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1.  Improving Melanoma Classification by Integrating Genetic and Morphologic Features 
PLoS Medicine  2008;5(6):e120.
In melanoma, morphology-based classification systems have not been able to provide relevant information for selecting treatments for patients whose tumors have metastasized. The recent identification of causative genetic alterations has revealed mutations in signaling pathways that offer targets for therapy. Identifying morphologic surrogates that can identify patients whose tumors express such alterations (or functionally equivalent alterations) would be clinically useful for therapy stratification and for retrospective analysis of clinical trial data.
Methodology/Principal Findings
We defined and assessed a panel of histomorphologic measures and correlated them with the mutation status of the oncogenes BRAF and NRAS in a cohort of 302 archival tissues of primary cutaneous melanomas from an academic comprehensive cancer center. Melanomas with BRAF mutations showed distinct morphological features such as increased upward migration and nest formation of intraepidermal melanocytes, thickening of the involved epidermis, and sharper demarcation to the surrounding skin; and they had larger, rounder, and more pigmented tumor cells (all p-values below 0.0001). By contrast, melanomas with NRAS mutations could not be distinguished based on these morphological features. Using simple combinations of features, BRAF mutation status could be predicted with up to 90.8% accuracy in the entire cohort as well as within the categories of the current World Health Organization (WHO) classification. Among the variables routinely recorded in cancer registries, we identified age < 55 y as the single most predictive factor of BRAF mutation in our cohort. Using age < 55 y as a surrogate for BRAF mutation in an independent cohort of 4,785 patients of the Southern German Tumor Registry, we found a significant survival benefit (p < 0.0001) for patients who, based on their age, were predicted to have BRAF mutant melanomas in 69% of the cases. This group also showed a different pattern of metastasis, more frequently involving regional lymph nodes, compared to the patients predicted to have no BRAF mutation and who more frequently displayed satellite, in-transit metastasis, and visceral metastasis (p < 0.0001).
Refined morphological classification of primary melanomas can be used to improve existing melanoma classifications by forming subgroups that are genetically more homogeneous and likely to differ in important clinical variables such as outcome and pattern of metastasis. We expect this information to improve classification and facilitate stratification for therapy as well as retrospective analysis of existing trial data.
Boris Bastian and colleagues present a refined morphological classification of primary melanomas that can be used to improve existing melanoma classifications by defining genetically homogeneous subgroups.
Editors' Summary
Skin cancers—the most commonly diagnosed cancers worldwide—are usually caused by exposure to ultraviolet (UV) radiation in sunlight. UV radiation damages the DNA in skin cells and can introduce permanent genetic changes (mutations) into the skin cells that allow them to divide uncontrollably to form a tumor, a disorganized mass of cells. Because there are many different cell types in the skin, there are many types of skin cancer. The most dangerous type—melanoma—develops when genetic changes occur in melanocytes, the cells that produce the skin pigment melanin. Although only 4% of skin cancers are melanomas, 80% of skin cancer deaths are caused by melanomas. The first signs of a melanoma are often a change in the appearance or size of a mole (a pigmented skin blemish that is also called a nevus) or a newly arising pigmented lesion that looks different from the other moles (an “ugly duckling”). If this early sign is noticed and the melanoma is diagnosed before it has spread from the skin into other parts of the body, surgery can sometimes provide a cure. But, for more advanced melanomas, the outlook is generally poor. Although radiation therapy, chemotherapy, or immunotherapy (drugs that stimulate the immune system to kill the cancer cells) can prolong the life expectancy of some patients, these treatments often fail to remove all of the cancer cells.
Why Was This Study Done?
Now, however, scientists have identified some of the genetic alterations that cause melanoma. For example, they know that many melanomas carry mutations in either the BRAF gene or the NRAS gene, and that the proteins made from these mutated genes (“oncogenes”) help cancer cells to grow uncontrollably. The hope is that targeted drugs designed to block the activity of oncogenic BRAF or NRAS might stop the growth of those melanomas that make these altered proteins. But how can the patients with these specific tumors be identified in the clinic? The expression of altered proteins is likely to affect the microscopic growth patterns (“histomorphology”) of melanomas. However, the current histomorphology-based classification system for melanomas, which distinguishes four main types of melanoma, does not help clinicians choose the best treatment for their patients. In this study, the researchers have tried to improve melanoma classification by looking for correlations between histomorphological features and genetic alterations in a large collection of melanomas.
What Did the Researchers Do and Find?
The researchers examined several histomorphological features in more than 300 melanoma samples and used statistical methods to correlate these features with the mutation status of BRAF and NRAS in the tumors. They found that some individual histomorphological features were strongly associated with the BRAF (but not the NRAS) mutation status of the tumors. For example, melanomas with BRAF mutations had more melanocytes in the upper layers of the epidermis (the outermost layer of the skin) than did those without BRAF mutations (melanocytes usually live at the bottom of the epidermis). Then, by combining several individual histomorphological features, the researchers built a model that correctly predicted the BRAF mutation status of more than 90% of the melanomas. They also found that, among the variables routinely recorded in cancer registries, being younger than 55 years old was the single most predictive factor for BRAF mutations. Finally, in another large group of patients with melanoma, the researchers found that those patients predicted to have a BRAF mutation on the basis of their age survived longer than those patients predicted not to have a BRAF mutation using the same criterion.
What Do These Findings Mean?
These findings suggest that an improved classification of melanomas that combines an analysis of known genetic factors with histomorphological features might divide melanomas into subgroups that are likely to differ in terms of their clinical outcome and responses to targeted therapies when they become available. Additional studies are needed to investigate whether the histomorphological features identified here can be readily assessed in clinical settings and whether different observers will agree on the scoring of these features. The classification model defined by the researchers also needs to be validated and refined in independent groups of patients. Nevertheless, these findings represent an important first step toward helping clinicians improve outcomes for patients with melanoma.
Additional Information.
Please access these Web sites via the online version of this summary at
A related PLoS Medicine Research in Translation article is available
The MedlinePlus encyclopedia provides information for patients about melanoma
The US National Cancer Institute provides information for patients and health professionals about melanoma (in English and Spanish)
Cancer Research UK also provides detailed information about the causes, diagnosis, and treatment of melanoma
PMCID: PMC2408611  PMID: 18532874
2.  Transcription analysis in the MeLiM swine model identifies RACK1 as a potential marker of malignancy for human melanocytic proliferation 
Molecular Cancer  2008;7:34.
