Disseminated Rasamsonia argillacea complex infection presenting as intraventricular brain hemorrhage in a German shepherd dog in Australia.

A German Shepherd Dog diagnosed with Rasamsonia argillacea based on fungal culture and DNA sequencing, is the first documented case in Australia, and the Southern Hemisphere. This species is part of R. argillacea complex, which is an emerging concern in immunocompromised human and veterinary patients. Intraventricular brain hemorrhage, noted on MRI, has not been reported previously in a dog with fungal encephalitis. The patient was euthanized due to progression of clinical signs before a final diagnosis was made, so no treatment was attempted in this case.

Can angiotropism and lymphovascular invasion refine the current cutaneous melanoma staging system?

BACKGROUND: Several prognostic factors for primary cutaneous melanoma (PCM) have been identified, and these predict metastasis and survival, to a certain extent. We sought to determine the frequency of angiotropism (AT) and lymphovascular invasion (LVI) in PCM and the relationship between AT, LVI, and other clinicopathological parameters and patient's prognosis. METHODS: This study included 538 cases of PCM diagnosed between 2003 and 2016. It comprised 246 females and 292 males whose clinicopathological variables were evaluated with respect to LVI and AT using univariate and multivariate analyses. Overall survival (OS) was assessed by Kaplan-Meier (KM) analysis and Cox regression multivariate analysis. RESULTS: AT occurred more frequently than LVI. Ulceration, mitotic rate, and Breslow thickness were found to be highly associated with both LVI and AT (p < 0.01). All LVI+ cases had AT, with a significant positive correlation (p < 0.01). Both AT and LVI predicted lymph node (LN) metastasis (odds ratio [OR] = 1.47, 1.12, respectively). Multivariate analysis showed LN metastasis, Breslow thickness, LVI, and AT as predictors of OS. LVI and AT independently predicted adverse OS by Cox regression analysis (hazard ratio [HR] = 1.66, 1.49, respectively) and with KM survival analysis. CONCLUSION: AT is a marker for angiotropic extravascular migratory tumor spread (angiotropic EVMM), and LVI is a marker for intra-lymphovascular tumor spread. Both predict poor prognosis. Given its ease of detection, AT could be adopted as a histologpathological feature in the routine assessment of primary cutaneous malignant melanoma cases.

Interobserver agreement in the histopathological classification of desmoplastic melanomas.

Desmoplastic melanoma is a subtype of melanoma characterised by amelanotic fusiform melanocytes dispersed in a collagenous stroma. Cell-poor and fibrous stroma-rich 'pure' variants have been distinguished from 'mixed' variants with areas of higher cell density and/or less desmoplastic stroma. This distinction is relevant because patients whose tumours display a pure phenotype have a lower risk for regional lymph node metastasis and distant recurrence. However, little is known about interobserver agreement among pathologists in the subclassification of desmoplastic melanoma. To address this issue, we conducted a study in which eleven dermatopathologists independently evaluated whole slide scanned images of excisions from 30 desmoplastic melanomas. The participating pathologists were asked to classify the tumours as pure or mixed. They were also asked to record the presence or absence of neurotropism and angiotropism. We found substantial interobserver agreement between the 11 dermatopathologists in the classification of tumours as pure versus mixed desmoplastic melanoma (kappa=0.64; p<0.0001). There was fair agreement between the 11 dermatopathologists in the evaluation of presence versus absence of neurotropism (kappa=0.26; p<0.0001), and slight agreement in the assessment of angiotropism (kappa=0.13; p<0.0001). The level of concordance in the subclassification of desmoplastic melanomas is encouraging for the acceptance of this prognostic parameter in the real-world practice of melanoma pathology.

Monitoring Angiotropic Extravascular Migratory Metastasis In Vitro.

The mechanism of cancer cell migration from the primary tumor toward secondary sites is not fully understood. In addition to intravascular cellular migration, angiotropic extravascular migratory metastasis (EVMM) has been recognized as a metastatic pathway involving tumor cells crawling along the abluminal vascular surface to distant sites. A very simple in vitro 3D assay is described here, which is based on a previous in vitro angiogenesis assay. The assay involves monitoring single fluorescence-tagged migrating cancer cells in the presence of vascular structures in real time. This coculture assay represents a quantitative approach for monitoring the migration processes of cancer cells along vessels, demonstrating phenotypic switching and migration dynamics. This protocol can be used for molecular analyses and can also be adapted for screening of therapeutic agents to block cancer metastasis.

