Allan C. Halpern

Randomized Double-Blind Trial of Prophylactic Oral Minocycline and Topical Tazarotene for Cetuximab-Associated Acne-Like Eruption

PURPOSE To evaluate the ability of either oral minocycline, topical tazarotene or both, to reduce or prevent cetuximab-related acneiform rash when administered starting on day 1 of cetuximab therapy. PATIENTS AND METHODS Metastatic colorectal cancer patients preparing to initiate cetuximab were randomly assigned to receive daily oral minocycline or placebo, and to receive topical tazarotene application to either left or right side of the face. Both therapies were administered for 8 weeks. RESULTS Forty-eight eligible patients were randomly assigned to minocycline (n = 24) or placebo (n = 24). Total facial lesion counts were significantly lower in patients receiving minocycline at weeks 1 through 4. At week 4, a lower proportion of patients in the minocycline arm reported moderate to severe itch than in the placebo arm (20% v 50%, P = .05). Facial photographs, obtained at week 4, were reviewed for rash global severity. Patients in the minocycline arm trended toward lower frequency of moderate to severe rash than patients receiving placebo (20% v 42%, P = .13). The differences in total facial lesion counts and subjectively assessed itch were diminished by week 8. Cetuximab treatment was interrupted because of grade 3 skin rash in four patients in the placebo arm, and none in the minocycline arm. There was no observed clinical benefit to tazarotene application. Tazarotene treatment was associated with significant irritation, causing its discontinuation in one third of patients. CONCLUSION Prophylaxis with oral minocycline may be useful in decreasing the severity of the acneiform rash during the first month of cetuximab treatment. Topical tazarotene is not recommended for management of cetuximab-related rash.

Guidelines of care for the management of primary cutaneous melanoma.

The incidence of primary cutaneous melanoma has been increasing dramatically for several decades. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is nearly always curative with early detection of disease. In this update of the guidelines of care, we will discuss the treatment of patients with primary cutaneous melanoma. We will discuss biopsy techniques of a lesion clinically suspicious for melanoma and offer recommendations for the histopathologic interpretation of cutaneous melanoma. We will offer recommendations for the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, we will provide recommendations for surgical margins and briefly discuss nonsurgical treatments. Finally, we will discuss the value and limitations of sentinel lymph node biopsy and offer recommendations for its use in patients with primary cutaneous melanoma.

A Prognostic Model for Predicting 10-Year Survival in Patients with Primary Melanoma

