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Background Melanoma is an aggressive cutaneous cancer. Acral lentiginous melanoma is a melanoma subtype arising on palms, soles, and nail-units. The incidence, prevalence and prognosis differ among populations. The link between expression of major histocompatibility complex Class II alleles and melanoma progression is known. However, available studies report variable results regarding the association of melanoma with specific HLA Class II loci. Aims The aim of the study was to determine HLA Class II allele frequencies in acral lentiginous melanoma patients and healthy Mexican Mestizo individuals. Methods Eighteen patients with acral lentiginous melanoma and 99 healthy controls were recruited. HLA Class II typing was performed based on the sequence-specific oligonucleotide method. Results Three alleles were associated with increased susceptibility to develop acral lentiginous melanoma, namely: HLA-DRB1*13:01; pC = 0.02, odds ratio = 6.1, IC95% = 1.4-25.5, HLA-DQA1*01:03; pC = 0.001, odds ratio = 9.3, IC95% = 2.7-31.3 and HLA-DQB1*02:02; pC = 0.01, odds ratio = 3.7, IC95% = 1.4-10.3. Limitations The small sample size was a major limitation, although it included all acral lentiginous melanoma patients seen at the dermatology department of Dr. Manuel Gea González General Hospital during the study period. Conclusion HLA-DRB1*13:01, HLA-DQB1*02:02 and HLA-DQA*01:03 alleles are associated with increased susceptibility to develop acral lentiginous melanoma in Mexican Mestizo patients.

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Resumen El melanoma es el cáncer de piel con mayor tasa de mortalidad a nivel mundial. Se han descrito 4 subtipos principales de melanoma cutáneo: el melanoma de extensión superficial, el melanoma nodular, el léntigo maligno y el melanoma lentiginoso acral. Existen diferencias raciales y geográficas en la distribución y frecuencia de estos subtipos. En caucásicos, el riesgo es mayor para melanomas de piel expuesta a radiación UV, ya sea de forma crónica o intermitente. En contraste, en asiáticos, afroamericanos e hispanos, la tendencia es mayor en sitios anatómicos no expuestos (palmas y plantas), encabezando el melanoma lentiginoso acral en una proporción mayor. Usualmente, este melanoma se diagnostica de manera tardía y en estadios avanzados, por cual se asocia con un peor pronóstico. La presente revisión pretende brindar una visión general sobre el conocimiento del melanoma lentiginoso acral, describiendo aspectos como la epidemiología, los factores de riesgo asociados, las características genéticas y los factores pronósticos.

Abstract Melanoma is the cutaneous cancer with the highest mortality worldwide. Four main subtypes of cutaneous melanoma have been described: superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. There are racial and geographical differences in the distribution and frequency of these subtypes. In Caucasians, the risk is higher to develop melanoma on skin exposed to UV radiation, either chronically or intermittently. In contrast, in Asians, African Americans, and Hispanics, there is a greater tendency towards unexposed anatomical sites (palms and soles), which is called acral lentiginous melanoma. This melanoma is usually diagnosed in advanced stages, and therefore has a worse prognosis. This review aims to provide an update on what is known about acral lentiginous melanoma, mainly describing its epidemiology, risk factors associated with genetic characteristics, and prognosis.

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Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to assemble into large filamentary structures called rods/rings (RR) or cytoophidium (cellular snakes). RR assembly induces a hyperactive state in IMPDH, usually to supply a high demand for GTP nucleotides, such as in highly proliferative cells. We investigate whether aggressive melanoma tumor cells present IMPDH-based RR structures. Forty-five ALM paraffin-embedded tissue samples and 59 melanocytic nevi were probed with anti-IMPDH2 antibody. Both the rod- and ring-shaped RR could be observed, with higher frequency in ALM. ROC curve analyzing the proportions of RR-positive cells in ALM versus nevi yielded a 0.88 AUC. Using the cutoff of 5.5% RR-positive cells, there was a sensitivity of 80% and specificity of 85% for ALM diagnosis. In ALM, 36 (80%) showed RR frequency above the cutoff, being classified as RR-positive, compared with only 9 (15%) of the nevi (p < .001). Histopathology showed that 71% of the RR-positive specimens presented Breslow thickness > 4.0mm, compared with only 29% in the RR-low/negative (p = .039). We propose that screening for RR structures in biopsy specimens may be a valuable tool helping differentiate ALM from nevi and accessing tumor malignancy.