Hematogenous metastasis and tumor dormancy as concepts or dogma? The continuum of vessel co-option and angiotropic extravascular migratory metastasis as an alternative.

It has been accepted for many years that tumor cells spread via the circulation to distant sites. The latency period between treatment and tumor recurrence has been attributed to dormant cells in distant organs that emerge and grow as metastatic tumors. These processes are accepted with an incomplete demonstration of their existence. Challenging such a well-established accepted paradigm is not easy as history as shown. An alternative or co-existing mechanism involving tumor cell migration along the outside of the vessels and co-option of the blood vessel has been studied for over 25 years and is presented. Several lines of data support this new mechanism of tumor spread and metastatic growth and is termed angiotropic extravascular migratory metastasis or EVMM. This slow migration along the outside of the vessel wall may explain the latency period between treatment and metastatic tumor growth. The reader is asked to be open to this possible new concept in how tumors spread and grow and the reason for this latency period. A full understanding of how tumors spread and grow is fundamental for the targeting of new therapeutics.

Vascular Co-Option and Other Alternative Modalities of Growth of Tumor Vasculature in Glioblastoma.

Non-angiogenic tumors grow in the absence of angiogenesis by two main mechanisms: cancer cells infiltrating and occupying the normal tissues to exploit pre-existing vessels (vascular co-option); the cancer cells themselves forms channels able to provide blood flow (the so called vasculogenic mimicry). In the original work on vascular co-option initiated by Francesco Pezzella, the non-angiogenic cancer cells were described as "exploiting" pre-existing vessels. Vascular co-option has been described in primary and secondary (metastatic) sites. Vascular co-option is defined as a process in which tumor cells interact with and exploit the pre-existing vasculature of the normal tissue in which they grow. As part of this process, cancer cells first migrate toward vessels of the primary tumor, or extravasate at a metastatic site and rest along the ab-luminal vascular surface. The second hallmark of vascular co-option is the interaction of cancer cells with the ab-luminal vascular surface. The first evidence for this was provided in a rat C6 glioblastoma model, showing that the initial tumor growth phase was not always avascular as these initial tumors can be vascularized by pre-existing vessels. The aim of this review article is to analyze together with vascular co-option, other alternative mode of vascularization occurring in glioblastoma multiforme (GBM), including vasculogenic mimicry, angiotropism and trans-differentiation of glioblastoma stem cells.

TFPI2 Promotes Perivascular Migration in an Angiotropism Model of Melanoma.

PURPOSE: Angiotropism is the process by which cancer cells attach to and migrate along blood vessels to acquire vasculature, disseminate, and metastasize. However, the molecular basis for such vessel-tumor interactions has not been fully elucidated, partly due to limited experimental models. In this study, we aimed to observe and explore the molecular mechanism underlying angiotropism in melanoma. METHODS: To monitor the interactions of human melanoma cells with the vasculature in vivo, a murine coxenograft model was employed by co-injecting highly and poorly invasive melanoma cells subcutaneously. To identify key pathways and genes involved in the angiotropic phenotype of melanoma, analysis of differentially expressed genes (DEGs) and gene set enrichment analysis (GSEA) were performed. The role of tissue factor pathway inhibitor 2 (TFPI2) in angiotropism was evaluated by immunostaining, adhesion assay, shRNA, and in vivo tumorigenicity. Angiotropism and TFPI2 expression were examined in surgical specimens of melanoma by immunohistochemical staining. Data from The Cancer Genome Atlas (TCGA) were analyzed to explore the expression and prognostic implications of TFPI2 in uveal and cutaneous melanoma. RESULTS: Highly invasive melanoma cells spread along the branches of intratumor blood vessels to the leading edge of invasion in the coxenograft model, resembling angiotropic migration. Mechanisms underlying angiotropism were primarily associated with molecular function regulators, regulation of cell population proliferation, developmental processes, cell differentiation, responses to cytokines and cell motility/locomotion. TFPI2 downregulation weakened the perivascular migration of highly invasive melanoma cells. High levels of TFPI2 were correlated with worse and better survival in uveal and cutaneous melanoma, respectively. CONCLUSION: These results provide a straightforward in vivo model for the observation of angiotropism and suggest that TFPI2 could inhibit the angiotropic phenotype of melanoma.

Visualizing Pericyte Mimicry of Angiotropic Melanoma by Direct Labeling of the Angioarchitecture.