Malignant melanoma is currently the eighth most common cancer in the United States; 10 years ago, it was the 20th most common. The population-based mortality rate has continued to increase, whereas the case fatality rate has steadily declined to less than 20% [1]. Diagnosis of malignant melanoma earlier than was previously possible is primarily responsible for this improved survival rate. Contributing to earlier recognition of malignant melanoma are the identification of risk markers (such as dysplastic nevi) and improved understanding of clinical characteristics of the biologically early forms [2-4]. Another substantive advance has been the clarification of prognostic factors for patients with primary American Joint Commission on Cancer stage I cutaneous melanoma ( 1.5 mm) and stage II cutaneous melanoma (>1.51 mm); these factors are predominantly pathologic variables that were described by Clark and colleagues [5], Breslow [6], and other investigators [7]. Survival is routinely predicted almost exclusively on the basis of tumor thickness. Although this is an excellent correlate of prognosis, it is imprecise. Death results from thin melanomas, and survival occurs with thick melanomas. Evaluation of other variables improves the ability to predict survival in patients with melanoma. Variables that can be added include the anatomical site of the primary tumor; sex and age of the patient; mitotic rate of the tumor; presence of ulceration, microscopic satellites, or tumor-infiltrating lymphocytes; tumor regression or angiogenesis; and the Clark level of invasion (maximum penetration of the melanoma lesion into levels of the dermis or subcutaneous tissue) [8, 9]. We previously described a multivariable model that predicted 8-year survival of patients with primary melanomas more accurately than did tumor thickness alone [10]. In that model, six variables were found to independently predict survival. These variables (in order of their relative predictive strength) are mitotic rate, presence of tumor-infiltrating lymphocytes, tumor thickness, site of the primary lesion, sex of the patient, and histologic regression of the tumor. Although this model includes powerful predictors of survival, some of the variables used to generate it are not routinely included in standard pathology reports. Therefore, the model cannot be readily generalized for clinical use. To document this, we reviewed 100 randomly selected pathology reports of primary melanomas from community-based hospital pathologists, independent pathology laboratories, and specialized dermatopathology laboratories. Tumor thickness was recorded in 76% of cases; Clark level, in 68%; and histologic subtype, in 64%. However, tumor infiltrating lymphocytes and tumor regression were described in fewer than 20% of cases, and the mitotic rate was reported even less frequently (fewer than 5% of cases). Notably, no pathologists specified pure, invasive, radial-growth-phase melanoma, although such lesions almost never metastasize [10]. Given the limited availability of these histologic variables, we sought to develop a prognostic model based on clinical and pathologic data that are routinely available to the clinician. The model is intended to estimate the chance of survival, within 10 years of definitive therapy, in a patient with primary malignant melanoma. The ability to predict outcome more accurately in these patients could identify patients who are at high risk for recurrence; these patients could then be included in trials of adjuvant therapy. Further trials are becoming increasingly important as effective therapies for post-surgical treatment of melanoma are identified and tested [11-13]. Methods Patients The Pigmented Lesion Group at the University of Pennsylvania prospectively evaluated 624 patients with primary melanoma between 1 September 1972 and 31 December 1979. The pathologic variables were ascertained in an independent study of the primary tumors on two separate occasions by two pathologists who had no knowledge of outcome. Definitive treatment of the primary melanoma consisted of wide re-excision of the primary site to yield negative margins. We excluded 136 cases from analysis. Reasons for exclusion were competing causes of death before 10 years of follow-up with no evidence of melanoma (n = 44), lack of prospective follow-up (n = 22), metastatic disease evident beyond the primary site at presentation (n = 29), inadequate surgical treatment (n = 14), unknown cause of death before 10 years of follow-up (n = 5), occurrence of a high-risk primary tumor after 1979 (n = 2), existence of noncutaneous primary tumors (n = 5), loss to follow-up (n = 10), and unclassified tumor thickness or level (n = 5). Therefore, the final study group consisted of 488 patients who were followed prospectively for at least 10 years. Surviving patients were followed for no more than 20 years. Five patients who died of melanoma after 10 years of follow-up were considered to be 