in women with endometriosis.

OBJECTIVE: To evaluate the expression of biomarkers of implantation, glycodelin A (GdA), osteopontin (OPN), lysophosphatidic acid receptor 3 (LPA3), and HOXA10, in eutopic endometrium of women with and without endometriosis. DESIGN: Prospective observational study. SETTING: Clinical research center. PATIENT(S): Twenty-four women with endometriosis and 23 healthy volunteers of similar age. INTERVENTION(S): Secretory phase endometrial biopsy. MAIN OUTCOME MEASURE(S): Expression of immunohistochemical staining intensity and localization of GdA, OPN, LPA3, and HOXA10 in eutopic endometrium. RESULT(S): Endometrial GdA expression was significantly reduced in patients after cycle day 22. The endometrium from women with endometriosis also showed decreased expression of OPN in the late secretory phase and LPA3 and HOXA10 expression in the midsecretory and late secretory phases. CONCLUSION(S): The decreased expression of these four biomarkers of implantation may indicate impaired endometrial receptivity in patients with endometriosis, providing one explanation for the subfertility observed even in women with few pelvic implants. Because many of these markers are P dependent, these findings suggest the possibility of reduced endometrial P action in this population.

Detection of isolated tumor cells in neuroblastoma by immunohistochemical analysis in bone marrow biopsy specimens: improved detection with use of beta-catenin.

Evaluation of the bone marrow is a critical component of accurate staging and surveillance for recurrent disease in neuroblastoma. The value of routine immunohistochemical analysis of otherwise histologically negative bone marrow biopsy specimens has not been adequately evaluated. By using synaptophysin, chromogranin, and beta-catenin, immunohistochemical analysis performed on otherwise histologically negative bone marrow specimens identified isolated tumor cells (ITCs) in 9.1%, 5.0%, and 10.0% of 220 biopsy specimens, respectively. Overall survival, as estimated by the Kaplan-Meier method, was not significantly different between patients with and without ITCs (P = .357). Of the immunohistochemical markers evaluated, beta-catenin showed the greatest sensitivity for identifying ITCs in the bone marrow and showed reactivity in primary tumor samples. We found that the presence of ITCs identified by immunohistochemical analysis may predict the persistence of disease but does not show significant overall survival differences. We also identified beta-catenin as a sensitive immunohistochemical marker of primary and metastatic neuroblastoma.

Minor elective surgical procedures using general anesthesia in children with sickle cell anemia without pre-operative blood transfusion.

BACKGROUND: Pre-operative red blood cell (RBC) transfusions are often recommended for patients with sickle cell disease (SCD) who require elective surgery under general anesthesia. However, definitive randomized studies demonstrating the benefit of transfusions in this setting have not been conducted. In particular, the merits of transfusion prior to minor or low-risk surgical procedures in children with SCD have not been demonstrated. PROCEDURE: We hypothesized that children with sickle cell anemia (Hb SS) who have minor elective surgical procedures develop few complications even without pre-operative transfusion. We accessed our Comprehensive Sickle Cell Program's Database to identify all such procedures performed during a 13-year period. Medical records were reviewed to characterize the surgical procedure, the use of transfusions, and perioperative complications. RESULTS: Twenty-eight children with Hb SS had a total of 38 minor surgical procedures. No perioperative transfusions were given in 34 of the cases (85%). Five of these 34 surgeries (15%) were associated with minor post-operative complications (fever or transient pain). No post-operative acute chest syndrome was encountered. CONCLUSIONS: Minor or low-risk elective surgical procedures in children with Hb SS may not routinely require pre-operative transfusion. A randomized clinical trial to compare transfusion with no transfusion for minor surgical procedures is needed.