In addition to intravascular dissemination, angiotropic melanoma cells have the propensity to spread along the external surface of blood vessels in a pericytic location, or pericytic mimicry. Such continuous migration without intravasation has been termed "extravascular migratory metastasis" or EVMM. In order to visualize this mechanism of tumor propagation, we used a murine brain melanoma model utilizing green fluorescent human melanoma cells and red fluorescent lectin-tagged murine vessels. This model allows the direct microscopic visualization and mapping of the interaction of melanoma cells with the brain vasculature. In this chapter, we describe the methodology of lectin perfusion to label the entire angioarchitecture in conjunction with confocal microscopy imaging to study the pericyte mimicry of the angiotropic GFP+ melanoma cells.

Conjunctival Melanoma Angiotropic Microsatellitosis: A Mechanism of Local Extravascular Migratory Metastasis.

PURPOSE: To report a case of local metastasis of conjunctival melanoma, which may occur via extravascular migratory metastasis (EVMM), and discuss its clinical relevance in conjunctival melanoma tumor staging and possible management implications. METHODS: Retrospective chart review of a single clinical case with clinicopathologic correlation. RESULTS: A 65-year-old male referred due to local recurrence of conjunctival melanoma at the caruncle was successfully treated after two excisional procedures with negative sentinel lymph node biopsies. Forty-eight months after initial presentation, the patient developed a nodular lesion representing local recurrence in the ipsilateral upper tarsal conjunctiva, distant from the primary tumor site. Histopathology showed nodules in the substantia propria in the absence of primary acquired melanosis. The tumor cells were found along the extravascular surface without intralymphatic or intravascular tumor cells consistent with local metastasis. One possible mechanism is angiotropic microsatellitosis leading to local EVMM. Additional neck CT imaging showed no lymphadenopathy. CONCLUSION: EVMM via angiotropic microsatellitosis is another possible mechanism of noncontiguous local recurrence of conjunctival melanoma. Angiotropic microsatellitosis may represent a high-risk finding possibly related to increased melanoma-related mortality.

Replacement and desmoplastic histopathological growth patterns in cutaneous melanoma liver metastases: frequency, characteristics, and robust prognostic value.

Among visceral metastatic sites, cutaneous melanoma (CM) metastasises initially to the liver in ~14-20% of cases. Liver metastases in CM patients are associated with both poor prognosis and poor response to immunotherapy. Histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colorectal cancer and uveal melanoma (UM), may impart valuable biological and prognostic information. Here, we have studied HGP in 43 CM liver metastases resected from 42 CM patients along with other prognostic factors from three institutions. The HGPs (replacement, desmoplastic, pushing) were scored at the metastasis-liver interface with two algorithms: (1) 100% desmoplastic growth pattern (dHGP) and any (≥1%) replacement pattern (any-rHGP) and (2) >50% dHGP, >50% rHGP or mixed (<50% dHGP and/or rHGP, pushing HGP). For 1 patient with 2 metastases, an average was taken to obtain 1 final HGP yielding 42 observations from 42 patients. 22 cases (52%) had 100% dHGP whereas 20 (48%) had any replacement. Cases with rHGP demonstrated vascular co-option/angiotropism. With the development of liver metastasis, only rHGP (both algorithms), male gender and positive resection margins predicted diminished overall survival (p = 0.00099 and p = 0.0015; p = 0.034 and p = 0.024 respectively). On multivariate analysis, only HGP remained significant. 7 of 42 (17%) patients were alive with disease and 21 (50%) died with follow-up after liver metastases ranging from 1.8 to 42.2 months (mean: 20.4 months, median: 19.0 months). 14 (33%) patients with previously-treated metastatic disease had no evidence of disease at last follow up. In conclusion, we report for the first time replacement and desmoplastic HGPs in CM liver metastases and their prognostic value, as in UM and other solid cancers. Of particular importance, any rHGP significantly predicted diminished overall survival while 100% dHGP correlated with increased survival. These results contribute to a better understanding of the biology of CM liver metastases and potentially may be utilised in managing patients with these metastases.

Models and molecular mechanisms of blood vessel co-option by cancer cells.