10-year survivors. Our description of what is generally included in melanoma pathology reports was drawn from the last 100 cases submitted for review at the Hospital of the University of Pennsylvania. Forty-three percent of the reports were from community-based hospitals, 17% were from independent pathology laboratories, and 40% were from specialized dermatopathology practices. We did not intend to evaluate current melanoma pathology reporting in nonacademic settings but rather to evaluate which prognostic factors are frequently reported on pathology reports. Validation of the model required a test using patient data that had not been used to generate the model. This sample consisted of 142 patients who had primary melanoma and were identified in an identical manner in 1980 and 1981, with blinded histopathologic assessment of melanoma and 10 years of follow-up data. Clinical and pathologic variables that have been identified as prognostic indicators of survival and that are readily available to the clinician were used to develop the prediction model [7, 9]. Clinical variables included age and sex of the patient and site of the primary lesion. Pathologic variables included histologic subtype, Clark level, and tumor thickness. Tumor thickness was measured from the stratum granulosum epidermidis to the depth of the tumor at its thickest part, according to the method of Breslow [6]. Anatomical site of the primary melanoma was divided into two categories: extremity (upper and lower) and axis. Axial or volar primaries, including melanomas arising on the trunk, head, neck, and palms and soles (volar) and under the nails (subungual), were designated as axis lesions. Lesions on other parts of the body were designated as extremity lesions. Female and male patients were studied. Histologic subtypes of melanoma included superficial spreading melanoma (71%), nodular melanoma (12%), lentigo maligna melanoma (6%), acral-lentiginous melanoma (3%), and other lesions (8%), using standard pathologic criteria. Age at the time of diagnosis was recorded. The Clark level of invasion was determined as described elsewhere [5]. Patient outcome was assigned to two categories: alive at 10 years (with or without evidence of melanoma) or dead from melanoma before 10 years. The 10-year interval was chosen because death from melanoma beyond 10 years is uncommon. We chose to analyze survival as a binary outcome (alive at 10 years compared with dead before 10 years). This method was chosen instead of evaluating the survival time or time to death because our primary objective was to differentiate between patients with high and low probabilities for surviving disease. This differentiation, in turn, can aid patient management and identify candidates for adjuvant therapy trials. Therefore, we were not interested in determining the contribution of prognostic factors that lengthen survival but do not necessarily prevent death. Statistical Analysis We used a univariate logistic regression model to test the six clinical and pathologic variables for their association with death. Patient age and tumor thickness were tested as continuous and nominal variables, and the Clark level was tested as a nominal variable. Tumor site was initially evaluated as a variable falling into one of four categories (trunk, head or neck, subungual or volar location, and extremity) but was subsequently reduced to two categories, axis and extremity. Variables that were statistically significantly associated with survival were retained for testing in a multivariable logistic regression model [14]. A manual stepwise procedure was used to determine the best model. The predicted probability that a patient would survive 10 years was generated using the estimated model variables. The logistic equation is presented as a footnote in Table 1. Table 1. Adjusted Odds Ratios for Independent Predictors of Survival* Figure 1 is a box and whisker plot that shows the distribution of probabilities that were estimated by our model for survival of patients who were alive and those who were dead at 10 years [15]. The boundary lines of the boxes represent the 25th and 75th percentiles of the data; the lines drawn through the interior of the boxes mark the 50th percentiles (the medians). The whiskers are drawn from the edges of each box to the most extreme point a maximum distance of 1.5 times greater and 1.5 times less than the interquartile ranges. Any value more extreme is considered an outlier and is designated by an asterisk. The predictive ability of the four-variable model was compared with that of tumor thickness in two ways. First, receiver-operating characteristic (ROC) curves were calculated [16, 17]. Second, the McNemar test was used to compare the percentages of correct predictions. Goodness of fit was assessed by using the Hosmer-Lemeshow test [14]. Figure 1. Results Overall Of the 488 prospectively followed patients, 108 died of melanoma before 10 years. The median follow-up was 13.