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INTRODUCCIÓN: El melanoma acral lentiginoso es una neoplasia maligna que afecta a población predominantemente no caucásica. Debido al diagnóstico tardío suele tener mal pronóstico, además de que se considera una neoplasia biológicamente más agresiva, incluso cuando se detecta tempranamente. OBJETIVO: Determinar la expresión de Ki67 en el melanoma acral lentiginoso invasor y compararla con los nevos acrales. MÉTODO: Estudio transversal, descriptivo, observacional. Se realizó inmunohistoquímica con marcador Ki67 en 17 biopsias de melanoma acral lentiginoso invasor (casos) y 17 biopsias de nevos palmoplantares (controles). Se determinó la expresión nuclear de Ki-67 y se comparó entre ambos grupos. RESULTADOS: La media de expresión de Ki67 fue del 8.5% en el grupo control y del 34% en el grupo de melanomas, siendo esta diferencia estadísticamente significativa (p < 0.0001). DISCUSIÓN: La expresión de Ki67 en los melanomas acrales es considerablemente mayor que en los nevos acrales. El valor pronóstico del marcador Ki67 sigue siendo considerado controversial. Sin embargo, hay estudios en los que en combinación con otros marcadores se refuerza su valor pronóstico. CONCLUSIONES: Por la gran diferencia en inmunorreactividad de Ki67 entre melanomas y nevos, la expresión de Ki67, referida como índice proliferativo, podría ser considerada como factor pronóstico incluso más objetivo que el índice mitótico. BACKGROUND: Acral lentiginous melanoma is a malignant neoplasm which appears in hands and feet. Acral lentiginous melanoma has an unclear etiology, and usually affects non-Caucasian population. Because it is frequently diagnosed lately, acral melanoma has bad prognosis; however, it is biologically more aggressive than other clinicopathological types of melanoma, even when diagnosed early. OBJECTIVE: To determine the expression of Ki67 in invasive lentiginous acral melanoma and to compare it with acral nevi. METHOD: Cross-sectional, descriptive, observational study. Immunohistochemistry with Ki67 marker was performed on 17 biopsies of invasive lentiginous acral melanoma (cases) and 17 biopsies of palmoplantar nevi (controls). Nuclear expression of Ki-67 was determined and both were compared between both groups. RESULTS: The mean expression of Ki67 was 8.5% in the control group, and 34% in the melanoma group, which was statistically significant (p < 0.0001). DISCUSSION: Ki67 expression in acral lentiginous melanomas is higher than in acral nevi. Prognostic value of Ki67 is still considered controversial. However, there are several studies where, in combination with other markers, their prognostic value is reinforced. CONCLUSIONS: Due to the wide gap in Ki67 expression between melanomas and nevi showed in this study, Ki67 expression, referred to as a proliferative index, could be considered as a prognostic factor even more objective than the mitotic index.

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AIMS: Acral lentiginous melanoma (ALM) is the most common type of melanoma in people with darker skin phototypes. There is some evidence that the aetiology, pathogenesis, risk factors and natural history of ALM differ from those of superficial spreading melanoma (SSM). ALM behaves more aggressively than SSM, but the biological explanation for these differences remains unknown. The presence of one subtype of macrophages, termed M2-macrophage (M2-M), has been found to be related to local progression, metastasis and poor prognosis in several neoplasms. The aim of this study was to compare the density of M2-Ms in ALMs versus SSMs, and to examine whether or not the density of M2-Ms is associated with histopathological features predictive of adverse prognosis in cutaneous melanoma (CM), as well as development of metastasis. METHODS AND RESULTS: Sixty-seven ALMs and 67 SSMs cases were analysed. The tumours were classified according to thickness, ulceration, mitosis and metastasis. M2-M quantity was evaluated using immunohistochemistry with anti-CD163 and anti-CD206 antibodies. M2-Ms were increased in ALM compared with SSM, and were related to the histopathological features predictive of adverse prognosis in CM, such as thickness > 1.0 mm, ulceration and mitotic activity, and the development of metastasis. CONCLUSIONS: Our study is the first, to our knowledge, to demonstrate the increased presence of M2-Ms in ALM compared with SSM. Our findings suggest that the increased M2-Ms in ALM are associated with the main histopathological features predictive of adverse prognosis in CM, as well as the presence of metastasis, and that these cells can be related to the aggressive behaviour seen in ALMs.