Cancer cells have diverse mechanisms for utilizing the vasculature; they can initiate the formation of new blood vessels from preexisting ones (sprouting angiogenesis) or they can form cohesive interactions with the abluminal surface of preexisting vasculature in the absence of sprouting (co-option). The later process has received renewed attention due to the suggested role of blood vessel co-option in resistance to antiangiogenic therapies and the reported perivascular positioning and migratory patterns of cancer cells during tumor dormancy and invasion, respectively. However, only a few molecular mechanisms have been identified that contribute to the process of co-option and there has not been a formal survey of cell lines and laboratory models that can be used to study co-option in different organ microenvironments; thus, we have carried out a comprehensive literature review on this topic and have identified cell lines and described the laboratory models that are used to study blood vessel co-option in cancer. Put into practice, these models may help to shed new light on the molecular mechanisms that drive blood vessel co-option during tumor dormancy, invasion, and responses to different therapies.

Pathological features of vessel co-option versus sprouting angiogenesis.

Cancer cells can use existing blood vessels to acquire a vasculature. This process is termed 'vessel co-option'. Vessel co-option is an alternative to the growth of new blood vessels, or angiogenesis, and is adopted by a wide range of human tumour types growing within numerous tissues. A complementary aspect of this process is extravascular migratory tumour spread using the co-opted blood vessels as a trail. Vessel co-opting tumours can be discriminated from angiogenic tumours by specific morphological features. These features give rise to distinct histopathological growth patterns that reflect the interaction of cancer cells with the microenvironment of the organ in which they thrive. We will discuss the histopathological growth patterns of vessel co-option in the brain, the liver and the lungs. The review will also highlight evidence for the potential clinical value of the histopathological growth patterns of cancer. Vessel co-option can affect patient outcomes and resistance to cancer treatment. Insight into the biological drivers of this process of tumour vascularization will yield novel therapeutic strategies.

Angiotropism, pericytic mimicry and extravascular migratory metastasis: an embryogenesis-derived program of tumor spread.

Intravascular dissemination of tumor cells is the accepted mechanism of cancer metastasis. However, the phenomenon of angiotropism, pericyte mimicry (PM), and extravascular migratory metastasis (EVMM) has questioned the concept that tumor cells metastasize exclusively via circulation within vascular channels. This new paradigm of cancer spread and metastasis suggests that metastatic cells employ embryonic mechanisms for attachment to the abluminal surfaces of blood vessels (angiotropism) and spread via continuous migration, competing with and replacing pericytes, i.e., pericyte mimicry (PM). This is an entirely extravascular phenomenon (i.e., extravascular migratory metastasis or EVMM) without entry (intravasation) into vascular channels. PM and EVMM have mainly been studied in melanoma but also occur in other cancer types. PM and EVMM appear to be a reversion to an embryogenesis-derived program. There are many analogies between embryogenesis and cancer progression, including the important role of laminins, epithelial-mesenchymal transition, and the re-activation of embryonic signals by cancer cells. Furthermore, there is no circulation of blood during the first trimester of embryogenesis, despite the fact that there is extensive migration of cells to distant sites and formation of organs and tissues during this period. Embryonic migration therefore is a continuous extravascular migration as are PM and EVMM, supporting the concept that these embryonic migratory events appear to recur abnormally during the metastatic process. Finally, the perivascular location of tumor cells intrinsically links PM to vascular co-option. Taken together, these two new paradigms may greatly influence the development of new effective therapeutics for metastasis. In particular, targeting embryonic factors linked to migration that are detected during cancer metastasis may be particularly relevant to PM/EVMM.

Angiotropism in primary cutaneous melanoma is associated with disease progression and distant metastases: A retrospective study of 179 cases.

BACKGROUND: Angiotropism is the histopathological correlate of pericytic mimicry and extravascular migratory metastasis (EVMM), a mechanism of melanoma spread by migration along the external surface of blood and lymphatic vessels. The frequency of angiotropism in primary cutaneous melanoma and the clinical utility of its detection remain unclear. METHODS: We investigated angiotropism in 179 primary cutaneous melanomas by hematoxylin and eosin (H&E), CD31, and S100/D240 stains. RESULTS: We detected angiotropism in 31 cases (17%) by H&E. CD31 immunohistochemistry increased detection to 59 cases (33%). When lymphatic vessels were included by using S100/D240 stains, 67 cases (37%) cases were positive. Angiotropism was associated with lymphatic invasion and mitotic rate with all detection methods. There was an association with increased tumor thickness when detected by H&E and CD31. No association with sentinel lymph node status was seen. By H&E and CD31 staining, angiotropism was associated with disease progression and distant metastases by univariate, but not multivariate analysis. Overall survival was not affected by the presence of angiotropism. CONCLUSIONS: Angiotropism is relatively common in primary melanoma when immunohistochemical stains are used for detection and associated with mitotic rate and intravascular lymphatic invasion. The association with disease progression and distant metastasis suggests that it represents an alternative pathway of metastasis, that is, EVMM/pericytic mimicry vs intravascular spread.