Metastatic melanoma is a severe disease. Few experimental animal models of metastatic melanoma exist. MeLiM minipigs exhibit spontaneous melanoma. Cutaneous and metastatic lesions are histologically similar to human's. However, most of them eventually spontaneously regress. Our purpose was to investigate whether the MeLiM model could reveal markers of malignancy in human melanocytic proliferations.
We compared the serial analysis of gene expression (SAGE) between normal pig skin melanocytes and melanoma cells from an early pulmonary metastasis of MeLiM minipigs. Tag identification revealed 55 regulated genes, including GNB2L1 which was found upregulated in the melanoma library. In situ hybridisation confirmed GNB2L1 overexpression in MeLiM melanocytic lesions. GNB2L1 encodes the adaptor protein RACK1, recently shown to influence melanoma cell lines tumorigenicity. We studied the expression of RACK1 by immunofluorescence and confocal microscopy in tissues specimens of normal skin, in cutaneous and metastatic melanoma developped in MeLiM minipigs and in human patients. In pig and human samples, the results were similar. RACK1 protein was not detected in normal epidermal melanocytes. By contrast, RACK1 signal was highly increased in the cytoplasm of all melanocytic cells of superficial spreading melanoma, recurrent dermal lesions and metastatic melanoma. RACK1 partially colocalised with activated PKCαβ. In pig metastases, additional nuclear RACK1 did not associate to BDNF expression. In human nevi, the RACK1 signal was low.
RACK1 overexpression detected in situ in human melanoma specimens characterized cutaneous and metastatic melanoma raising the possibility that RACK1 can be a potential marker of malignancy in human melanoma. The MeLiM strain provides a relevant model for exploring mechanisms of melanocytic malignant transformation in humans. This study may contribute to a better understanding of melanoma pathophysiology and to progress in diagnosis.
PMCID: PMC2387171  PMID: 18442364
3.  Appearance of New Vemurafenib-associated Melanocytic Nevi on Normal-appearing Skin 
Background: Vemurafenib, a selective BRAF inhibitor that has antineoplastic activity in patients with unresectable or metastatic malignant melanoma whose tumor harbors a BRAF V600E mutation, has multiple drug-associated cutaneous adverse effects. Purpose: To provide a detailed and comprehensive review of reported changing or new pigmented lesions in oncology patients who have been treated with vemurafenib. Methods: The new appearance of melanocytic nevi on normal-appearing skin after initiating treatment with vemurafenib is described in two men with metastatic malignant melanoma whose tumors demonstrated a BRAF V600E mutation. Using the PubMed database, an extensive literature search was performed for the following topics: vermurafenib, nevus, nevi, melanoma, pigmented lesion, cutaneous, adverse effect, side effect. The results of the search were used to secure all reports of new or changing pigmented lesions after initiating treatment with vemurafenib. Results: Vemurafenib is associated with both changes in existing pigmented lesions (including involution, alteration of color and size, and progression to melanoma) and the onset of new melanocytic lesions—nevi (in 5 patients) and primary melanomas (in 2 patients). Visual examination, dermoscopic evaluation, and reflectance confocal microscopy have been used to document the changes in existing or new melanocytic lesions subsequent to initiating treatment with vermurafenib. Histopathology analysis has shown these lesions to usually be either dysplastic nevi or new primary melanomas. Conclusion: Vemurafenib-treated patients can develop new pigmented lesions (such as nevi) and/or morphological changes in their existing melanocytic lesions (such as involution, increase in size, or alternation of color). In addition, they can develop new primary malignant melanomas that either occur de novo on normal-appearing skin or develop in pre-existing melanocytic lesions. Therefore, total body skin examination should be considered prior to initiating treatment with vemurafenib. Regularly scheduled follow-up skin examinations are also recommended for patients while they are receiving this drug. In addition, for patients who are being treated with vemurafenib, either dermoscopic or photographic or visual modalities should be used to evaluate new or changing pigmented lesions. Also, biopsy for histopathology should be considered for vemurafenib-treated patients who develop new pigmented lesions or whose existing melanocytic lesions have morphological changes in size or color.
PMCID: PMC3662681  PMID: 23710269
4.  Cell surface antigens of human melanocytes and melanoma. Expression of adenosine deaminase binding protein is extinguished with melanocyte transformation 
It has been proposed that the pathogenesis of melanoma proceeds through multiple stages, ranging from benign proliferation of melanocytic cells to acquisition of the capacity to invade tissues and metastasize. During investigations of cell surface antigens expressed by melanocytes and melanoma, we identified an antigen system that was expressed by cultured normal melanocytes but not by melanoma cell lines. mAbs against this antigen detected a 120-kD cell surface glycoprotein on melanocytes. This molecule had been identified previously as the binding protein for adenosine deaminase (ADAbp). ADAbp was expressed by 51 melanocyte cell lines derived from normal fetal, newborn, and adult skin and adult choroid, but not by 102 melanoma cell lines derived from primary and metastatic lesions. Studies with radiolabeled bovine adenosine deaminase, confirmed that melanocytes expressed binding sites for adenosine deaminase, but no binding sites were detected on cultured melanoma cells. Further studies showed that ADAbp+ melanocytes became ADAbp- upon malignant transformation in vitro. Immunohistochemical studies on a panel of frozen tissues demonstrated reactivity of anti- ADAbp mAbs with epidermal melanocytes and benign junctional nevi, but not with potentially premalignant dysplastic nevi or primary/metastatic melanoma lesions. These studies demonstrate that ADAbp expression is lost with malignant transformation of melanocytes, presumably at an early stage in the transformation process.
PMCID: PMC2188806  PMID: 2891780
5.  The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis 
BMC Medical Genomics  2008;1:13.
The process of malignant transformation, progression and metastasis of melanoma is poorly understood. Gene expression profiling of human cancer has allowed for a unique insight into the genes that are involved in these processes. Thus, we have attempted to utilize this approach through the analysis of a series of primary, non-metastatic cutaneous tumors and metastatic melanoma samples.
We have utilized gene microarray analysis and a variety of molecular techniques to compare 40 metastatic melanoma (MM) samples, composed of 22 bulky, macroscopic (replaced) lymph node metastases, 16 subcutaneous and 2 distant metastases (adrenal and brain), to 42 primary cutaneous cancers, comprised of 16 melanoma, 11 squamous cell, 15 basal cell skin cancers. A Human Genome U133 Plus 2.0 array from Affymetrix, Inc. was utilized for each sample. A variety of statistical software, including the Affymetrix MAS 5.0 analysis software, was utilized to compare primary cancers to metastatic melanomas. Separate analyses were performed to directly compare only primary melanoma to metastatic melanoma samples. The expression levels of putative oncogenes and tumor suppressor genes were analyzed by semi- and real-time quantitative RT-PCR (qPCR) and Western blot analysis was performed on select genes.
