Differential Expression of Cancer Testis Antigens on Lentigo Maligna and Lentigo Maligna Melanoma.

The cancer/testis antigens (CTA) are a group of antigens expressed on germ cells of healthy testis and malignant tumors. We studied whether CTA are present on lentigo maligna (LM) and LM melanoma (LMM) samples. Immunohistochemical expression of a panel of CTA (MAGE-A1, A2- A3, NY-ESO-1, PRAME, SSX-2, and a MAGE-A antibody reactive with -A1, -A2, -A3, -A4, -A6, -A10, and -A12) was investigated in formalin-fixed paraffin-embedded samples from LMM (n = 20), LM (n = 8), chronically sun-exposed skin (n = 7), and healthy skin (n = 7). In 4 LMM lesions, the MAGE-A marker was positive. Another 3 LMM lesions were positive for MAGE-A1, MAGE-A2, and MAGE-A3. PRAME was positive in 18/20 LMM and 6/8 LM. We did not find expression of MAGE, NY-ESO-1, or SSX-2 in LM, thereby excluding these CTA as diagnostic markers to discern malignant melanocytes in LM from normal melanocytes. LMM did express MAGE, NY-ESO-1, and SSX-2. If a biopsy from a lesion suspect for LM shows positivity for MAGE, NY-ESO-1, and SSX-2, the lesion may actually be LMM. In contrast, PRAME expression was found in LM at low levels and in LMM at much higher levels, and absent in normal melanocytes. PRAME can potentially be used to discern normal melanocytes from malignant melanocytes.

Lentigo maligna melanoma in situ with neurotropism.

Perineural invasion, or neurotropism, is defined by the presence of cancer cells either within the neuronal sheath or found along the nerves. In melanoma, it is most commonly associated with invasive desmoplastic melanoma, a melanoma that is most commonly associated with malignant melanoma in situ, lentigo maligna type. Initially, perineural invasion was included in the reported Breslow thickness; however, recent data suggest that it should not be included. In this report, we describe a case of malignant melanoma in situ, lentigo maligna type, with associated neurotropism in the absence of invasive component.

Superficial dermal melanocytosis of the elderly: An exceptional occurrence?

The development of flat pigmented lesions on chronically sun-damaged (CSD) skin of the face may represent the clinical manifestation of a wide variety of hyperplastic/neoplastic melanocytic proliferations. We report the exceptional case of an acquired pigmented patch occurring on CSD skin, histopathologically characterized by diffuse hyperplasia of dendritic/spindled melanocytes in the superficial dermis within a widened band of actinic elastosis. This lesion was associated with a small focus of early invasive lentigo maligna melanoma (LMM). We show the melanocytic nature of the population of dermal pigmented cells by means of single and double immunohistochemical staining for melanocytic and histiocytic markers. The biologic significance of the focus of LMM within the hyperpigmented lesion (whether random collision phenomenon or causally related occurrence), as well as the pathogenesis of the whole dermal lesion are difficult to elucidate. Our case emphasizes the need for a better understanding of the pathophysiology of so-called dermal melanocytes.

A Distinct Pretreatment Immune Gene Signature in Lentigo Maligna Is Associated with Imiquimod Response.

Lentigo maligna (LM) is a common subtype of in situ melanoma on chronically sun-exposed skin, particularly the head and neck of older patients. Although surgery is the standard treatment, there is associated morbidity, and options such as imiquimod cream or radiotherapy may be used if surgery is refused or inappropriate. Complete response rates following imiquimod treatment are variable in the literature. The aim of this study was to evaluate the host immune response both before and following treatment with imiquimod to better identify likely responders. Paired pre- and post-imiquimod treatment specimens were available for 27 patients. Patients were treated with imiquimod 5 days per week for 12 weeks; at 16 weeks, lesions were excised for histological assessment. Of the 27 patients, 16 were responders and 11 failed to clear the disease. PDL1 protein expression was increased, accompanied by a unique gene signature in lesions from patients that subsequently histologically cleared LM by 16 weeks. This comprised 57 upregulated immune genes in signaling networks for antigen presentation, type I interferon signaling, and T-cell activation. This may represent an early responder group to imiquimod, and this unique gene signature potentially can be used as a biomarker of LM response to imiquimod.

