Histological type and biological behavior of primary cutaneous malignant melanoma

Summary Primary cutaneous malignant melanomas are generally divided into 3 separate clinico-pathological variants, lentigo maligna melanoma (LMM), superficial spreading melanoma (SSM), and nodular melanoma (NM). Recently an additional variant, acral lentiginous melanoma (ALM), has been defined, occurring on acral regions, defined as plantar, palmar, and sub-/parungual areas. Histological examination of 86 primary melanomas on acral regions revealed 24 (28%) acral lentiginous melanomas (ALM), 23 (27%) superficial spreading melanomas (SSM), 18 (21%) nodular melanomas (NM), and 21 (24%) unclassifiable melanomas. No LMM was seen. The prognosis was found to be the same in patients with SSM and ALM. However, by correlating histological type with frequency of antecedent nevus, duration of melanoma and dominant invasive tumor cell, it was demonstrated that histologically typical ALM differed from histologically typical SSM by their infrequent origin from antecedent nevi, their lower local growth rate, and their more frequent content of spindle cells. These findings support ALM as a valid melanoma subtype only when clearly defined histologically.     

Acral lentiginous melanoma and its precursor--heterogeneity of palmo-plantar melanomas

Malignant melanomas occur with high frequency in the volar skin and with heterogeneity consisting of acral lentiginous melanoma (ALM) and nodular melanoma in Japan. Analytical study has revealed the precursor of ALM which we designate plantar or palmar premalignant melanosis (PPM), and whose cellular characteristics appear to be similar to those of pagetoid premalignant melanosis or the radial phase of superficial spreading melanoma (SSM).     

RSK1 Activation Promotes Invasion in Nodular Melanoma

The two major melanoma histologic subtypes, superficial spreading and nodular melanomas, differ in their speed of dermal invasion but converge biologically once they invade and metastasize. Herein, we tested the hypothesis that distinct molecular alterations arising in primary melanoma cells might persist as these tumors progress to invasion and metastasis. Ribosomal protein S6 kinase, 90 kDa, polypeptide 1 (RSK1; official name RPS6KA1) was significantly hyperactivated in human melanoma lines and metastatic tissues derived from nodular compared with superficial spreading melanoma. RSK1 was constitutively phosphorylated at Ser-380 in nodular but not superficial spreading melanoma and did not directly correlate with BRAF or MEK activation. Nodular melanoma cells were more sensitive to RSK1 inhibition using siRNA and the pharmacological inhibitor BI-D1870 compared with superficial spreading cells. Gene expression microarray analyses revealed that RSK1 orchestrated a program of gene expression that promoted cell motility and invasion. Differential overexpression of the prometastatic matrix metalloproteinase 8 and tissue inhibitor of metalloproteinases 1 in metastatic nodular compared with metastatic superficial spreading melanoma was observed. Finally, using an in vivo zebrafish model, constitutive RSK1 activation increased melanoma invasion. Together, these data reveal a novel role for activated RSK1 in the progression of nodular melanoma and suggest that melanoma originating from different histologic subtypes may be biologically distinct and that these differences are maintained as the tumors invade and metastasize.Superficial spreading melanoma (SSM) and nodular melanoma (NM) represent the two most common primary melanoma histologic subtypes, accounting for 70% and 15% to 20% of cases, respectively.^1,2 SSM is characterized by a radial growth phase (RGP) consisting of an intraepidermal component. Whereas SSM can proceed from a RGP to a vertical growth phase (VGP) and finally to distant metastases, NM grows rapidly in a vertical manner (VGP), with no horizontal growth phase.³To date, the prognostic and therapeutic impact of melanoma histologic subtypes has been relatively limited. The American Joint Committee on Cancer staging system uses tumor thickness, ulceration, mitotic index, and lymph node status, but not histologic subtype, in the recurrence/metastasis risk assessment of patients with primary localized melanoma.⁴ This is, in part, due to the current linear model of melanoma progression, which dictates that melanoma begins with the transformation of epidermal melanocytes and an initial RGP, followed by a subsequent transition to a VGP and distant metastasis.^5–7 Hence, it is generally accepted that the speed of dermal invasion is the only aspect that differentiates the NM and SSM subtypes.Recent discoveries in other solid tumor types emphasize the potential role of histology-driven molecular characterization to assist in the diagnosis and treatment of cancer.^8–11 Indeed, the utility of histologic classification in melanoma has been demonstrated with acral lentiginous melanoma, which composes approximately 10% of primary melanomas. The prevalence of molecular alterations in the c-KIT oncogene in this histologic melanoma subtype has defined acral lentiginous melanoma as a distinct and useful subclassification of melanoma, and a phase 2 trial of the c-KIT inhibitor imatinib validated the rationale of subtype-specific therapy for this group of melanoma patients.¹² In contrast, the clinical relevance of the SSM and NM subtypes has been largely overlooked.Recent reports by our groups and others suggest that primary SSM and NM might be distinct biological entities.^13–19 Unbiased, high-throughput genetic techniques, such as comparative genomic hybridization, single nucleotide polymorphism arrays, and microarrays, have revealed the presence of recurrent SSM-specific deletions that are present or even amplified in NM and, thus, cannot be reconciled with the linear progression model, even when epigenetic modifications are taken into account. Similarly, significant alterations in mRNA and miRNA gene expression are observed when comparing SSM with nevi and NM, and these alterations cannot be explained by the existing stepwise (linear) model.^16,17 Together, these findings suggest that distinct molecular alterations between SSM and NM might underlie the biological differences between these subtypes. However, it is unclear whether differences that exist between primary SSM and NM are retained during progression to invasion and metastasis.Herein, we tested the hypothesis that subtype-specific differences between SSM and NM persist throughout progression of primary melanoma to metastatic disease. We used a combination of human melanoma cell lines representing SSM and NM, human tissues from metastatic SSM and NM, and a zebrafish model of melanoma to demonstrate the role of protein S6 kinase, 90 kDa, polypeptide 1 (RSK1; official name RPS6KA1) in melanoma invasion in vitro and in vivo. These data suggest that metastatic melanoma originating from different histologic subtypes might be biologically distinct and reveal differences that are maintained from the primary tumor to metastatic disease.     