We find that primary basal cell carcinomas, squamous cell carcinomas and thin melanomas express dramatically higher levels of many genes, including SPRR1A/B, KRT16/17, CD24, LOR, GATA3, MUC15, and TMPRSS4, than metastatic melanoma. In contrast, the metastatic melanomas express higher levels of genes such as MAGE, GPR19, BCL2A1, MMP14, SOX5, BUB1, RGS20, and more. The transition from non-metastatic expression levels to metastatic expression levels occurs as melanoma tumors thicken. We further evaluated primary melanomas of varying Breslow's tumor thickness to determine that the transition in expression occurs at different thicknesses for different genes suggesting that the "transition zone" represents a critical time for the emergence of the metastatic phenotype. Several putative tumor oncogenes (SPP-1, MITF, CITED-1, GDF-15, c-Met, HOX loci) and suppressor genes (PITX-1, CST-6, PDGFRL, DSC-3, POU2F3, CLCA2, ST7L), were identified and validated by quantitative PCR as changing expression during this transition period. These are strong candidates for genes involved in the progression or suppression of the metastatic phenotype.
The gene expression profiling of primary, non-metastatic cutaneous tumors and metastatic melanoma has resulted in the identification of several genes that may be centrally involved in the progression and metastatic potential of melanoma. This has very important implications as we continue to develop an improved understanding of the metastatic process, allowing us to identify specific genes for prognostic markers and possibly for targeted therapeutic approaches.
PMCID: PMC2408576  PMID: 18442402
6.  Primary Cilium Depletion Typifies Cutaneous Melanoma In Situ and Malignant Melanoma 
PLoS ONE  2011;6(11):e27410.
Cutaneous melanoma is a lethal malignancy that arises spontaneously or via in situ precursor neoplasms. While melanoma in situ and locally invasive malignant melanoma can be cured surgically, these lesions can sometimes be difficult to distinguish from melanocytic nevi. Thus, the identification of histolopathologic or molecular features that distinguish these biologically distinct lesions would represent an important advance. To this end, we determined the abundance of melanocytic primary cilia in a series of 62 cases composed of typical cutaneous melanocytic nevi, melanoma in situ, invasive melanoma, and metastatic melanoma. Primary cilia are sensory organelles that modulate developmental and adaptive signaling and notably, are substantially depleted from the neoplastic epithelium of pancreatic carcinoma at a stage equivalent to melanoma in situ. In this series, we find that while nearly all melanocytes in 22 melanocytic nevi possessed a primary cilium, a near-complete loss of this organelle was observed in 16 cases of melanoma in situ, in 16 unequivocal primary invasive melanomas, and in 8 metastatic tumors, each associated with a cutaneous primary lesion. These findings suggest that the primary cilium may be used to segregate cutaneous invasive melanoma and melanoma in situ from melanocytic nevi. Moreover, they place the loss of an organelle known to regulate oncogenic signaling at an early stage of melanoma development.
PMCID: PMC3214062  PMID: 22096570
7.  PAX3 Expression in Normal Skin Melanocytes and Melanocytic Lesions (Naevi and Melanomas) 
PLoS ONE  2010;5(4):e9977.
Cutaneous Malignant Melanoma is an aggressive form of skin cancer, arising in cutaneous melanocytes. The transcription factor PAX3 regulates melanocyte specification from neural crest cells during development but expression in differentiated melanocytes is uncertain. By contrast it is frequently found in melanomas and naevi and is a marker for melanoma staging and detection. In this study we analysed the expression of PAX3 across the spectrum of melanocytic cells, from normal melanocytes to cells of benign and malignant lesions to better assess its function in these various tissues. Pax3 and PAX3 (italicized) refer to the mouse and human gene, respectively; whereas Pax3 and PAX3 (non-italicized) refer to the corresponding mouse and human protein.
Methodology and Principal Findings
PAX3 expression was analysed by immunohistochemistry and qRT-PCR. Immunofluorescence was used for co-expression with differentiation, migration and survival markers. As expected PAX3 expression was observed in naevi and melanoma cells. It was also found in melanocytes of normal skin where it co-expressed with melanocyte markers, MITF and MLANA. Co-expression with its downstream target, antiapoptotic factor BCL2L1 confirms PAX3 as a cell survival regulator. PAX3 was also co-expressed with melanoma cell migration marker MCAM in dermal naevi and melanoma cell nests, but this downstream target of PAX3 was not present in normal epidermal melanocytes, suggesting differential roles for PAX3 in normal epidermal melanocytes and melanoma cells. Most interestingly, a proportion of PAX3-positive epidermal melanocytes in normal skin show HES1 and Ki67 co-expression, indicating their less differentiated proliferative phenotype.
Conclusions and Significance
Our results suggest that a previously identified role for PAX3, that of regulator of an undifferentiated plastic state, may operate in melanocytes of normal skin. This role, possibly required for cellular response to environmental stimuli, may contribute to formation and development of melanocytic lesions in which PAX3 expression is prominent.
PMCID: PMC2858648  PMID: 20421967
8.  Quantitative Measurement of Melanoma Spread in Sentinel Lymph Nodes and Survival 
PLoS Medicine  2014;11(2):e1001604.
In this study, Klein and colleagues investigated the impact of minimal cancer sentinel lymph node spread and of increasing numbers of disseminated cancer cells on melanoma-specific survival. The authors found that cancer cell dissemination to the sentinel node is a quantitative risk factor for melanoma death and the best predictor of outcome was a model based on combined quantitative effects of DCCD, tumor thickness, and ulceration.
Please see later in the article for the Editors' Summary
Sentinel lymph node spread is a crucial factor in melanoma outcome. We aimed to define the impact of minimal cancer spread and of increasing numbers of disseminated cancer cells on melanoma-specific survival.