Patterns of detection in patients with cutaneous melanoma

Despite the importance of early detection in preventing mortality from melanoma, little is known regarding how patients with the disease come to diagnosis.

Screening and surveillance of patients at high risk for malignant melanoma result in detection of earlier disease

Screening, surveillance, and educational programs have been recommended for members of hereditary melanoma kindreds with dysplastic nevi, who are at very high risk for melanoma. For melanomas detected in a surveillance program offered to 555 such persons, the average thickness was 0.52 mm for 28 surveillance incident melanomas, 0.55 mm for 64 nonsurveillance incident melanomas, and 1.44 mm for 48 index lesions (p less than 0.001). The proportion of cases with level I or II invasion was 60.8%, 58.3%, and 36.2% respectively (p = 0.002). The nonsurveillance incident melanomas were diagnosed before entry into the surveillance program, but these patients were presumably aware of the earlier occurrence of two index melanomas in their families. These findings are consistent with a favorable effect of surveillance and education in a high-risk population and suggest that patient factors as well as physician factors may contribute to early diagnosis.

Instruments and new technologies for the in vivo diagnosis of melanoma

The principal objective of screening individuals at risk for melanoma is detection of cutaneous melanoma during the curable stages of its early evolution. Unaided visual inspection of the skin is often suboptimal at diagnosing melanoma. Improving the diagnostic accuracy for melanoma remains an area of active research. These research efforts have focused on both the detection of early melanoma and the in-depth evaluation of suspicious pigmented lesions for the presence or absence of melanoma. Numerous instruments are under investigation to determine their usefulness in imaging and ascertaining a correct in vivo diagnosis of melanoma. It is anticipated that some of these tools, alone or in combination, will improve our ability to differentiate, in vivo, melanoma from its simulators. Ultimately, these advances may prevent unnecessary biopsies (increased specificity) while increasing the sensitivity for diagnosing melanoma. This article reviews the current instruments and new technologies for the in vivo diagnosis of melanoma. Learning objective At the conclusion of this learning activity, participants should be acquainted with the instruments designed to facilitate the early detection of melanoma. They should also be familiar with the basic technology behind these instruments and should recognize the potential benefits and limitations inherent in each.

Melanoma awareness and self-examination practices: Results of a United States survey

BACKGROUND Skin cancers are common and there has been a dramatic increase in their incidence, particularly melanoma. However, little is known about awareness of melanoma and early detection practices in the general U.S. population. OBJECTIVE In 1995, the American Academy of Dermatology increased their efforts to promote awareness of melanoma. This study was conducted to document current knowledge of melanoma and self-examination practices. METHODS In February 1995, a telephone survey was conducted in a nationally representative sample of 1001 persons at least 18 years of age (3% margin of error) that included questions on knowledge, attitudes, and practices regarding early detection of melanoma. RESULTS Almost 42% of those surveyed were unaware of melanoma, and only 26% of those who were aware could identify its specific signs. Most recognized at least one common risk factor for melanoma (e.g., sun exposure, fair skin). However, many did not distinguish melanoma from other skin cancers in terms of risk factors, signs of early disease, and body site distribution. The lowest measures of melanoma knowledge and attitudes were found among those who are male, nonwhite, and parents, and those with the lowest level of education and income. More than half (54%) did not conduct a self-examination. This practice was most frequently reported by women, white persons, and the elderly, as well as those with a greater knowledge of melanoma. CONCLUSION Our research documents deficiencies in knowledge and practices related to early detection of melanoma in the general U.S. population and supports the need for public education about melanoma.

Cutaneous melanoma risk and phenotypic changes in large congenital nevi: A follow-up study of 46 patients

BACKGROUND Large congenital melanocytic nevi may undergo malignant transformation. Few prospective studies have evaluated the incidence of melanoma in large congenital nevi or have described how their phenotypic characteristics change over time. OBJECTIVE We attempted to ascertain the incidence of cutaneous melanoma in a cohort of patients with large congenital nevi and to evaluate the frequency and nature of several morphologic changes over time. METHODS Forty-six patients with large congenital nevi were prospectively followed up in our Pigmented Lesion Group. Large congenital nevi were defined as those occurring at birth and comprising 5% body surface area or greater in infants, children, and preadolescents and more than 20 cm in adolescents and adults. Information was obtained on location, satellitosis, changes in color and nodularity, and incidence of melanoma. The most atypical histologic findings from those who underwent biopsy were also noted. Standardized morbidity ratios (SMR) and 5-year cumulative risk were calculated and presented with corresponding 95% confidence intervals (CI). RESULTS Twenty-four male and 22 female patients (age range, 7 days to 36.7 years; mean, 8.4 years) with large congenital nevi were followed up prospectively for a total of 335 person-years (range, 0.17 to 17.5 person-years; mean, 7.3 person-years). Two patients (4.3%) experienced 3 cutaneous melanomas that originated in their primary congenital nevi. We found one case of neurocutaneous melanosis. No satellite, extremity, or extracutaneous melanomas were detected. The majority of nevi in our cohort were located on the posterior trunk, were accompanied by multiple satellite congenital nevi, and became lighter over time. In the 27 patients who underwent biopsies, the most atypical histologic findings included melanoma, atypical melanocytic dysplasia, neurocristic dysplasia, atypical neural crest hamartomas, atypical spindle cell tumors, and congenital nevi with dysplasia. The SMR comparing observed-to-expected melanoma incidence was 148 (95% CI 18, 535; P = .0002) indicating a substantially increased risk of melanoma in patients with large congenital nevi. The cumulative 5-year risk of cutaneous melanoma was 5.7% (95% CI 0%, 13.5%). CONCLUSION Our findings are consistent with the previously observed increased risk for the occurrence of cutaneous melanoma in patients with large congenital nevi. Although the number of patients with melanoma in this study is small, our observations and those of previous studies suggest that location and age correlates with melanoma risk. The majority of large congenital nevi are located on the trunk and may undergo several clinical changes as these patients age. Additional prospective studies are needed to gain more insight into the natural history and optimal management of large congenital nevi.