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En la última década se ha avanzado en la caracterización genética y mapeo molecular del melanoma cutáneo con el objetivo de identificar y comprender mejor los mecanismos patogénicos propios de cada subgrupo y así desarrollar tratamientos específicos. El melanoma lentiginoso acral (MLA) constituye un subtipo de melanoma con características clínicas, epidemiológicas, histopatológicas, pronósticas y terapéuticas distintivas y su perfil mutacional no es la excepción. A diferencia del melanoma ubicado en zonas fotoexpuestas, el MLA presenta una baja tasa de mutaciones BRAF (15%) y mayor frecuencia de amplificaciones y ganancias genéticas de KIT (15-30%), CCND1 (15-40%) y TERT (20%). En esta revisión se describen las características más relevantes del MLA con énfasis en el rol que cumplen los principales genes que participan en la patogenia del MLA.

Over the last decade, the genetic characterization and molecular mapping of cutaneous melanoma has been developed in order to identify and better understand the pathogenic mechanisms of each subgroup and to develop specific treatments. Acral lentiginous melanoma (ALM) is a melanoma subtype with distinctive clinical, epidemiological, histopathological, prognostic and therapeutic features and its mutational profile is not an exception. Unlike melanoma located in photoexposed areas, MLA has a low rate of BRAF mutations (15%) and a higher frequency of amplifications and genetic gains at KIT (15-30%), CCND1 (15-40%) and TERT (20%). In this review we will describe the most relevant characteristics of MLA with emphasis on the role of the main genes involved in its pathogenesis.

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El melanoma es considerado una neoplasia melanocítica maligna; la localización subungueal corresponde al 0.7-3.5% de todos los melanomas. Clínicamente se presenta como una melanoniquia en general asintomática. Comunicamos un paciente masculino de 67 años, que consulta por presentar melanoniquia estriada en el cuarto dedo de la mano izquierda. El estudio histopatológico de biopsia informa un melanoma acral, por lo que se procede a realizar resección completa de la lesión con amputación de la falange distal; el paciente evolucionó satisfactoriamente. Este melanoma se origina de la matriz ungular, aunque se ha propuesto la asociación con traumas, su etiología no está clara. Histológicamente, se caracteriza por una proliferación de melanocitos atípicos o fusiformes, con grados variables de invasión; algunas lesiones son pigmentadas y otras amelanóticas. Se debe establecer el diagnóstico diferencial con: hematomas, osteomielitis, onicomicosis, granuloma piógeno, paroniquia, enfermedad de Kaposi, carcinoma espinocelular, entre otras. Algunos factores pronósticos incluyen profundidad de invasión, índice mitótico, ulceración, índice de proliferación con Ki 67 para nombrar solo algunos factores del denominado “histopronóstico”. El retraso en el diagnóstico del melanoma subungueal condiciona un mal pronóstico. El tratamiento apunta hacia la intervención quirúrgica en estadios tempranos, con evaluación del ganglio centinela (esto varía según la escuela académica). Sin embargo, actualmente se hace referencia a nuevos fármacos, que modifican la respuesta inmune o que intervienen en el metabolismo celular, con lo que se dan los primeros pasos para modificar la historia natural de esta enfermedad.