Lentigo maligna and superficial spreading melanoma are different in their in situ phase: an immunohistochemical study

Clinical and pathologic observations have prompted the categorization of malignant melanoma into 4 subtypes. Although some authorities challenge the value of this classification, nevertheless it is generally accepted that lentigo maligna (LM), or melanoma on sun-damaged skin, has a different biological behavior than so-called superficial spreading melanoma (SSM), at least in the early stage of its evolution. To characterize some aspects of this different behavior, the in situ phase of SSM and LM was studied using immunohistochemical methods. Seventeen cases of SSM in situ and 13 cases of LM were chosen for the study. All cases qualified with strict histologic criteria. Sections from these lesions were stained with antibodies against HMB-45 antigen, basic fibroblast growth factor (bFGF), proliferating cell nuclear antigen (PCNA), and factor VIII. Semiquantitative analysis was performed. Cases classified as either LM or SSM corresponded well to the epidemiologic and clinical characteristics as described in the literature; that is, LM appeared in older patients and occurred mostly on the face, whereas SSM occurred mostly on the trunk and lower limbs. Although no difference in HMB-45 stain was observed, melanoctyes of SSM showed greater proliferative activity, as reflected by PCNA stain (P < 0.02) and higher levels of bFGF (P < 0.001), than melanocytes of LM. More blood vessels were counted under SSM than under LM (P < 0.05). These results are in accordance with the biological behavior of SSM and LM, that is, the longer in situ phase of the latter. bFGF is both a growth factor for melanocytes and an angiogentic factor. The differences in PCNA, a proliferation marker, and blood vessel count may be related to the bFGF effect. Thus this study reveals some of the biological differences between LM and SSM. Location and sun exposure habits may contribute to these differences, which already exist in the in situ phase.     

KIT amplification and gene mutations in acral/mucosal melanoma in Korea

Mucosal and acral melanomas have demonstrated different genetic alterations and biological behavior compared with more common cutaneous melanomas. It was recently reported that gain-of-function KIT mutations and/or copy number increases are more common in mucosal and acral melanomas. Thus, we studied the frequency and pattern of KIT aberrations in mucosal and acral melanomas in Korea. We analyzed 97 patients who were pathologically confirmed with mucosal or acral melanoma between 1997 and 2010 at Samsung Medical Center. Of the 97 melanoma patients, 92 were screened for mutations in KIT exons 11, 13, 17, and 18, BRAF and NRAS genes. KIT copy number was assessed by quantitative, real-time PCR. Of the 97 patients, 55 (56.7%) were mucosal, 40 (41.2%) were acral melanoma, and two were of unknown primary origin. Among seven cases with KIT mutation, five (60.0%) occurred in exon 11, one (20.0%) in exon 17, and one (20.0%) in exon 13. Point mutations were the most common, resulting in substitutions in exon 11 (K558R, T574A, L576P, and V559A), exon 13 (N655K), and exon 17 (N822K). A novel Thr574Ala (c.1720A>G) KIT mutation, which has not been reported in melanoma or other tumor types, was identified in one genital melanoma case. Of the 97 mucosal or acral melanoma specimens, 49 were tested for KIT gene copy number changes using quantitative PCR. Increased KIT copy number was identified in 15 patients: seven (40%) of 20 acral melanomas and eight (31%) of 26 mucosal melanomas. Our study implicates that a significant proportion of acral and mucosal melanomas have KIT mutations in Asian population.     

