Malignant melanoma cells in the eccrine apparatus

A case of malignant melanoma arising on the sole of a 75-year-old Japanese man is presented. Histopathologically, in addition to the intraepidermal and intradermal malignant melanoma cells reaching the upper part of the dermis, cells were also found in the deep part of the ductal epithelium of the eccrine apparatus. Melanoma cells, and melanocytic nevus cells as well, are rarely found within the epithelial structure of sweat glands, yet they are frequently found in that of hair follicles. In order to avoid a residue of melanoma cells in the deep part of the eccrine apparatus, a fairly deep excision should be performed even for this melanoma.     

Non–pigmented modular plantar melanoma in 12 Japanese patients

In the Japanese, melanoma most commonly involves the plantar surface. Among 61 patients with plantar melanoma, we diagnosed 50 patients as acral lentiginous melanoma (ALM), nine as nodular melanoma, and two as superficial spreading melanoma. Partial or complete loss of pigment was observed in four of the nine nodular melanoma cases and in the nodular portions of eight ALM cases. All 12 such nodular lesions were ulcerated. The clinical diagnosis of malignant melanoma was easily made in the eight patients with ALM by the characteristic pigmentary changes around the nodule. The presence of some remaining pigment was found to be helpful in making the diagnosis in two lesions of nodular melanoma which, at first, had been clinically diagnosed as eccrine poromas. One of two completely amelanotic nodular melanomas was strongly suspected to be a melanoma because there was a history of a pre–existing pigmented macule before the development of the nodule. The other one required histopathological differentiation from Merkel cell carcinoma. Based on these findings and compared with melanoma on other parts of the body, pigmentation noted in the ulcerative nodule of plantar melanoma seems to disappear easily. This causes difficulty in distinguishing it from other skin tumours.     

Epidermotropic xanthoma mimicking balloon cell melanoma

Xanthomas of the skin may mimic balloon cell melanoma because 1) both lesions may exhibit a diffuse dermal proliferation of cytologically similar large vacuolated or clear cells with distinct cytoplasmic membranes, 2) dermal maturation (smaller deep dermal nuclei) is absent in both lesions, 3) melanin pigment is usually absent in balloon cell melanoma, 4) cellular atypia may be minimal in balloon cell melanoma, and 5) mitoses may be absent or rare in balloon cell melanoma. We report a unique xanthoma, which further simulated melanoma by exhibiting epidermotropism and a pseudonesting pattern at the dermal-epidermal junction. The correct diagnosis was made with an immunohistochemical panel revealing tumor cell positivity for CD68 and negativity for S-100 protein and MART-1. Immunohistochemical studies may be required in the critical differential diagnosis of epidermotropic xanthoma and amelanotic balloon cell melanoma.     

Influence of cultured dermal fibroblasts on human melanoma cell proliferation,matrix metalloproteinase-2 (MMP-2) expression and invasion in vitro

The dermis is the main site of melanoma invasion. Matrix metalloproteinases (MMPs), especially MMP-2, produced by melanoma or surrounding stromal cells, are essential for the destruction of dermal extracellular matrix. Here, we examined how dermal fibroblasts influenced proliferation, MMP-2 secretion and invasion of human melanoma cell lines in vitro. Human melanoma cell lines M3 Da and M1Dor were cocultured with dermal fibroblasts under non-contact and contact conditions in order to assess both soluble and insoluble factors, respectively. Zymographic analysis showed that the levels of MMP-2 and TIMP-2 in melanoma cells were not altered in non-contact cocultures when compared with those in individual cultures. However, in contact cocultures, the expression of MMP-2 in membrane extracts was enhanced. Under our coculture conditions, dermal fibroblasts failed to upregulate melanoma cell invasion through a three-dimensional type I collagen matrix. Since stromal and cancer cell contacts have been shown to occur after disruption of the extracellular matrix, we hypothesized that fibroblasts may influence melanoma cell invasion after the beginning of tumor progression through the dermis.     

Lentigo maligna melanoma in situ with neurotropism

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

The nature of melanoma. A critical review

The main object of this review was to examine the various histogenetic types of melanoma in order to determine their nature. Nodular melanoma and superficial spreading melanoma differ in the more rapid growth of the former. For tumors of equal depth of invasion in patients of the same sex, the prognoses are similar. Clinical features with prognostic significance are sex, age, and site of the lesion. Women have a decided superiority in survival up to the age of about 50 years when their superiority declines. Survival rates for men also decline after the age of 50 years but to a lesser degree. Melanomas of the extremities have a better prognosis than melanomas of the axial regions. The histological feature of most prognostic significance is depth of invasion (thickness). Ulceration is partly bound to thickness of the lesion, but has an augmentative effect of its own which is related to rate of growth. Thin lesions with or without regression are often associated with meta-stases.
Melanomas arising in Hutchinson's melanotic freckle have a better prognosis than nodular or superficial spreading melanoma but there has not been any series large enough for definitive markers with prognostic significance lo be determined. A similar state pertains in palmar, plantar and subungual melanomas.
The initial surgical approach in nodular and superficial melanoma should be based upon the thickness of the tumour, site of the tumour, and sex of the patient. The current classification of malignant melanoma is unsatisfactory. Melanoma arising in Hutchinson's melanotic freckle seems to be a distinct entity. Melanomas of other histogenetic types would be best classified according to site.     

