Glen M. Bowen

Metastatic Melanoma in Pregnancy: Risk of Transplacental Metastases in the Infant

PURPOSE Although metastases to the fetus via the placenta are rare, melanoma is the most common culprit. When it occurs, maternally derived melanoma metastasis in the infant is almost invariably fatal. PATIENTS AND METHODS This article reviews current guidelines for placental evaluation in pregnant women with metastatic melanoma and presents surveillance recommendations for their infants. Comprehensive literature reviews were performed on melanoma in pregnancy and melanoma metastasis to the placenta and fetus. The use of interferon alfa in the pediatric population was also reviewed. A comprehensive search of the MEDLINE database (1966 to 2002) was performed. Articles were reviewed and additional references were obtained from the bibliographies. Translation of non-English articles was performed, and authors of previous publications were contacted. RESULTS Eighty-seven patients with placental or fetal metastasis were identified. Twenty-seven occurrences were attributed to melanoma (31%). The fetus was affected in six of 27 melanoma patients (22%), with five of six infants dying of disease. The use of high-dose interferon alfa adjuvant therapy in pediatric patients has not been reported. CONCLUSION The placentas of women with known or suspected metastatic melanoma should be carefully examined grossly and histologically by pathologists. With placental involvement, fetal risk of melanoma metastasis is approximately 22%. Neonates delivered with concomitant placental involvement should be considered a high-risk population. The risk-benefit ratio of adjuvant treatment for a potentially affected infant should be carefully weighed.

Metastatic melanoma – A review of current and future treatment options

Despite advances in treatment and surveillance, melanoma continues to claim approximately 9,000 lives in the US annually (SEER 2013). The National Comprehensive Cancer Network currently recommends ipilumumab, vemurafenib, dabrafenib, and high-dose IL-2 as first line agents for Stage IV melanoma. Little data exists to guide management of cutaneous and subcutaneous metastases despite the fact that they are relatively common. Existing options include intralesional Bacillus Calmette-Guérin, isolated limb perfusion/infusion, interferon-α, topical imiquimod, cryotherapy, radiation therapy, interferon therapy, and intratumoral interleukin-2 injections. Newly emerging treatments include the anti-programmed cell death 1 receptor agents (nivolumab and pembrolizumab), anti-programmed death-ligand 1 agents, and oncolytic vaccines (talimogene laherparepevec). Available treatments for select sites include adoptive T cell therapies and dendritic cell vaccines. In addition to reviewing the above agents and their mechanisms of action, this review will also focus on combination therapy as these strategies have shown promising results in clinical trials for metastatic melanoma treatment.

Comparative Analysis of Total Body and Dermatoscopic Photographic Monitoring of Nevi in Similar Patient Populations at Risk for Cutaneous Melanoma

BACKGROUND Our previous experience monitoring nevi in high‐risk patients using serial digital epiluminescence microscopy (DELM) photography achieved low biopsy rates but was limited by melanomas presenting as new lesions or arising from nevi that had not been photographed. OBJECTIVE To determine whether biopsy rates, efficiency of melanoma detection, and melanoma origin (de novo vs nevus derived) differed in a similar patient population monitored using total body (TB) photography. METHODS One thousand seventy‐six patients (including 187 from a prior cohort) underwent TB photography and were monitored using photographs obtained at the initial visit. Risk factors and median monitoring periods for these patients were comparable with those of patients previously monitored using DELM photography. RESULTS Two hundred seventy‐five biopsies were performed in 467 patients on follow‐up visits. Of 12 melanomas detected on follow‐up, five were invasive, five presented as changing lesions and two as new lesions, nine arose de novo, and the remainder were nevus derived. CONCLUSIONS In our experience with both approaches, monitoring patients at risk for melanoma using TB photography was associated with lower biopsy rates and lower nevus‐to‐melanoma ratios than using DELM and facilitated detection of new and changing lesions. In both cohorts, the majority of melanomas detected on follow‐up arose de novo. The authors have indicated no significant interest with commercial supporters.

CD158k/KIR3DL2 is a useful marker for identifying neoplastic T-cells in Sézary syndrome by flow cytometry.