Melanocytic nevi simulant of melanoma with medicolegal relevance

A group of melanocytic benign nevi are prone to be misdiagnosed as nodular or superficial spreading melanoma. This review illustrates the most frequent forms of these nevi in direct comparison with their malignant morphologic counterparts. The nevi are: hyper-cellular form of common nevus to be distinguished from nevoid melanoma, Spitz nevus (vs spitzoid melanoma), Reed nevus (vs melanoma with features of Reed nevus), cellular atypical blue nevus (vs melanoma on blue nevus), acral nevus (vs acral melanoma), Clark dysplastic nevus (vs superficial spreading melanoma), desmoplastic nevi (vs desmoplastic melanoma), benign proliferative nodules in congenital nevi (vs melanoma on congenital nevi), epithelioid blue nevus (vs animal type melanoma) and regressed nevus (vs regressed melanoma). For each single ‘pair’ of morphological look-alikes, a specific set of morphological, immunohistochemical and genetic criteria is provided.     

Acral melanoma

Basing on 18 observations, histological features of malignant melanomas on the soles and the terminal phalanges of the toes were revealed and described in detail. A specific character of melanomas with such localization is evident from the histological pattern and clinical manifestations. It is suggested to distinguish the described acral lentiginous melanoma as a separate clinico-morphologic form of melanoma.     

Performance of PRAME immunohistochemistry compared with that of c-Kit,c-Myc,or cyclin D1 for the diagnosis of acral melanocytic tumors

The diagnostic role of preferentially expressed antigen in melanoma (PRAME) immunohistochemistry has not been thoroughly evaluated for acral melanocytic tumors. The objective of this study was to evaluate the utility of this modality for the diagnosis of acral melanocytic tumors compared with other potential markers. Melanocytic tumors were classified as either acral nevi, challenging melanocytic tumors (superficial atypical melanocytic proliferation of uncertain significance (SAMPUS)-favor benign (SAMPUS-FB), SAMPUS-favor malignant (SAMPUS-FM)) or acral melanomas. A total of 106 acral melanocytic tumors including acral nevi (n = 32), SAMPUS-FB (n = 17), SAMPUS-FM (n = 20), and acral melanomas (n = 37) were included. Diagnostic power, assessed using an area under the receiver operating characteristic curve (AUC) for distinguishing acral melanomas and acral nevi, was highest for PRAME (AUC = 0.997), followed by c-Myc (AUC = 0.755), cyclin D1 (AUC = 0.652), and c-Kit (AUC = 0.573). At a PRAME expression level ≥30% as a positive test for acral melanoma, the sensitivity and specificity of this marker for discriminating acral melanoma from acral nevus were 100% and 96.9%, respectively. PRAME immunohistochemistry also discriminated SAMPUS-FM from SAMPUS-FB with a sensitivity and specificity of 90.0% and 76.5%, respectively. In conclusion, PRAME immunohistochemistry can be used effectively to distinguish between various spectra of acral melanocytic neoplasms.     

Melanoma and its relationship with solarium use: health knowledge, attitudes and behaviour of young women

Despite growing evidence of a relationship between solarium use and melanoma development, few studies have examined knowledge, attitudes and behaviour towards solarium use among young women. Females aged 18-26 years attended one of six focus groups (N = 27, seven solarium users and 20 non-users). Three specific themes were endorsed: (1) melanoma knowledge; (2) perceptions of melanoma risk and ways to encourage behaviour change; and (3) health promotion and government regulation. Many young women appear to lack knowledge about melanoma and its relationship with solarium use. Knowledge deficits are highlighted and implications for health prevention/promotion campaigns and future research are discussed.     