Descripción de los pacientes intervenidos mediante cirugía de Mohs en España. Datos basales del registro español de cirugía de Mohs (REGESMOHS) / Description of Patients Undergoing Mohs Surgery in Spain: Initial Report on Data From the Spanish Registry of Mohs Surgery (REGESMOHS)

INTRODUCCIÓN: En julio de 2013 se inició la recogida de datos del registro español de cirugía micrográfica de Mohs, que describe la aplicación y los resultados de esta técnica en España. En este artículo se describen las características del paciente y de los tumores tratados. MATERIAL Y MÉTODOS: Se trata de un estudio de cohortes prospectivo en el que participan centros en los que se practica al menos una intervención semanal de cirugía micrográfica de Mohs. En cada centro se incluyen todos los pacientes que son valorados para realizar cirugía de Mohs, excepto los declarados judicialmente incapaces. En este artículo describimos las características de los pacientes y los tumores incluidos en la cohorte. RESULTADOS: El número de pacientes incluidos desde julio de 2013 hasta octubre de 2014 es de 655. La mayoría de los tumores cutáneos intervenidos correspondieron a carcinoma basocelular, siendo el infiltrante el subtipo histológico más frecuente. La mayoría de las cirugías se practicaron en tumores localizados en la cara y el cuero cabelludo, siendo la localización más frecuente la nariz. Casi el 40% de los tumores operados son recurrentes o persistentes, y el tamaño tumoral prequirúrgico es similar en nuestro medio al descrito en otros estudios australianos o europeos. Hasta el 45,5% de los pacientes había recibido algún tratamiento quirúrgico previo. CONCLUSIÓN: Los datos observados son similares a los de otras series publicadas, y son relevantes para poder valorar la aplicabilidad en nuestro contexto de estudios realizados en otros medios

INTRODUCTION: The Spanish registry of Mohs micrographic surgery started collecting data in July 2013. The aim of the registry is to report on the use of this technique in Spain and the outcomes achieved. In the present article, we describe the characteristics of patients and the tumors treated. MATERIAL AND METHODS: This is a prospective cohort study of patients treated with Mohs micrographic surgery. The participating centers are hospitals where at least one intervention of this type is performed each week. All patients considered for Mohs micrographic surgery in participating centers are included in the registry except those who have been declared legally incompetent. RESULTS: Between July 2013 and October 2014, data from 655 patients were included in the registry. The most common tumor involved was basal cell carcinoma, and the most common histological subtype was infiltrative basal cell carcinoma. Most of the tumors treated were located on the face or scalp, and the most common site was the nose. Almost 40% of the tumors treated were recurrent or persistent, and preoperative tumor size was similar to that reported in other European studies and in Australia. In total, 45.5% of patients had received previous surgical treatment. CONCLUSION: The findings are similar to those reported in other studies, and the data collected are useful for assessing whether the results of studies carried out elsewhere are applicable in Spain

Expression of soluble adenylyl cyclase in lentigo maligna: use of immunohistochemistry with anti-soluble adenylyl cyclase antibody (R21) in diagnosis of lentigo maligna and assessment of margins.

CONTEXT: Soluble adenylyl cyclase (sAC) is an enzyme that generates cyclic adenosine monophosphate, a signaling molecule involved in regulating melanocyte functions. R21, a mouse monoclonal antibody against sAC, shows a striking pan-nuclear staining in lentigo maligna, indicating possible utility for diagnosis and margin assessment. OBJECTIVE: To evaluate R21 in the diagnosis and evaluation of margins in lentigo maligna. DESIGN: Thirty one re-excision specimens for lentigo maligna were evaluated for R21 expression using previously published protocol. In addition, 153 cases including 41 lentigo malignas, 30 non-lentigo maligna-type melanomas, 38 lentigos, and 44 nevi were evaluated using a modified stringent protocol to eliminate all nonmelanocyte staining. RESULTS: The sensitivity of nuclear staining with R21 in lentigo maligna was 87.8%. Nuclear expression of sAC was observed in 40% of other melanomas and 2.3% of benign nevi. R21 did not stain nuclei of resting melanocytes but was observed in 28.9% of melanocytic hyperplasias. These cases were easily distinguished from lentigo maligna in routine sections. R21 staining facilitated extent of the lesion in resection margins. In cases examined under the less stringent conditions, interpretation was facilitated by comparing R21 and Mart1/Melan A staining. Greater than 9 pan-nuclear staining melanocytes within one high-power field along with a pan-nuclear sAC/Melan A ratio greater than 0.5 was consistent with a positive margin whereas 5 or less pan-nuclear staining melanocytes along with a sAC/Melan A ratio of less than 0.3 constituted a negative margin. CONCLUSION: R21 is a useful diagnostic adjunct in the diagnosis and evaluation of margins in re-excision specimens in lentigo maligna.