Introduction: melanoma is considered a biologically aggressive neoplasm. It’s more common in the 6th decade. Subungual melanoma corresponding to 0.7-3.5% of all melanomas. The most common locations are hallux, thumb, index and ring. Clinically, it presents as an asymptomatic melanonychia. Case Report: male aged 67 who consulted for striated melanonychia fourth finger left hand. Biopsy histopathological study reports malignant melanoma. Complete resection of the lesion was performed with amputation of distal phalanx. Patient evolves satisfactorily. Discussion: this melanoma originates from the nail matrix. Although it has been proposed partnership with traumas, its etiology is unclear. Hasn’t been able to establish an association with race, skin type and sun exposure, as in other melanoma’s types. Histologically it is characterized by a proliferation of atypical melanocytes or fusiform with varying degrees of invasion. Some injuries are pigmented and others may be amelanotic. Should be established the differential diagnosis with hematomas, osteomyelitis, onychomycosis, pyogenic granuloma, paronychia, among other injuries. Some prognostic factors include depth of invasion, mitotic rat, ulceration, proliferation index among others. The delay in diagnosis of subungual melanoma determines a poor prognosis. The treatment aims to surgery in early stages, with evaluation of sentinel node. But now referred to new drugs that modify the immune response or that involve its cellular metabolism thus taking the first steps to modify the natural history of this disease.

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Se presenta el caso clínico de una fémina de 58 años de edad, de raza negra, quien acudió a la consulta de Cirugía del Hospital Gubernamental de Mbabane en Suazilandia por presentar una lesión pigmentada y ulcerada en el talón del pie derecho, donde se le practicó una biopsia por escisión cuyo resultado fue un melanoma lentiginoso acral invasivo. Posteriormente fue evaluada en la consulta de Oncología y luego de realizarle los exámenes complementarios necesarios, la neoplasia se clasificó en estadio IIC. La paciente fue remitida a Sudáfrica para recibir tratamiento con citosinas inmunomoduladoras, factor estimulante de colonias de granulocitos y macrófagos o inhibidores del gen BRAF.

The case report of a 58 years black woman is presented. She went to the Surgery Service of Mbabane Government Hospital in Suaziland due to a pigmented and ulcerated injury in her right foot heel, where she had an excisional biopsy whose result was an invasive acral lentiginous melanoma. Later on she was evaluated in the Oncology Service and after carrying out the necessary complementary tests, the neoplasm was classified in stage IIC. The patient was referred to South Africa to receive treatment with immunomodulatory cytokines, stimulating factor of granulocytes and macrophages colonies or BRAF gene inhibitors.

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Se presenta el caso clínico de una paciente ecuatoriana de 58 años, blanca, con antecedentes de hernias discales en regiones cervical y lumbar, quien hace 2 años asistió a la Consulta de Dermatología por presentar cambio de coloración en la uña del tercer dedo de la mano derecha, síntomas que se correspondían con un lentigo simple. En esta ocasión acude con destrucción de la lámina ungueal y aumento de la coloración que se extiende a todo el pulpejo del dedo, por lo cual se le realizó otra biopsia y se confirmó el diagnóstico histológico de melanoma lentiginoso acral (in situ).

The case report of a 58 years white patient is presented with a history of disk herniation in cervical and lumbar regions, who 2 years ago attended the Dermatology Service due to a color change in the fingernail of the third finger of her right hand, symptoms that belonged to a lentigo simplex. In this occasion she presented destruction of the ungueal bed and increase of color which covers the whole fingertip, so another biopsy was carried out and the histological diagnosis of acral lentiginous melanoma (in situ) was confirmed.

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El melanoma lentiginoso acral (MLA) es una variante rápidamente progresiva del melanoma maligno (MM). Constituye el 5-10% de los MM y se presenta con mayor frecuencia en pacientes de raza negra, asiáticos y latinoamericanos. En Colombia, la frecuencia de MM se encuentra en aumento y el MLA es una de las variantes más comunes (14,7% de todos los melanomas). La edad promedio de presentación es de 58 años, con una tasa de supervivencia menor para las personas de raza negra, asociada al diagnóstico tardío. EL MLA se localiza en las plantas, palmas y regiones subungueales y en su etiopatología se ha descrito la presencia de mutaciones en varios genes: 9p21 p16: (67%), 11q13 (CCND1) (47%), 22q11-q13 (40%) y 5p15 (20%). El diagnóstico de MLA se ha fundamentado clásicamente en la histopatología; sin embargo, otros métodos como la dermatoscopia, la evaluación del ganglio centinela y la detección de alteraciones en las proteínas del ciclo celular pueden contribuir al diagnóstico precoz y a mejorar el pronóstico tanto del MLA como del MM en general.