Acral myxoinflammatory fibroblastic sarcoma with unique clonal chromosomal changes

Acral myxoinflammatory fibroblastic sarcoma is a rare tumor of the distal extremities. We present the hitherto unreported karyotypic abnormalities of this new entity. The tumor presented as a mass in the dorsum of the foot in a 53-year-old woman and showed the typical virocyte-like and lipoblast-like cells in a myxoid and inflammatory background. Cytogenetic analysis revealed a complex karyotype with a reciprocal translocation t(1;10) (p22;q24) in addition to the loss of chromosomes 3 and 13. Fluorescence in situ hybridization with the 769E11YAC and BAC 31L5 and 2H23 probes showed the breakpoint to be located proximally to BCL10 and distally to GOT1 genes on chromosomes 1p22 and 10q24, respectively. The presence of these clonal chromosomal changes supports the neoplastic nature of acral myxoinflammatory fibroblastic sarcoma and underscores that it represents a separate entity.     

Histopathological diagnosis of acral lentiginous melanoma in early stages

Acral lentiginous melanoma is a rare variant of melanoma that is associated with a relatively low survival rate. The latter is partly due to the advanced stage in which the tumor is usually diagnosed. The diagnostic delay is mainly due to difficulties in identifying the very early histopathological signs of acral melanoma. The current article is a review of diagnostic clues, concepts, and definitions from the literature, as well as illustrating examples from our own archives. We have sought to provide an article that can be easily consulted in difficult cases of acral lentiginous melanoma.     

Treatment and Outcomes of Melanoma in Acral Location in Korean Patients

Purpose

A retrospective study was conducted to review the treatment and outcomes of mainly melanomas in acral location in a single institution in Korea, and to evaluate the prognostic significance of anatomic locations of the tumor.

Materials and Methods

A retrospective review was completed on 40 patients between 2001 and 2006 to obtain pertinent demographic data, tumor data, treatment characteristics, and follow-up data.

Results

Forty melanoma patients were identified and analyzed. Of these, 18 were male and 22 were female patients and the mean age at the time of diagnosis was 55.9 years. Of the tumors, 65% were located on the hands and feet with acral lentiginous melanoma being the most common histological subtype. Univariate analysis for the overall melanoma survival revealed that the thickness of the tumor and the clinical stage have prognostic significances. The most significant factor as analyzed by a multivariate analysis was shown to be the advanced clinical stage. Acral melanomas did not show statistically significant differences in the age at diagnosis, thickness of the tumor, stage, ulceration, and survival rates compared to non-acral melanomas. There was also no significant difference in the survival rate between the patients treated by amputation versus wide local excision in acral melanomas.

Conclusion

In Korean melanoma patients, thickness and advanced stages are significant factors for poorer prognosis. However, the location of melanoma did not have a significant prognostic value. In treating the melanomas in acral location, local wide excisions resulted in a similar prognosis compared to amputations.     

BRONCHIOLOALVEOLAR LUNG CARCINOMAS: K-ras MUTATIONS ARE CONSTANT EVENTS IN THE MUCINOUS SUBTYPE

Bronchioloalveolar carcinoma (BAC) is a form of peripheral lung adenocarcinoma growing as a single layer of malignant cells along the walls of terminal airways. The existence of BAC as a separate clinico-pathological entity has been a matter of controversy, mainly because its histogenesis is uncertain and it is not easily distinguishable from conventional lung adenocarcinoma (CLA). Three subtypes of BAC have been described using histological and cytological criteria: mucinous, non-mucinous, and sclerosing. The clinical behaviour of BAC appears to be dependent on the histological subtype. The different morphological patterns and clinical outcome of the subtypes of BAC suggest that their biological behaviour may be different from one another and from CLA. This study has investigated 58 BACs (10 mucinous, 40 non-mucinous, and 8 sclerosing) and 50 control CLAs for mutations at codon 12 of the K- ras oncogene. Twenty-one (36 per cent) BACs and 13 (26 per cent) CLAs showed K- ras mutations. A clear association ( P <0·0001) between K- ras mutations and the mucinous type of BAC was observed: all 10 mucinous tumours examined were scored positive for mutations in the K- ras gene, while only 9 (23 per cent) of the 40 non-mucinous and 2 (25 per cent) of the 8 sclerosing BACs were found to be positive. The frequency of ras mutations in non-mucinous BAC, sclerosing BAC, and CLA was not statistically different. Our data indicate that BACs are a heterogeneous group of lung tumours and that the mucinous form might represent a biological entity separate from both the other two BAC types and CLA.     