Distinction of melanoma in situ from solar lentigo on sun-damaged skin using morphometrics and MITF immunohistochemistry.

Distinction between melanoma in situ (MIS) and solar lentigo (SL) on chronically sun-damaged skin (CSDS) by hematoxylin and eosin (H&E) criteria alone can be difficult and in frozen section (FS) material, may be virtually impossible without immunohistochemistry (IHC). In this study, we used microphthalmia-associated transcription factor (MITF) IHC-directed image analysis to compare melanocyte nuclear morphometrics of MIS, SL, and sections of sun-damaged skin from redundant tissue acquired during Mohs micrographic surgery. The mean nuclear diameter and melanocytic density figures for MIS were greater than those for SL and CSDS by both independent t-test and analysis of variance statistics. No significant differences in these parameters were found between SL and sun-damaged skin. Cutoff values that favored MIS over SL included melanocyte density ≥10 nuclei per 200 µm, nuclear diameter ≥9 µm, and a product of density and diameter of 80 or more, as each of these values was associated with 100% specificity of MIS diagnosis. Our results suggest that image analysis of melanocytes labeled with MITF IHC can be used to produce morphometric data that distinguish MIS from SL and CSDS. The study was conducted using permanent sections, but previous studies with FSs indicate that the findings would apply to FSs as well. Quantitative assessment of melanocytic parameters using image analysis will likely become increasingly important as an adjunct to conventional histopathology for the diagnosis and surgical management of MIS on sun-damaged skin.

Melanocitoma meníngeo del ángulo pontocerebeloso, ¿Un tumor benigno? / Cerebellopontine angle meningeal melanocytoma: a benign tumor?

Se presenta un paciente con un raro melanocitoma meníngeo del ángulo pontocerebeloso que, tras su extirpación quirúrgica radical, evolucionó en el plazo de un año hacia una melanomatosis meníngea fulminante. Se realiza una revisión bibliográfica en busca de las claves para hacer una aproximación diagnóstica preoperatoria de este tipo de tumor y obtener información sobre su tratamiento y manejo postoperatorio (AU)

We report a case of a rare meningeal melanocytoma in the cerebellopontine angle. One year after tumor gross total removal, the patient suffered a sudden and devastating meningeal melanomatosis. The relevant literature is reviewed looking for the keys to establish preoperative diagnosis and to obtain information about its treatment and postsurgical management (AU)

Identification of progenitor cancer stem cell in lentigo maligna melanoma.

The potential role of stem cells in neoplasia has aroused considerable interest over the past few years. A number of known biologic characteristics of melanomas support the theory that they may originate in a mutated stem cell. Melanocytic stem cell markers have been described recently. Moreover, the CD133 cells that show surface markers for CD34 are stem cells primitive. These stem cells are capable of differentiating into neurons, glia, keratinocytes, smooth muscle cells, and melanocytes in vitro. The identification of cancer stem/initiating cells with a crucial role in tumor formation may open up new pharmacologic perspectives. The purpose of this study is to detect the expression of CD133 and CD34, two putative markers of cancer stem cells in the lentigo maligna melanoma. Thirty cases of lentigo maligna melanoma were analyzed using indirect immunohistochemical staining. The vast majority of the samples analyzed showed the presence of rare cells, which were clearly positive for CD133 and CD34. Strong CD133 and CD34 staining was found in the outer root sheath of the mid-lower hair follicles, intermixed with atypical melanocytes extending along layers of the hair follicles. A number of these staminal cells were adjacent and intermixed with melanoma cells. This study supports the stem cell origin of this tumor and suggests that the precursor of the melanoma in question is a stem-like cell rather than the primitive melanoblast committed to be exclusively involved in melanocytic differentiation.