Eight autopsy cases of melanoma brain metastases showing angiotropism and pericytic mimicry. Implications for extravascular migratory metastasis.

BACKGROUND: Metastatic tumor spread is a complex multistep process. Due to the blood-brain barrier, metastasis to the central nervous system is restrictive with a distinct predilection for certain tumor types. In melanoma patients, brain metastasis is a common endpoint with the majority showing evidence of widespread disease at autopsy. In a previous murine melanoma model, we have shown that melanoma cells migrate along preexisting vessels into the brain, showing angiotropism/vascular co-option and pericytic mimicry. METHODS: Using conventional morphology and immunohistochemistry, we analyze brain metastases from eight autopsy cases. In addition, tissue clearing, which enables three-dimensional visualization over a distance of 100 µm is used. RESULTS: We show the angiotropic localization of melanoma deposits in the brains in all eight autopsy cases. Tissue clearing techniques have allowed visualization of melanoma cells in one case exclusively along the abluminal surface of brain blood vessels over a distance of 100 µm, thus showing pericytic mimicry. CONCLUSIONS: Our analyses show clear-cut evidence of angiotropism and pericytic mimicry of melanoma cells within the brain over some distance. In addition, these results support the hypothesis of metastasis along pathways other than hematogenous spread, or extravascular migratory metastasis (EVMM). During EVMM, melanoma cells may metastasize to the brain through pericytic mimicry, circumventing the blood-brain barrier.

Angiotropism in recurrent cutaneous squamous cell carcinoma: Implications for regional tumor recurrence and extravascular migratory spread.

Extravascular migratory metastasis is a form of cancer metastasis in which tumor cells spread by tracking along the abluminal aspect of vessel walls without breaking the vascular endothelial lining or intraluminal invasion. This phenomenon has been extensively described in melanoma and is being increasingly recognized in other neoplasms. Various modalities of treatment, including radiation-, chemo-, targeted-, and immune- therapies may potentially induce angiotropic behavior in neoplastic cells. Although there is a risk for tumor recurrence and metastasis, angiotropism may be under-recognized and is rarely reported. Here, we report a case of recurrent poorly-differentiated acantholytic squamous cell carcinoma of the scalp with extensive perineural invasion, previously treated with multiple therapies. There was multifocal extravascular cuffing of neoplastic cells around and focally involving the walls of small to medium-caliber blood vessels within and surrounding the tumor, without obvious tumor intravasation. In addition, small subtle nests of neoplastic keratinocytes were noted along the abluminal aspect of a large-caliber deep dermal blood vessel in an en-face margin, away from the main tumor mass. Such involvement can be difficult to identify; and thus, may be missed particularly during intra-operative frozen section evaluation, leading to false-negative margins and is therefore, a diagnostic pitfall.

Replacement and desmoplastic histopathological growth patterns: A pilot study of prediction of outcome in patients with uveal melanoma liver metastases.

Up to 50% of uveal melanomas (UM) metastasise to the liver within 10 years of diagnosis, and these almost always prove rapidly fatal. As histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colon and breast carcinoma, may import valuable biological and prognostic information, we have studied HGP in a series of 41 UM liver metastases originating from 41 patients from the period 2006-2017. Twenty patients underwent enucleation while 21 had radiation therapy. Analysis of UM by array comparative genomic hybridisation revealed: 25 (64%) patients with high risk (monosomy3/8q gain); 13 (33%) intermediate risk (M3/8normal or disomy3/8q gain); and 1 low risk (disomy3/8normal). The principal HGP was replacement in 30 (73%) cases and desmoplastic in 11 (27%) cases. Cases with replacement demonstrated striking vascular co-option/angiotropism. With the development of liver metastasis, only the replacement pattern, largest primary tumour diameter, and R2 (incomplete resection) status predicted diminished overall survival (OS; p < 0.041, p < 0.017, p < 0.047, respectively). On multivariate analysis, only HGP (hazard ratio; HR = 6.51, p = 0.008) and resection status remained significant. The genomic high-risk variable had no prognostic value at this stage of liver metastasis. Chi-square test showed no association of HGP with monosomy 3 or 8q gain. Eighteen of 41 (44%) patients are alive with disease and 23 (56%) patients died with follow-up ranging from 12 to 318 months (mean: 70 months, median: 47 months). In conclusion, we report for the first time the frequency of the replacement and desmoplastic HGPs in liver UM metastases resected from living patients, and their potential important prognostic value for UM patients, as in other solid cancers. These results may potentially be utilised to develop radiological correlates and therapeutic targets for following and treating patients with UM metastases.