Enumeration of neoplastic T‐cells in peripheral blood specimens is necessary for the diagnosis of Sézary syndrome (SS) and monitoring treatment responses. Because neoplastic T‐cells in SS can be difficult to identify by morphology alone, flow cytometry immunophenotyping is often utilized. However, the reported immunophenotypic criteria for identifying neoplastic T‐cells in SS are variable, not present in all cases, or sometimes found in reactive T‐cell populations. Peripheral blood lymphocytes from 33 cases of SS were evaluated for the expression of pan‐T cell antigens and killer cell immunoglobulin‐like MHC receptors (KIR) CD158a, CD158b, CD158e, CD158i, and CD158k by multiparameter flow cytometry using monoclonal antibodies EB6, GL183, FES172, Z27, and Q66. A variety of abnormalities related to expression of pan‐T‐cell antigens typical of neoplastic T‐cells were observed. Expression of CD158k was observed in 32/33 cases and restricted to the phenotypically abnormal T‐cell populations, while expression of other KIR was mostly negative. Our findings confirm and extend recent reports by one group that CD158k is expressed by most SS cases. Moreover, our observation that CD4 positive, CD7 negative T‐cells are mostly CD158k negative further suggests that CD158k may be able to help identify and enumerate neoplastic T‐cells in SS even when present at low levels.

A Randomized Trial of the Off-label Use of Imiquimod, 5%, Cream With vs Without Tazarotene, 0.1%, Gel for the Treatment of Lentigo Maligna, Followed by Conservative Staged Excisions

OBJECTIVE To determine if the complete response rates of lentigo maligna (LM) to imiquimod, 5%, cream can be improved by the addition of a topical retinoid. DESIGN Prospective randomized study of patients treated with imiquimod alone vs imiquimod plus a topical retinoid, followed by conservative staged excisions. SETTING Mohs surgical clinic in an academic institution. PATIENTS Ninety patients with biopsy-confirmed LM. INTERVENTIONS Ninety patients with 91 LMs were randomized into 2 groups. One group received imiquimod, 5%, cream 5 d/wk for 3 months, while the other group also received tazarotene, 0.1%, gel 2 d/wk for 3 months. Following topical therapy, all patients underwent staged excisions and frozen section analysis with Melan-A immunostaining to confirm negative margins. MAIN OUTCOME MEASURE The presence or absence of residual LM at the time of staged excision. RESULTS Forty-six patients with 47 LMs were randomized to receive monotherapy: 42 of 47 LMs reached the intended treatment duration, with 27 complete responses (64%). Forty-four patients with 44 LMs were randomized to receive combined therapy: 37 of 44 LMs reached the intended treatment duration, with 29 complete responses (78%). This difference did not reach statistical significance (P=.17). There have been no recurrences to date, with a mean follow-up period of 42 months. CONCLUSIONS Among patients who received topical imiquimod with vs without tazarotene, 22% (8 of 37) of lesions vs 36% (15 of 42) of lesions showed residual LM on staged excisions. Pretreating LM with imiquimod, 5%, cream may decrease surgical defect sizes; however, total reliance on topical imiquimod as an alternative to surgery may put the patient at increased risk of a local recurrence.

Usefulness (or Lack Thereof) of Immunophenotyping in Atypical Cutaneous T-Cell Infiltrates

Our purpose was to evaluate the interobserver concordance for the diagnoses of mycosis fungoides (MF), atypical dermatoses (AD), and benign dermatoses (BD) and the impact of T-cell immunophenotyping on the diagnoses MF, AD, and BD. Specimens of MF (n = 57), AD (n = 27), BD and normal skin (n = 54) were reviewed by 2 hematopathologists and 1 dermatopathologist to establish diagnostic interobserver concordance by routine morphologic examination. Immunophenotyping was performed to evaluate expression of CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, and MIB-1. The interobserver concordance was fair to moderate compared with the original diagnosis. Partial deletion of CD2 alone was associated significantly with MF. Epidermal deletions of 2 or 3 T-cell antigens or 2 T-cell antigens not including CD7 were associated significantly with MF. An elevated CD4/CD8 ratio correlated with MF. Morphologic features were most diagnostic of MF. Immunophenotyping generally resulted in downgrading of the reaction pattern but was helpful in distinguishing MF from benign dermatoses.

Immunohistochemical staining with Melan-A of uninvolved sun-damaged skin shows features characteristic of lentigo maligna.