Methods and Findings
We analyzed 1,834 sentinel nodes from 1,027 patients with ultrasound node-negative melanoma who underwent sentinel node biopsy between February 8, 2000, and June 19, 2008, by histopathology including immunohistochemistry and quantitative immunocytology. For immunocytology we recorded the number of disseminated cancer cells (DCCs) per million lymph node cells (DCC density [DCCD]) after disaggregation and immunostaining for the melanocytic marker gp100. None of the control lymph nodes from non-melanoma patients (n = 52) harbored gp100-positive cells. We analyzed gp100-positive cells from melanoma patients by comparative genomic hybridization and found, in 45 of 46 patients tested, gp100-positive cells displaying genomic alterations. At a median follow-up of 49 mo (range 3–123 mo), 138 patients (13.4%) had died from melanoma. Increased DCCD was associated with increased risk for death due to melanoma (univariable analysis; p<0.001; hazard ratio 1.81, 95% CI 1.61–2.01, for a 10-fold increase in DCCD + 1). Even patients with a positive DCCD ≤3 had an increased risk of dying from melanoma compared to patients with DCCD = 0 (p = 0.04; hazard ratio 1.63, 95% CI 1.02–2.58). Upon multivariable testing DCCD was a stronger predictor of death than histopathology. The final model included thickness, DCCD, and ulceration (all p<0.001) as the most relevant prognostic factors, was internally validated by bootstrapping, and provided superior survival prediction compared to the current American Joint Committee on Cancer staging categories.
Cancer cell dissemination to the sentinel node is a quantitative risk factor for melanoma death. A model based on the combined quantitative effects of DCCD, tumor thickness, and ulceration predicted outcome best, particularly at longer follow-up. If these results are validated in an independent study, establishing quantitative immunocytology in histopathological laboratories may be useful clinically.
Please see later in the article for the Editors' Summary
Editors' Summary
Because the skin contains many different cell types, there are many types of skin cancer. The most dangerous type—melanoma—develops when mutations occur in melanocytes, the cells that produce the pigment melanin. Less than 5% of skin cancers are melanomas, but melanoma causes most skin cancer deaths. Early signs of melanoma are a change in the appearance of a mole (a pigmented skin blemish) or the development of a new and unusual pigmented lesion. If these signs are noticed and the melanoma is diagnosed before it has spread from the skin into nearby lymph nodes and other tissues, surgery often provides a cure. For advanced melanomas, the outlook is generally poor, although novel therapies may prolong a patient's life.
Why Was This Study Done?
When a person is diagnosed with melanoma, it is important to “stage” the tumor. Knowing the extent and severity of the melanoma helps oncologists plan treatments and estimate their patients' likely outcomes. The detection of isolated melanoma cells in sentinel lymph nodes (the nodes to which cancer cells are most likely to spread from a primary tumor) is included in melanoma staging recommendations. However, finding rare tumor cells in sentinel lymph node biopsies by examining the tissue requires the analysis of many slides from each node removed from the patient and is extremely time-consuming. In this study, the researchers investigate the predictive value of a quantitative immunocytological assay that involves disaggregation of the sentinel node and detection of disseminated cancer cells (DCCs) by immunostaining for gp100 (a marker for melanoma cells). They also use this new assay to examine the effect of increasing numbers of DCCs on melanoma-specific survival.
What Did the Researchers Do and Find?
The researchers used routine histopathology and immunocytology to analyze 1,834 sentinel lymph nodes from 1,027 patients with melanoma who underwent sentinel lymph node biopsy at one German hospital. For immunocytology, the researchers recorded the number of gp100-positive cells per million lymph node cells (the DCC density). During follow-up, 138 patients (13.4%) died from melanoma. The results indicated that increased DCC density was associated with an increased risk of death due to melanoma. Specifically, every 10-fold increase in DCC density + 1 was associated with a near doubling of the risk of death from melanoma (a hazard ratio of 1.81). Even patients with three or fewer gp100-positive cells per million lymph node cells had an increased risk of dying from melanoma compared to patients with no gp100-positive cells (hazard ratio 1.63). When other predictors of outcome such as age and primary tumor location were taken into account, DCC density was a stronger predictor of death than histopathology. Finally, a survival model that included tumor thickness, tumor ulceration, and DCC density provided survival prediction superior to that of a model based on the current standard staging recommendations.
What Do These Findings Mean?
These findings show that quantification of cancer cell dissemination from melanomas to sentinel lymph nodes is feasible and can be combined with other characteristics of the primary tumor to provide an accurate prediction of outcomes for individual patients with melanoma. Notably, the new prediction model identifies a group of patients at high risk of progression for whom the current clinical standard underestimates the risk of death. These patients may benefit from adjuvant therapies, so the new analysis presented in this study may help to stratify patients for clinical trials. Importantly, quantitative immunocytology and the new model, although internally validated in this study, need to be validated in an independent group of patients before they can be considered for routine clinical use. If external validation is successful, quantitative immunocytology, which is much less labor-intensive than histopathology, has the potential to change the routine clinical care of patients with melanoma and probably with other solid tumors, conclude the researchers.
Additional Information
Please access these websites via the online version of this summary at
The US National Cancer Institute provides information for patients and professionals on melanoma, cancer staging, and sentinel lymph node biopsy (in English and Spanish)
The nonprofit organization American Cancer Society provides information in several languages on cancer and how it develops and specific information on melanoma, including the AJCC system for staging and personal stories
The UK National Health Service Choices website includes an introduction to cancer and a page on melanoma that includes personal stories
The nonprofit organization Cancer Research UK provides basic information about cancer and detailed information on melanoma
PMCID: PMC3928050  PMID: 24558354
With the increase in sentinel lymph node biopsies in melanoma patients, pathologists are frequently confronted with small deposits of morphologically bland melanocytes in the node, which occasionally cannot be readily classified as benign nodal nevi or melanoma. As most melanomas harbor characteristic chromosomal aberrations which can be used to distinguish it from benign nevi, we used fluorescence in-situ hybridization (FISH) with markers for three regions on chromosome 6 and one on chromosome 11 to determine the presence of chromosomal aberrations in sentinel lymph node specimens with small foci of melanocytes that had been diagnosed as metastatic melanoma or nodal nevi by histopathology. 59 tissue samples from 41 patients (24 lymph node metastases, 17 with nodal nevi, and 18 of the available corresponding primary melanomas) were analyzed by FISH. 20 of 24 (83%) cases diagnosed as metastatic melanoma showed aberrations by FISH. Of the four negative cases, three were unequivocal melanoma metastases, while one on re-review was histopathologically equivocal. Of the 17 nodal nevi one (6%) also showed aberrations by FISH, while the remainder were negative. Multiple aberrations were present in the positive case, some of which were also found in the corresponding primary tumor, identifying this case as a deceptively bland melanoma metastasis that had been misclassified by histomorphology. Our data indicate that FISH is a useful adjunct tool to traditional methods in the diagnostic workup of deposits of melanocytes in the lymph node that are histopathologically ambiguous.