Cross-validation of a short form of the Marlowe-Crowne Social Desirability Scale

This research is a cross-validation and extension of Reynolds' (1982) short form of the Marlowe-Crowne Social Desirability Scale, using three separate groups (N = 233). Unlike Reynolds, the present researchers administered the 13 items as a separate entity, calculated Cronbach's Alpha for each sex, and also computed a test-retest correlation for one of the three groups. The authors conclude that this 13-item short form is a viable alternative to the full scale.     

Goblet cell carcinoid of the appendix: a specific type of carcinoma

AIMS: Goblet cell carcinoid is a poorly understood tumour of the appendix. The aim of this study was to determine whether it should be regarded as a separate entity or as a variant of classical carcinoid. METHODS AND RESULTS: The immunohistochemical expression pattern of 21 markers and the mutation status of KRas codon 12 were determined in 16 goblet cell carcinoids and compared with 14 classical carcinoids, 19 colonic adenocarcinomas and 10 appendiceal mucinous cystadeno (carcino)mas. The results were subjected to a stepwise linear discriminant analysis. Goblet cell carcinoids were significantly different from the control groups. The most important markers for discriminating between the groups were CEA (classical carcinoid versus all others), KRas mutation (present in all mucinous cystadeno (carcino)mas), beta-catenin (goblet cell carcinoid versus left sided colonic adenocarcinoma) and chromogranin (goblet cell carcinoid versus right sided colonic adenocarcinoma). Expression of Math1 and HD5 was similar in goblet cell carcinoid and colonic adenocarcinoma but absent in classical carcinoid. CONCLUSION: The results suggest that goblet cell carcinoids should be regarded as a separate entity. The formerly used term 'crypt cell carcinoma' may be more appropriate because it reflects the more aggressive clinical behaviour of these tumours as well as their greater similarity to adenocarcinomas rather than to carcinoids.     

A xanthomatous lesion resembling balloon cell melanoma of the iris and ciliary body of a dog

A slow-growing xanthomatous tumour which diffusely infiltrated the iris and ciliary body of a dog was composed of large, pale, vacuolated cells which contained scattered fine pigment granules. Electron microscopy revealed coalescing vacuoles, lamellar membranous structures, and small groups of melanosomes in the cytoplasm, suggesting melanocytic origin. The lesion resembled balloon cell melanoma of the ciliary body of man. The behaviour of the tumour was benign. This is a clinical and pathological entity which has not been reported previously in the dog.     

Anatomic site-specific patterns of gene copy number gains in skin, mucosal, and uveal melanomas detected by fluorescence in situ hybridization

To assess the differences between melanomas of different location and different etiology, 372 malignant melanomas were brought in a tissue microarray format. The collection included 23 acral and 118 non-acral skin melanomas, 9 mucosal melanomas, 100 uveal melanomas, and 122 melanoma metastases. Fluorescence in situ hybridization (FISH) was used to assess copy number changes of the cyclin D1 (CCND1), MDM2, c-myc (MYC), and HER2 genes. FISH analysis revealed distinct differences between melanomas from different locations. CCND1 amplifications were detected in skin melanomas from sites with chronic sun exposure (6 of 32 cases), acral melanomas (4 of 17 cases), and mucosal melanomas (one of ten cases) but not in uveal melanomas. High-level MDM2 amplifications were exclusively present in acral melanomas (2 of 19 cases). MYC copy number gains were detected in 32 of 71 uveal melanomas, five of eight mucosal melanomas, and 6 of 67 melanomas from sites with intermittent sun exposure but not in acral melanomas nor melanomas from sites with chronic sun exposure. Alterations of the MYC gene were associated with advanced tumor stage. There were no high-level HER2 amplifications. Site-specific genetic and epigenetic features may impact the response of melanomas to various anti-cancer drugs and should be considered in future studies on the molecular pathogenesis of malignant melanomas.     

Molecular genetic analysis of HLA class II alleles in Japanese patients with melanoma

Distribution of HLA-DQA, -DQB and -DPB alleles in ninety-six Japanese patients with melanoma was analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, and the association between clinical parameters and the presence of certain HLA class II alleles investigated. The frequency of HLA-DQB 1*0302 was increased, while those of DQA1*0101(04), -DQA1*0401 and DRB1*0802 were decreased in melanoma patients compared with controls. Moreover, the frequency of HLA-DQA 1*0103 in patients with acral lentiginous melanoma was increased compared with controls. However, none of these HLA class II alleles showed significant positive or negative associations after correction of the P value. In addition, there was no correlation between these antigens and clinical parameters. These results indicate that HLA class II alleles may not contribute to a strong susceptibility to melanoma in the Japanese