Immunohistochemistry of pigmented actinic keratoses, actinic keratoses, melanomas in situ and solar lentigines with Melan-A.

Distinguishing lentigo maligna from solar lentigo, and pigmented actinic keratosis can sometimes be problematic. Melan-A is an immunohistochemical marker which that can be helpful in decorating the melanocytes of pigmented lesions. A recent report has suggested that Melan-A may spuriously label nests of junctional keratinocytes, potentially leading to the misdiagnosis of melanoma in situ. We compared Melan-A immunohistochemical staining in pigmented actinic keratosis , non-pigmented actinic keratoses , melanoma in situ of lentigo maligna type and solar lentigines. We found a statistically significant increase of Melan-A staining in melanoma in situ, but no statistical difference in the number of junctional Melan-A positively staining cells, in solar lentigines, pigmented actinic keratoses, and non-pigmented actinic keratoses, respectively. In the non non-melanoma samples, the Melan-A A-positive cells located at the dermal-epidermal junction were interspersed and not observed in clusters. Increased staining with Melan-A, in an actinic keratosis, or solar lentigo should raise the possibility of a contiguous melanoma in situ.

Collision tumor composed of Merkel cell carcinoma and lentigo maligna melanoma.

We report the case of an immunocompetent 79-year-old white man with a history of melanoma in situ on the back with a collision tumor composed of a Merkel cell carcinoma (MCC) and lentigo maligna melanoma on the left cheek. The cells of the MCC expressed cytokeratin 20 (CK 20) in a diffuse cytoplasmic pattern, AE1 and AE3 in a perinuclear dot-like pattern and diffusely with neuron-specific enolase. The tumor cells of the MCC failed to express thyroid transcription factor-1. The atypical melanocytes of lentigo maligna melanoma expressed Melan-A and S-100. At the same visit, a lentigo maligna was diagnosed by excisional biopsy on the right cheek. The variability in expression of CK 20, AE1 and AE3 in MCC are reviewed. Prior reports of MCC in collision with non-melanoma skin cancers are reviewed. Additionally, the role of immunosuppression in the development of MCC is considered.

A subgroup of melanocytic nevi on the distal lower extremity (ankle) shares features of acral nevi, dysplastic nevi, and melanoma in situ: a potential misdiagnosis of melanoma in situ.

Melanocytic lesions in certain locations (eg, genital, breast, acral) may have histologic and clinical features simulating melanoma. Here we describe a group of lesions from the lower distal extremity and analyze their histologic features and possible relation to dysplastic nevi (DN) and melanomas. One hundred fifteen melanocytic lesions from the ankle were retrieved from January 1990 to August 2006 from the files of M. D. Anderson Cancer Center and were classified as benign melanocytic nevi (BN; n=17), DN (n=35), melanomas (MM; n=52), and melanocytic nevi of the ankle with atypical features (MNAAF; ie, cases that did not readily fit in any of the previous categories, n=11). Data analyzed included clinical (age and sex) and histologic features (circumscription, symmetry, cohesiveness of nests, suprabasal melanocytes, confluence, single-cell proliferation, nuclear chromasia, size, and nucleolar features). Follow-up was collected for all MNAAF. MNAAF differ from the other types of lesions in regard to sex incidence (73% in women). The median age of those patients MNAAF was 47 years (range 29 to 76 y). All MNAAF showed moderate-severe architectural disorder whereas 78% showed only mild-moderate cytologic atypia. No MNAAF cases had recurred after follow-up (4 mo to 13 y). This study highlights a group of melanocytic lesions located on the ankle that share histologic features with acral nevi, DN, and melanoma. These lesions are more predominant in females and have moderate to severe architectural atypia but only mild-moderate cytologic atypia. After complete excision, follow-up data indicate an apparently benign outcome. Pathologists should be aware of this type of lesions to avoid overdiagnosis of melanoma.

Histological evolution of lentiginous melanoma: a report of five new cases.