PMCID: PMC2831773  PMID: 20087158
10.  Expression of vitamin D receptor (VDR) decreases during progression of pigmented skin lesions 
Human pathology  2011;42(5):618-631.
1,25-dihydroxyvitamin D3 affects proliferation, differentiation and apoptosis and protects DNA against oxidative damage with a net tumorostatic and anticancerogenic effects. It acts through a specific nuclear receptor that is widely distributed through the body. Although a beneficial role of vitamin D in melanoma patients has been suggested, there is a lack of information on the changes in the expression pattern of vitamin D receptor during progression of pigmented lesions. Using immunohistochemistry, we analyzed expression of vitamin D receptor in 140 samples obtained form 82 patients, including 25 benign nevi, 70 primary cutaneous melanomas, 35 metastases, 5 re-excisions, and 5 normal skin biopsies. The strongest expression was observed in normal skin that significantly decreased in melanocytic proliferations with the following order of expression: normal skin > melanocytic nevi > melanomas = metastases. The vitamin D receptor expression in skin surrounding nevi and melanoma was also significantly reduced as compared to normal skin. Tumor-infiltrating and lymph node lymphocytes retained high levels of vitamin D receptor. There was negative correlation between tumor progression and vitamin D receptor expression with a remarkable decrease of the immunoreactivity in nuclei of melanoma cells at vertical versus radial growth phases, and with metastatic melanomas showing the lowest cytoplasmic receptor staining. Furthermore, lack of the receptor expression in primary melanomas and metastases was related to shorter overall patients’ survival. In addition, the receptor expression decreased in melanized melanoma cells in comparison to amelanotic or poorly pigmented cells. Therefore, we propose that reduction or absence of vitamin D receptor is linked to progression of melanocytic lesions, that its lack affects survival of melanoma patients, and that melanogenesis can attenuate the receptor expression. In conclusion, changes in vitamin D receptor expression pattern can serve as important variables for diagnosis, predicting clinical outcome of the disease and/or as a guidance for novel therapy of melanomas based on use of vitamin D or its derivatives.
PMCID: PMC3078192  PMID: 21292298
Melanogenesis; melanoma; tumor progression; Vitamin D; vitamin D receptor
11.  Parkinson's Disease-Related Protein, α-Synuclein, in Malignant Melanoma 
PLoS ONE  2010;5(5):e10481.
Melanoma is the major cause of skin cancer death worldwide. Parkinson's disease is a neurodegenerative disorder that is caused by mutation of α-synuclein or other genes. Importantly, epidemiological studies have reported co-occurrence of melanoma and Parkinson's disease, suggesting that these two diseases could share common genetic components.
Methodology/Principal Findings
Recently, we found that human melanoma cell lines highly express α-synuclein, whereas the protein is undetectable in the non-melanoma cancer cell lines tested. To investigate the expression of α-synuclein in human melanoma tissues, we immunostained sections of melanoma, nevus, non-melanocytic cutaneous carcinoma, and normal skin. α-Synuclein was positively detected in 86% of the primary and 85% of the metastatic melanoma sections, as well as in 89% of nevus sections. However, α-synuclein was undetectable in non-melanocytic cutaneous carcinoma and normal skin.
The Parkinson's disease-related protein, α-synuclein, is expressed in both malignant and benign melanocytic lesions, such as melanomas and nevi. Although α-synuclein cannot be used to distinguish between malignant and benign melanocytic skin lesions, it might be a useful biomarker for the diagnosis of metastatic melanoma.
PMCID: PMC2864738  PMID: 20463956
12.  Tumor-Immune Interaction, Surgical Treatment, and Cancer Recurrence in a Mathematical Model of Melanoma 
PLoS Computational Biology  2009;5(4):e1000362.
Malignant melanoma is a cancer of the skin arising in the melanocytes. We present a mathematical model of melanoma invasion into healthy tissue with an immune response. We use this model as a framework with which to investigate primary tumor invasion and treatment by surgical excision. We observe that the presence of immune cells can destroy tumors, hold them to minimal expansion, or, through the production of angiogenic factors, induce tumorigenic expansion. We also find that the tumor–immune system dynamic is critically important in determining the likelihood and extent of tumor regrowth following resection. We find that small metastatic lesions distal to the primary tumor mass can be held to a minimal size via the immune interaction with the larger primary tumor. Numerical experiments further suggest that metastatic disease is optimally suppressed by immune activation when the primary tumor is moderately, rather than minimally, metastatic. Furthermore, satellite lesions can become aggressively tumorigenic upon removal of the primary tumor and its associated immune tissue. This can lead to recurrence where total cancer mass increases more quickly than in primary tumor invasion, representing a clinically more dangerous disease state. These results are in line with clinical case studies involving resection of a primary melanoma followed by recurrence in local metastases.
Author Summary
Melanoma is a deadly skin cancer that invades into the dermis and metastasizes into the surrounding tissue. In clinical cases, surgical excision of the primary tumor has led to widespread and accelerated growth in metastases. We develop a mathematical model describing the basic process of melanoma invasion, metastatic spread, and the anti-tumor immune response. This model is formulated using partial differential equations that describe the spatial and temporal evolution of a number of different cellular populations, and it uses a realistic skin geometry. Using simulations, we examine the importance of the immune response when a primary tumor is spawning satellite metastases. We find that local metastases can be suppressed by the immune response directed against the primary tumor, but grow aggressively following surgical treatment. We also find that moderately metastatic tumors optimally activate the local immune response against disseminated disease, and in this case tumor excision may have profound effects on metastatic growth. We conclude that surgical perturbation of the immune response controlling local metastases is one mechanism by which cancer can recur. This could have implications as to the appropriate clinical management of melanomas and other solid tumors.
PMCID: PMC2667258  PMID: 19390606
13.  Use of neoadjuvant electrochemotherapy to treat a large metastatic lesion of the cheek in a patient with melanoma 
Approximately 200,000 new cases of melanoma are diagnosed worldwide each year. Skin metastases are a frequent event, occurring in 18.2% of cases. This can be distressing for the patient, as the number and size of cutaneous lesions increases, often worsened by ulceration, bleeding and pain. Electrochemotherapy (ECT) is a local modality for the treatment of cutaneous or subcutaneous tumors that allows delivery of low- and non-permeant drugs into cells. ECT has been used in palliative management of metastatic melanoma to improve patients’ quality of life. This is, to our knowledge, the first application of ECT as neoadjuvant treatment of metastatic subcutaneous melanoma.