BACKGROUND The greater density and unusual patterning of melanocytes in chronically sun‐exposed skin complicates interpretation of intraoperative Melan‐A immunohistochemical stained margins during margin‐controlled surgery for lentigo maligna (LM) and lentigo maligna melanoma (LMM). OBJECTIVE To identify the immunohistochemical similarities and differences in melanocyte distribution between LM and LMM and chronically sun‐exposed skin. METHODS Retrospective review of Melan‐A‐stained original biopsy specimens of LM and LMM and uninvolved sun‐damaged skin (negative controls), from 70 LM and LMM cases from the University of Utah in 2008. RESULTS Histologic features commonly associated with LM were common in negative controls from chronically sun‐exposed skin. Melanocyte confluence (27/70, 39%), stacking (34/70, 49%), theque formation (9/70, 13%), adnexal extension (59/68, 87%), and suprabasilar scatter (23/70, 33%) were observed in the negative controls from sun‐damaged skin. Such features were present nearly uniformly in the LM and LMM specimens. Epidermal melanocyte density in LM and LMM differed significantly from that in negative controls (82.7 ± 29.3 and 25.6 ± 9.3 per × 400 field, respectively; p<.001). CONCLUSION Epidermal melanocytic features often ascribed to LM, such as melanocyte confluence, stacking, theque formation, adnexal extension, and suprabasilar scatter, are frequently observed in chronically sun‐exposed Caucasian skin and may lead to overestimation of surgical margins. The authors have indicated no significant interest with commercial supporters.

A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma

Purpose Intratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 combination and to obtain data on clinical efficacy. Results There was no dose limiting toxicity. While local response of injected lesions was observed in 67% patients (95% CI, 40%-93%), an abscopal response was seen in 89% (95% CI, 68%-100%). The overall response rate and clinical benefit rate by immune-related response criteria (irRC) was 40% (95% CI, 10%-70%) and 50% (95% CI, 19%-81%), respectively. Enhanced systemic immune response was observed in most patients and correlated with clinical responses. Experimental Design Twelve patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3 design was employed to assess highest tolerable intratumoral dose of ipilimumab and IL-2 based on toxicity during the first three weeks. Escalated doses of ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of three patients. A fixed dose of IL-2 was injected three times a week into the same lesion for two weeks, followed by two times a week for six weeks. Conclusions Intratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients.

Patterns of failure and predictors of outcome in cutaneous malignant melanoma of the scalp

BACKGROUND Patients with melanoma of the scalp may have higher failure (recurrence) rates than melanoma of other body sites. OBJECTIVE We sought to characterize survival and patterns of failure for patients with scalp melanoma. METHODS Between 1998 and 2010, 250 nonmetastatic patients underwent wide local excision of a primary scalp melanoma. Kaplan-Meier analyses were performed to evaluate overall survival, scalp control, regional neck control, distant metastases-free survival, and disease-free survival. RESULTS Five-year overall survival was 86%, 57%, and 45% for stages I, II, and III, respectively, and 5-year scalp control rates were 92%, 75%, and 63%, respectively. Five-year distant metastases-free survival for these stages were 92%, 65%, and 45%, respectively. Of the 74 patients who recurred, the site of first recurrence included distant disease in 47%, although 31% recurred in the scalp alone. LIMITATIONS This is a retrospective review. CONCLUSION Distant metastases-free survival and overall survival for stage II and III patients with scalp melanoma are poor, and stage III patients experience relatively high rates of scalp failure suggesting that these patients may benefit from additional adjuvant systemic and local therapy. Further research is needed to characterize the environmental, microenvironmental, and genetic causes of the increased aggressiveness of scalp melanoma and to identify more effective treatment and surveillance methods.

Case Series of Multiple Recurrent Reactive Keratoacanthomas Developing at Surgical Margins

Keratoacanthomas (KAs) are rapidly proliferating epidermal tumors that are usually considered a subtype of squamous cell carcinoma (SCC). There are several clinical subtypes of KA, including solitary, multiple, and KAs as part of a syndrome. The solitary KA is the most common form of this eruption, typically occurring in middle-aged, fair-skinned individuals on sun-exposed skin. Eruptions of multiple simultaneous KAs have been described and fall into three subtypes: multiple self-healing KAs of Ferguson-Smith, eruptive KAs of Grzybowski, and multiple familial KAs of Witten and Zak. KAs may occur as part of a syndrome such as Muir-Torre. In rare instances, trauma has been implicated in the pathogenesis of KA, and when arising in this setting, the term reactive KA has been used to describe this subset of KAs.