BACKGROUND: The term lentiginous melanoma was recently used for atypical melanocytic proliferations sharing some histological features with lentigo maligna and associated with a protracted in situ stage before invasion. Lentiginous melanoma was characterized by predominantly single-cell lentiginous growth pattern with focal junctional nests and pagetoid spread, preservation of the dermoepidermal junction, limited cytological atypia, and lack of significant solar elastosis. We report five similar cases. METHODS: Histological review of routine sections with clinicopathological correlation. RESULTS: Three patients were male and two were female. The age at presentation ranged from 24 to 66 years. All lesions arose on the truck or proximal extremities. All five cases fulfilled histological criteria proposed for lentiginous melanoma. None of the lesions showed significant solar elastosis. One lesion was followed clinically and histologically for 16 years without intervening treatment. It had three local recurrences before culminating in invasive melanoma. CONCLUSIONS: Our observations support recent efforts to distinguish lentiginous melanoma as a distinct clinicopathological entity. Lentiginous melanoma can remain in situ for a long time before invasion and may be considered an analogue of lentigo maligna occurring on non-severely sun-damaged skin. Familiarity with the histological features of this variant is important for its early recognition and treatment.

Oestrogen receptor-beta expression in melanocytic lesions.

Melanomas rarely occur before puberty, have a higher death rate for males, and tend to be more invasive during pregnancy. Prior to the discovery of a second oestrogen receptor (ERbeta), studies with the initial oestrogen receptor, ERalpha, showed no obvious role for oestrogen in the pathophysiology of benign or malignant melanocytic lesions. To investigate the specific immunostaining patterns of ERalpha and ERbeta, benign nevocytic nevi, dysplastic nevi with mild, moderate and severe cytological atypia, lentigo malignas and melanomas of varying depth (Clark) and thickness (Breslow) were studied. ERbeta but not ERalpha was the predominant oestrogen receptor we found in all types of benign and malignant melanocytic lesions. The most intense ERbeta immunostaining was seen in melanocytes in dysplastic nevi with severe cytological atypia and in lentigo malignas. ERbeta expression levels also correlated with the malignant tumor microenvironment; i.e., melanocytes in proximity with keratinocytes>deeper dermal melanocytes in contact with stroma>minimally invasive melanomas>Clark Level III/IV or thick melanomas (Breslow). Discovery that ERbeta expression varies in relation to the tumor microenvironment and increasing depth of invasion suggests its possible usefulness as a surrogate marker for neoplasia and prognosis in malignant melanoma.

A collision tumor involving Basal cell carcinoma and lentigo maligna melanoma.

Basal cell carcinomas (BCC) are known to co-exist with other cutaneous lesions, but the collision of BCC with malignant melanoma is rare. We report on the case of an 82-year-old woman with a translucent papule set on a beige-brown plaque on the right side of the nose. Histologic examination showed lesions of lentigo maligna melanoma (LMM) in situ and invasive melanoma involving nests of BCC that invaded the dermis. Immunohistochemical studies with S100 protein, HMB-45, and Melan-A antibodies showed the melanocytic component in the epidermis and dense clusters of "atypical" melanocytes in the dermal nests of BCC. On examination of the biopsy specimen, melanoma was still in situ because it was limited to the nests of BCC and not detectable between dermal collagen bundles. However, the re-excision of the lesion showed residual BCC and invasive LMM, level II, measuring 0.2 mm in thickness. The diagnosis, pathogenesis, and prognosis of this collision tumor are discussed.

Follicular malignant melanoma: a variant of melanoma to be distinguished from lentigo maligna melanoma.

Follicular malignant melanoma can be regarded as a rare and unique presentation of melanoma. It is characterized by a deep-seated follicular structure in which atypical melanocytes extend downward along the follicular epithelium and permeate parts of the follicle as well as the adjacent dermis. The clinical diagnosis of follicular malignant melanoma may be difficult because the tumor mostly resembles a comedo or a pigmented cyst. We studied five cases of follicular malignant melanoma in which the patients were between 61 and 82 years old. Three lesions were localized on the nose, one on the cheek, and one on the back of the neck. Clinically, all five cases measured distinctly less than 0.5 cm in size. While lentigo maligna is traditionally known as a pigmented macule in actinically damaged skin that gradually evolves in a slow process before invasive growth, three follicular malignant melanomas had developed in relatively short timeframes of 9 months to 1 1/2 years. In all five cases the inconspicuous clinical appearance did not herald a malignant melanoma with invasive growth. Follicular malignant melanoma underlines the importance of a correct excision technique with subsequent histologic workup and diagnosis. Superficial shave excision or even laser treatment in these specific cases may lead to a fatal prognosis for the patient.