Methods and results
A 44-year-old Caucasian woman underwent extensive surgical resection of a melanoma, with a Breslow thickness of 1.5 mm, located on the right side of her scalp. No further treatment was given and the woman remained well until she came to our attention with a large nodule in her right cheek. Whole-body fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) was performed for staging and treatment monitoring. Baseline FDG PET/CT showed the lesion in the cheek to have a maximal standardized uptake value (SUVmax) of 19.5 with no evidence of further disease spread. Fine needle aspiration cytology confirmed the presence of metastatic melanoma. The patient underwent two sessions of ECT with intravenous injections of bleomycin using a CliniporatorTM as neoadjuvant treatment permitting conservative surgery three months later.
Follow-up PET/CT three months after the first ECT treatment showed a marked decrease in SUVmax to 5. Further monitoring was performed through monthly PET/CT studies. Multiple cytology examinations showed necrotic tissue. Conservative surgery was carried out three months after the second ECT. Reconstruction was easily achieved through a rotation flap. Pathological examination of the specimen showed necrotic tissue without residual melanoma. One year after the last ECT treatment, the patient was disease-free as determined by contrast-enhanced CT and PET/-CT scans with a good functional and aesthetic result.
ECT represents a safe and effective therapeutic approach that is associated with clear benefits in terms of quality of life (minimal discomfort, mild post-treatment pain and short duration of hospital stay) and may, in the neoadjuvant setting as reported here, offer the option of more conservative surgery and an improved cosmetic effect with complete local tumor control.
PMCID: PMC3403981  PMID: 22800396
Electrochemotherapy; Melanoma; Adjuvant treatment
14.  Ciliary Body Melanoma – A Particularly Rare Type of Ocular Tumor. Case Report and General Considerations 
Mædica  2013;8(4):360-364.
Uveal melanoma is the most common primary malignancy of the eye in white adults. Frequently, uveal melanoma arises from choroid or iris. Ciliary body melanoma is a rare if not exceptional subtype of uveal melanoma. Furthermore, ciliary melanoma is often seen in association with the other two subtypes of uveal melanoma. This paper presents a case of primary ciliary melanoma with invasion of the iris. The patient presented with blurred vision, but this symptom could not doubtless be related with the existence of the tumor, because of the small dimension of the malignancy and the lack of medical history of the patient.
This tumor was included in the category of "very small ciliary melanoma", a rare diagnosis considering the fast local invasion and the lack of symptoms in such a small tumor. Histopathological and imunohistochemical examinations confirmed the diagnosis of ciliary melanoma
This type of ocular melanoma has a low prognosis due to early metastases.
PMCID: PMC3968473  PMID: 24790669
ciliary body; uveal melanoma; genetic predisposition; unfavorable prognosis
15.  BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs 
Journal of Clinical Pathology  2005;58(6):640-644.
Background: Malignant melanoma arising from different body compartments may be associated with differing aetiological factors and clinical behaviour, and may manifest diverse molecular genetic profiles. Although many studies have focused on cutaneous melanoma, little is known of mucosal and other types of melanoma. In particular, malignant melanoma of soft parts is different from other melanomas in many respects, yet manifests a common melanocytic differentiation. Mutation of BRAF is now known to be common in cutaneous melanomas, and raises possible new therapeutic options of anti-RAF treatment for these patients. Few data are available for non-cutaneous melanomas.
Aims: To study the incidence of BRAF and NRAS mutations in melanomas arising in diverse internal organs.
Methods: Fifty one melanomas from various internal organs were investigated for BRAF and NRAS mutation by direct DNA sequencing.
Results: BRAF and NRAS mutations were found in two and five mucosal melanomas arising from the aerodigestive and female genital tracts (n = 36). Their occurrence is mutually exclusive, giving a combined mutation incidence rate of 19.4% in mucosal melanomas. Both BRAF and NRAS mutations were absent in malignant melanoma of soft parts (n = 7). BRAF mutation was also absent in uveal melanoma (n = 6), but was seen in two of five cutaneous melanomas. The incidence of BRAF or combined BRAF/NRAS mutations in all non-cutaneous groups was significantly lower than published rates for cutaneous melanomas.
Conclusion: Each melanoma subtype may have a unique oncogenetic pathway of tumour development, and only a small fraction of non-cutaneous melanomas may benefit from anti-RAF treatment.
PMCID: PMC1770697  PMID: 15917418
BRAF; NRAS; mucosal melanoma; malignant melanoma of soft parts
16.  Metastatic breast disease from cutaneous malignant melanoma☆ 
Malignant melanoma is one of the most rapidly increasing cancer in the world. Breast metastases from melanoma are uncommon but could reflect a widespread disease.
We report a case of malignant widespread melanoma presenting with bilateral breast nodules in a 39 year-old pre-menopausal Caucasian woman with an history of cutaneous melanoma of the trunk. Breast clinical examination revealed the presence of a hard and mobile lump located on the left breast. Ultrasound detected two bilateral nodules corresponding to oval opacities with well-defined edges and without calcifications or architectural distortion on mammography. Fine needle aspiration cytology performed on both breast nodules confirmed that the breast lesions were metastases from primary cutaneous malignant melanoma. A total-body CT examination detected brain, lung and abdominal lymph nodes metastases.
The breast represents an uncommon site of metastatic disease from extra-mammary tumors. Imaging features of breast metastases from melanoma usually do not allow a differential diagnosis with breast primary tumors. Breast metastases may be asymptomatic or palpable as dense and well-circumscribed nodules. Breast metastases indicate a widespread disease and should lead to avoid aggressive surgical procedures because of the poor prognosis of patients affected by metastatic melanoma.
The detection of bilateral breast metastases from melanoma is highly suggestive of metastatic multi-organ disease and could be useful to address the therapeutic approach.
PMCID: PMC3907203  PMID: 24394861
Melanoma; Breast; Metastasis; Ultrasound; Mammography
17.  Mining Gene Expression Signature for the Detection of Pre-Malignant Melanocytes and Early Melanomas with Risk for Metastasis 
PLoS ONE  2012;7(9):e44800.
Metastatic melanoma is a highly aggressive skin cancer and currently resistant to systemic therapy. Melanomas may involve genetic, epigenetic and metabolic abnormalities. Evidence is emerging that epigenetic changes might play a significant role in tumor cell plasticity and metastatic phenotype of melanoma cells.