Intravital Imaging of Human Melanoma Cells in the Mouse Ear Skin by Two-Photon Excitation Microscopy.

Noninvasive imaging of reporter gene expression by two-photon excitation (2PE) laser scanning microscopy is uniquely suited to perform dynamic and multidimensional imaging down to single-cell detection sensitivity in vivo in deep tissues. Here we used 2PE microscopy to visualize green fluorescent protein (GFP) as a reporter gene in human melanoma cells implanted into the dermis of the mouse ear skin. We first provide a step-by-step methodology to set up a 2PE imaging model of the mouse ear's skin and then apply it for the observation of the primary tumor and its associated vasculature in vivo. This approach is minimally invasive and allows repeated imaging over time and continuous visual monitoring of malignant growth within intact animals. Imaging fluorescence reporter gene expression in small living animals by 2PE provides a unique tool to investigate critical pathways and molecular events in cancer biology such as tumorigenesis and metastasis in vivo with high-spatial and temporal resolutions.

Satellite in transit metastases in rapidly fatal conjunctival melanoma: implications for angiotropism and extravascular migratory metastasis (description of a murine model for conjunctival melanoma).

Little information is currently available concerning loco-regional metastases such as satellite and in transit metastases and their natural history in conjunctival melanoma as compared to cutaneous melanoma. Angiotropism, a marker of extravascular migration of melanoma cells along vascular channels, often appears responsible for microscopic satellite, satellite and in transit metastases development in cutaneous melanoma. In addition, diffuse tissue microscopic satellites are correlated with widespread melanoma dissemination and death. Herein we report rapid conjunctival melanoma progression and a fatal outcome in four of five patients following recurrence as satellite in transit metastases. Five patients aged 31, 60, 63, 56, and 67 years developed primary conjunctival melanoma, histologically characterised by tumour thicknesses of 4, 4, 1.1, 3, and 2 mm. Two or more conjunctival melanomas manifested ulceration, significant mitotic rates, necrosis, angiotropism, and intralesional transformation. The conjunctival melanoma recurred in a matter of months as one or more discrete satellite in transit lesions in the vicinity of the primary melanoma. Histological examination revealed well-defined micronodules containing atypical melanocytes in the subepithelial connective tissue stroma. All lesions were extravascular and most appeared angiotropic. Four of five patients subsequently developed parotid or other loco-regional nodal disease and rapidly ensuing widespread metastases and death. The time course from diagnosis to the demise of the patients averaged about 13 (range 7-20) months. Our findings suggest that satellite in transit metastases constitute an important new risk marker for possible rapid metastatic disease progression and death in patients with conjunctival melanoma. This finding appears to take on even greater significance if such lesions develop rapidly, i.e., in a matter of weeks or months following diagnosis of primary conjunctival melanoma, and if the primary melanoma manifests additional high-risk features. Additional studies are underway in order to further elucidate the mechanism of these metastases.

Epidermotropic Metastatic Malignant Melanoma / 대한피부과학회지

Cutaneous metastases of malignant melanoma are usually confined to the dermis or subcutaneous fat. In some instances, however, they may involve the epidermis. A 68-year-old woman with a malignant melanoma on the subungual area of the right great toe presented with multiple blackish pinhead-sized macules surrounding an ulcerative lesion on the right great toe. Histopathological study of the macules showed atypical melanocytes and melanocytic nests in the papillary dermis and the dermoepidermal junction. A thinning of the epidermis, widening of the dermal papillae by aggregated atypical melanocytes, epidermal collarette formation, and angiotropism were also seen. A diagnosis of epidermotropic metastatic malignant melanoma (EMMM) was made. EMMM is a specific form of metastatic malignant melanoma that is associated with epidermotropism of melanoma cells and several histopathological features. The differential diagnosis between primary malignant melanoma and EMMM can be difficult because of their similar clinical and histological features. Here, we report a case demonstrating EMMM.