Acral lentiginous melanoma (ALM) is a rapidly progressive variant of malignant melanoma (MM). It constitutes 5-10% of all cases of MM and its prevalence is higher in blacks, Asians and Latin Americans. In Colombia, the incidence of MM is increasing and ALM is one of its most common variants (14.7% of all melanoma cases). The mean age at presentation of the disease is 58 years, and the survival rate is lower in black people, partly due to delayed diagnoses. ALM is located in the soles, palms and subungual regions. Mutations in several genes have been described in the pathogenesis of ALM, namely: 9p21 (p16: 67%), 11q13 (CCND1) (47%), 22q11-q13 (40%) and 5p15 (20%). The diagnosis of ALM has been traditionally based on histopathology; however, other diagnostic tools such as dermoscopy, evaluation of the sentinel lymph node and detection of alterations in proteins that control the cell cycle, may contribute to earlier diagnoses and, consequently, improve the prognosis of both ALM and MM.

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Antecedentes: El melanoma maligno es una neoplasia derivada de los melanocitos que suelen localizarse en la unión dermoepidérmica. A pesar de que su incidencia es baja, menor de 10%, 75% de las muertes por cáncer cutáneo se debe a esta neoplasia. Existen cuatro variantes: de extensión superficial, léntigo melanoma maligno, acral lentiginoso y nodular. En la población caucásica predomina el melanoma de extensión superficial; en series mexicanas se ha encontrado que prevalece el nodular. El objetivo de este estudio fue describir los casos de melanoma maligno del Hospital General “Dr. Manuel Gea González” para establecer la frecuencia de presentación y el subtipo clínico. Métodos: Se realizó estudio retrospectivo, descriptivo y transversal, de marzo de 1981 a diciembre del 2006, de los pacientes con melanoma; se registró sexo, edad, residencia, ocupación, evolución de la lesión, topografía y manifestaciones clínicas. Histológicamente se valoró el índice de Breslow y el nivel de Clark. Resultados: Se incluyeron 165 pacientes, de los cuales 112 fueron del sexo femenino y 53 del masculino. La localización más frecuente fue la extremidad inferior. El melanoma acral lentiginoso fue el que mostró mayor prevalencia. Conclusiones: En esta serie los subtipos con mayor prevalencia fueron el melanoma acral lentiginoso y el léntigo maligno melanoma, a diferencia de otras series donde se informa el nodular y el de extensión superficial. La proporción mujer:hombre fue de 2.1:1, mayor a la indicada en otras series.

BACKGROUND: Melanoma is a type of tumor that arises from melanocytes generally located in the dermoepidermal junction. Although melanoma is found in less than 10% of cases, mortality is high representing 75% of deaths attributed to cutaneous cancer. There are four major subtypes: Superficial spreading melanoma, lentigo malignant melanoma, acral lentiginous melanoma and nodular melanoma. Superficial spreading melanoma is the most common type among Caucasians. In a Mexican case series, the nodular type is the most common type reported. The aim of this study was to determine the most common type seen at our medical facility. METHODS: We analyzed patient's medical records from March 1981 to December 2006. Demographic data included sex, age, place of residence, occupation, tumor progression, location and clinical description. Histologically we evaluated tumor thickness using the Breslow scale; invasion was measured using the Clark scale. This is a descriptive, cross-sectional and retrospective study. RESULTS: 165 patients were studied, 112 were females and 53 males. The most common location was the lower limb. Acral lentiginous melanoma was the most common subtype. CONCLUSIONS: Our findings differ from the other series where they report nodular and superficial spreading melanoma as the most common types. The most common subtypes in our study were acral lentiginous melanoma and lentigo malignant melanoma among females, with a ratio of female-male of 2.1:1.

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