Principal findings
In this study, we developed a systematic approach to identify genes implicated in melanoma progression. To do this, we used the Affymetrix GeneChip Arrays to screen 34,000 mouse transcripts in melan-a melanocytes, 4C pre-malignant melanocytes, 4C11− non-metastatic and 4C11+ metastatic melanoma cell lines. The genome-wide association studies revealed pathways commonly over-represented in the transition from immortalized to pre-malignant stage, and under-represented in the transition from non-metastatic to metastatic stage. Additionally, the treatment of cells with 10 µM 5-aza-2′-deoxycytidine (5AzaCdR) for 48 hours allowed us to identify genes differentially re-expressed at specific stages of melan-a malignant transformation. Treatment of human primary melanocytes with the demethylating agent 5AzaCdR in combination to the histone deacetylase inhibitor Trichostatin A (TSA) revealed changes on melanocyte morphology and gene expression which could be an indicator of epigenetic flexibility in normal melanocytes. Moreover, changes on gene expression recognized by affecting the melanocyte biology (NDRG2 and VDR), phenotype of metastatic melanoma cells (HSPB1 and SERPINE1) and response to cancer therapy (CTCF, NSD1 and SRC) were found when Mel-2 and/or Mel-3-derived patient metastases were exposed to 5AzaCdR plus TSA treatment. Hierarchical clustering and network analyses in a panel of five patient-derived metastatic melanoma cells showed gene interactions that have never been described in melanomas.
Despite the heterogeneity observed in melanomas, this study demonstrates the utility of our murine melanoma progression model to identify molecular markers commonly perturbed in metastasis. Additionally, the novel gene expression signature identified here may be useful in the future into a model more closely related to translational research.
PMCID: PMC3439384  PMID: 22984562
18.  NKT Cell Exacerbation of Liver Metastases Arising from Melanomas Transplanted into Either the Eyes or Spleens of Mice 
Metastatic disease of the liver is the most common cause of death in patients with uveal melanoma. This study showed that a unique population of lymphocytes, natural killer T cells, suppress the immune response in the liver and promote metastasis of intraocular melanomas in mice.
To explore the role of natural killer T (NKT) cells in the development of liver metastases in mice harboring intraocular melanomas.
Cells derived from the cutaneous B16 melanoma cell line (B16LS9) were transplanted either into the vitreous body or under the spleen capsules of wild-type C57BL/6 mice and NKT-cell–deficient Jα18−/− and CD1d−/− mice. The development of liver metastases was evaluated by histopathology. The effect of NK cells on liver metastases was determined by selective depletion with anti-asialo-GM1 antiserum in vivo and NK-cell–mediated cytolysis of B16LS9 melanoma cells in vitro. The role of IL-10 and transforming growth factor (TGF)-β in the inhibition of liver NK resistance to liver metastases was determined by in vivo and in vitro neutralization with monoclonal antibodies.
Liver NKT cells, especially type I NKT cells, enhanced liver metastases arising from intraocular melanomas. NKT-cell–deficient mice developed significantly fewer liver metastases that were NK-cell dependent. Tumor-induced liver NKT cells, especially type I NKT cells, inhibited liver NK-cell cytotoxicity by an IL-10-dependent process.
NKT cells exert protective effects in many murine tumor models. However, the present results reveal that NKT cells exacerbate liver metastases arising from intraocular melanomas. To the authors' knowledge, this is the first report that liver NKT cells, especially type I NKT cells, inhibit liver NK-cell antimetastatic activity by the production of IL-10. These results suggest that hepatic NKT cell activity can have an important effect in the immune surveillance of liver metastases.
PMCID: PMC3109018  PMID: 21330669
19.  Loss of nuclear receptor RXRα in epidermal keratinocytes promotes the formation of Cdk4-activated invasive melanomas 
Pigment cell & melanoma research  2010;23(5):635-648.
Keratinocytes contribute to melanocyte transformation by affecting their microenvironment, in part, through the secretion of paracrine factors. Here we report a loss of expression of nuclear receptor RXRα in epidermal keratinocytes during human melanoma progression. We show that absence of keratinocytic RXRα in combination with mutant Cdk4 generated cutaneous melanoma that metastasized to lymph nodes in a bigenic mouse model. Expression of several keratinocyte-derived mitogenic growth factors (Et-1, Hgf, Scf, α-MSH and Fgf2) were elevated in skin of bigenic mice, while Fas, E-cadherin and Pten, implicated in apoptosis, cellular invasion and melanomagenesis, respectively, were downregulated within the microdissected melanocytic tumors. We demonstrated that RXRα is recruited on the proximal promoter of both Et-1 and Hgf, possibly directly regulating their transcription in keratinocytes. These studies demonstrate the contribution of keratinocytic paracrine signaling during the cellular transformation and malignant conversion of melanocytes.
Malignant melanoma continues to evade modern curative efforts as a result of the complex and elusive nature of metastatic tumors. We demonstrated that RXRα expression is lost in epidermal keratinocytes during melanoma progression in humans. We have presented evidence for the association of keratinocytic nuclear receptor RXRα-mediated paracrine/juxtacrine signaling and the malignant transformation of melanocytic tumors. The present work highlights cooperative effects of aberrant keratinocytic signaling and activated Cdk4 in melanoma metastasis. This mouse model will allow greater understanding of the mechanisms responsible for transition towards a malignant phenotype. Manipulation of these receptor-mediated signaling pathways could hold therapeutic value when combating metastatic disease.
PMCID: PMC2939934  PMID: 20629968
RXRα; melanomagenesis; Cdk4; DMBA/TPA; paracrine; ChIP; LCM
20.  Expression of cyclins and cyclin dependent kinases in human benign and malignant melanocytic lesions* 
Journal of Clinical Pathology  2001;54(3):229-235.
Aims—The regulation of cell proliferation is a key event in normal development, pathophysiological responses to injury, and tumorigenesis. The orderly progression of cells through the cell cycle depends on a finely tuned balance between the concentrations of activated cyclins and cyclin dependent kinases. This study was undertaken to compare the expression of cell cycle regulators in benign and malignant melanocytic lesions during tumour progression.
Methods—Immunohistochemistry was used to analyse 49 primary cutaneous malignant melanomas, 18 metastatic melanomas, and 12 histologically confirmed naevus cell naevi for their expression of cyclins (A, B1, D1, D2, D3, and E) and cyclin dependent kinases (CDK1, CDK2, and CDK4).