Morphologic Features of Melanocytes, Pigmented Keratinocytes, and Melanophages by In Vivo Confocal Scanning Laser Microscopy

Confocal scanning laser microscopy (CSLM) represents a novel imaging technique for in vivo microscopic analysis of skin lesions at a level of resolution that allows morphologic analysis of microanatomic structures. We investigated the feasibility of recognizing the cellular constituents of pigmented skin lesions, such as pigmented keratinocytes, melanocytes, and melanophages, by CSLM. Fifteen pigmented lesions (five pigmented seborrheic keratoses, and 10 compound melanocytic nevi) from 15 patients were studied, as well as normal skin. After the clinical lesions were imaged by CSLM, they were biopsied or excised for examination by conventional histology for comparison of the morphologic features. In images obtained by CSLM, pigmented keratinocytes were seen as polygonal cohesive cells with variably bright granular cytoplasm. Melanocytes appeared as bright round, oval, fusiform, or dendritic cells. The architectural growth pattern of melanocytes could be analyzed. Melanocytes were identified by their nested growth pattern as aggregates of bright round to oval structures at the dermoepidermal junction or in the superficial dermis. Melanocytes were also recognizable as single cells along the dermoepidermal junction, usually separated from each other by a variable number of keratinocytes. Melanophages appeared as large bright plump cells with ill-defined cytoplasmic borders, usually located around or near vessels of the superficial dermis. Our results demonstrate that the cellular constituents of pigmented lesions can be recognized by CSLM. This technique sets a new paradigm for noninvasive quasihistologic examination of pigmented lesions in vivo and merits further evaluation for diagnostic use.

Accuracy in melanoma detection: A 10-year multicenter survey

BACKGROUND Early excision is the only strategy to reduce melanoma mortality, but unnecessary excision of benign lesions increases morbidity and healthcare costs. OBJECTIVE To assess accuracy in melanoma detection based on number-needed-to-excise (NNE) values over a 10-year period. METHODS Information was retrieved on all histopathologically confirmed cutaneous melanomas or melanocytic nevi that were excised between 1998 and 2007 at participating clinics. NNE values were calculated by dividing the total number of excised lesions by the number of melanomas. Analyses included changes in NNE over time, differences in NNE between specialized clinical settings (SCS) versus non-specialized clinical settings (NSCS), and patient factors influencing NNE. RESULTS The participating clinics contributed a total of 300,215 cases, including 17,172 melanomas and 283,043 melanocytic nevi. The overall NNE values achieved in SCS and NSCS in the 10-year period were 8.7 and 29.4, respectively. The NNE improved over time in SCS (from 12.8 to 6.8), but appeared unchanged in NSCS. Most of the effect on NNE in SCS was due to a greater number of excised melanomas. Higher NNE values were observed in patients younger than 40 years and for lesions located on the trunk. LIMITATIONS No data concerning the use of dermatoscopy and digital monitoring procedures were collected from the participating centers. CONCLUSION Over the 10-year study period, accuracy in melanoma detection improved only in specialized clinics maybe because of a larger use of new diagnostic techniques such as dermatoscopy.