Results—Cyclin E and CDK2 had the highest expression patterns in human cutaneous melanomas and metastases and correlated positively with histological type and tumour stage. Cyclins B1, D2, and D3 had significantly increased expression in metastases, but normal or even decreased expression in primary melanomas. However, cyclins A and D1, and CDK1 and CDK4 were expressed very weakly in situ with no significant differences between naevi, melanomas, or metastases, and there was no correlation with histopathological staging. The specificity of recognition by the antibodies used was confirmed by western blotting on a panel of seven human melanoma cell lines. Cyclins A, B, and E were expressed by all seven, whereas cyclin D1 was detectable in six of seven and CDK2 and cdc2 were present in five of seven lines analysed.
Conclusions—Taken together, this study demonstrated a significant increase of cyclin E and CDK2 expression during tumour progression in malignant melanomas.
Key Words: melanoma • immunohistology • naevus • cyclin E • cyclin dependent kinase 2 • cyclin B1
PMCID: PMC1731381  PMID: 11253137
21.  Gene expression profiles of human melanoma cells with different invasive potential reveal TSPAN8 as a novel mediator of invasion 
British Journal of Cancer  2010;104(1):155-165.
Metastatic melanoma requires early detection, being treatment resistant. However, the earliest events of melanoma metastasis, and especially of dermal invasion, remain ill defined.
Results and methods:
Gene expression profiles of two clonal subpopulations, selected from the same human melanoma cell line, but differing in ability to cross the dermal–epidermal junction in skin reconstructs, were compared by oligonucleotide microarray. Of 26 496 cDNA probes, 461 were differentially expressed (>2-fold; P< 0.001), only 71 genes being upregulated in invasive cells. Among them, TSPAN8, a tetraspanin not yet described in melanoma, was upregulated at mRNA and protein levels in melanoma cells from the invasive clone, as assessed by RT–PCR, flow cytometry and western blot analysis. Interestingly, TSPAN8 was the only tetraspanin in which overexpression correlated with invasive phenotype. Flow cytometry of well-defined melanoma cell lines confirmed that TSPAN8 was exclusively expressed by invasive, but not non-invasive melanoma cells or normal melanocytes. Immunohistochemistry revealed that TSPAN8 was expressed by melanoma cells in primary melanomas and metastases, but not epidermal cells in healthy skin. The functional role of TSPAN8 was demonstrated by silencing endogenous TSPAN8 with siRNA, reducing invasive outgrowth from tumour spheroids within matrigel without affecting cell proliferation or survival.
TSPAN8 expression may enable melanoma cells to cross the cutaneous basement membrane, leading to dermal invasion and progression to metastasis. TSPAN8 could be a promising target in early detection and treatment of melanoma.
PMCID: PMC3039798  PMID: 21081927
tetraspanin 8; marker; invasion; melanoma
22.  Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma 
Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model.
PMCID: PMC4066658  PMID: 24128326
melanoma; animal model; comparative study; clinical trial design; image analysis; digital telepathology; signal transduction
Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant pre-clinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intraepithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS and c-kit mutations uncommonly, compared to human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a pre-clinical model.
PMCID: PMC4066658  PMID: 24128326
melanoma; animal model; comparative study; clinical trial design; image analysis; digital telepathology; signal transduction
24.  The ultrastructure of conjunctival melanocytic tumors. 
The ultrastructure of conjunctival melanocytic lesions in 49 patients was evaluated to find significant differences between benign and malignant cells. The patients studied included 9 with benign epithelial (racial) melanosis, 2 with pigmented squamous cell papillomas, 16 with conjunctival nevi, 18 with primary acquired melanosis, and 11 with invasive nodules of malignant melanoma. In benign epithelial melanosis, dendritic melanocytes were situated along the basement membrane region of the conjunctival epithelium, with one basilar dendritic melanocyte lodged among every five or six basilar keratinocytes. The dendritic melanocytes extended arborizing cellular processes between the basilar and among the suprabasilar keratinocytes, which manifested considerable uptake of melanin granules into their cytoplasm. The benign dendritic melanocytes possessed nuclei with clumped heterochromatin at the nuclear membrane, small, tightly wound nucleoli, and large, elongated, fully melaninized melanin granules. In two patients with benign hyperplasia of the dendritic melanocytes, occasional dendritic melanocytes were located in a suprabasilar position, but were always separated from each other by keratinocytes or their processes. In the two black patients with benign pigmented squamous papillomas, the benign dendritic melanocytes were located hapharzardly at all levels of the acanthotic epithelium and not just along the basement membrane region. Melanin uptake by the proliferating keratinocytes was minimal. In benign melanocytic nevi of the conjunctiva, nevus cells within the intraepithelial junctional nests displayed a more rounded cellular configuration; short villi and broader cellular processes suggestive of abortive dendrites were found. The nuclear chromatin pattern was clumped at the nuclear membrane, but the nucleoli were somewhat larger than those of benign dendritic melanocytes in epithelial melanosis. The melanosomes were smaller and rounder than those in dendritic melanocytes and exhibited more haphazard arrangements of the melanofilaments, which were only partially melaninized. Mitochondria were more numerous than in dendritic melanocytes, and monoribosomes predominated over polyribosomes. Cytoplasmic filaments were inconspicuous. Cells in the immediate subepithelial connective tissue zone had features identical to those of the cells within the junctional nests. Smaller, lymphocytoid cells with less numerous and more rudimentary melanosomes were found in the middle and deeper portions of the lesions.(ABSTRACT TRUNCATED AT 400 WORDS)
PMCID: PMC1298677  PMID: 6398936
25.  Malignant peripheral nerve sheath tumour-like primary cutaneous malignant melanoma 
Journal of Clinical Pathology  2004;57(2):218-220.
Malignant melanoma is known for its protean cytomorphological features, architectural patterns, and stromal changes, in addition to its ability to mimic various benign and malignant non-melanocytic tumours. Anecdotal cases of metastatic malignant melanoma simulating soft tissue sarcomas have been reported. Interestingly, this mimicry is more often seen in recurrent lesions and metastatic deposits. This report describes a case of a primary spindle cell cutaneous malignant melanoma with a prominent neural-like fascicular pattern and nuclear palisading, simulating a conventional malignant peripheral nerve sheath tumour (MPNST). Clinical, microscopic, and immunohistochemical features of the different entities included in the differential diagnosis of cutaneous spindle cell malignant tumours, such as MPNST, atypical fibroxanthoma, and spindle cell squamous cell carcinoma are discussed. Of note, the presence of an atypical epidermal or junctional component, cell pigmentation, and cell nesting, in addition to diffuse and strong reactivity for S-100 protein and other melanocytic markers, are helpful in the diagnosis of these troublesome lesions.
PMCID: PMC1770219  PMID: 14747458
HMB45; S-100 protein; immunohistochemistry; neurofibrosarcoma

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