Malignant melanoma and acquired dermal melanocytosis on congenital nevus spilus

We reported a case of malignant melanoma and acquired dermal melanocytosis that appeared on congenital nevus spilus; this is the first report from Japan. An 85-year-old woman had had a nevus spilus on the right lower leg since birth. A black-brown nodule developed on the nevus three years before treatment. Blue-gray patches were found within the nevus on inspection. Histopathological analysis of these lesions revealed superficial spreading melanoma and acquired dermal melanocytosis, respectively. There have been 19 previous case reports of malignant melanoma on nevus spilus, and there have only been 4 cases of dermal melanocytosis (plaque-type blue nevus) on nevus spilus. We reviewed the reported cases in the literature and discussed the risk factors of nevus spilus.     

Malignant melanoma in situ associated with underlying sarcoidal granuloma: A histopathological mimicker of invasive epithelioid melanoma cells

Malignant melanoma is known to show diverse cellular morphologies, including a histiocyte‐like morphology. Therefore, many non‐melanocytic proliferations or infiltrates can mimic melanoma, and be confusing especially when they coexist with a true melanoma. Herein, we report an unusual case of a melanoma in situ with an underlying sarcoidal granuloma, which mimicked dermal invasion of melanoma. This case expands insight into non‐neoplastic lesions closely mimicking melanoma.     

Elastin-derived peptides upregulate matrix metalloproteinase-2-mediated melanoma cell invasion through elastin-binding protein

Type I collagen mediates melanoma cells invasion through upregulation of matrix metalloproteinases-1 and -2 (MMP-1 and -2) expression and activation. We investigated here the contribution of elastin-derived peptides (ED), degradation products of elastin, the main component of elastic fibers in melanoma cells invasion and MMP-1 and -2 expression. Our results evidenced fragmentation of elastin at the invasive front of melanoma, particularly in the most invasive tumors where those fibers nearly totally vanished. By electron microscopy, elastolysis was found to occur mainly at the periphery of melanoma cells, where close contact between elastic fibers and cells could be noticed. Therefore, we showed in vitro that plating melanoma cells high tumorigenic potential on ED-coated dishes, selectively enhanced MMP-2, as membrane-type MMP-1 (MT1-MMP) production and activation. Nevertheless, pro-MMP-2 activation was not observed owing to the parallel increase in tissue inhibitor of metalloproteinase (TIMP)-2 expression. The effects of ED on melanoma cells were found to be mediated by splicing form of beta-galactosidase (S-Gal) occupancy, as being suppressed by lactose. Supplementing collagen lattices with ED led to consistent activation of MMP-2 that can be attributed to TIMP-2 downregulation. Upregulation of MMP-2 activation by ED led to enhanced melanoma cells invasion through S-Gal occupancy. Immunohistochemistry studies, confirmed that S-Gal expression was more prominent at the melanoma invasion site associated with a strong expression of MMP-2 and MT1-MMP. We hypothesize that ED following interactions with S-Gal elastin receptor can favor melanoma cells invasion through a three-dimensional type I collagen matrix by upregulating MMP-2 activation.     

Autophagy in cutaneous malignant melanoma

We show that malignant melanoma cells display high levels of autophagy, a cytoplasmic process of protein and organelle digestion that provides an energy source in times of nutrient deprivation. In a panel of 12 cases of cutaneous malignant melanoma of the superficial spreading type, cells in florid melanoma in situ (MIS) and invasive cells in the dermis appeared to be undergoing autophagy. Autophagosomes were detected through immunohistochemistry using the marker LC3B (microtubule‐associated light chain 3B), and by electron microscopy. Some autophagosomes contained melanized melanosomes, accounting for the phenomenon of ‘coarse melanin’ in malignant melanoma. Autophagosomes also contained the Golgi 58k protein, a structural component of the Golgi apparatus, and β1, 6‐branched oligosaccharides, indicating that at least some of the autophagosomal proteins were glycosylated with these structures. The findings suggest that autophagy could be a constitutive metabolic state for invasive and metastatic melanoma cells. Interestingly, a similar phenotype was also expressed by tumor‐associated melanophages. The findings are consistent with previous reports that endoplasmic reticulum (ER) stress drives melanoma progression, since ER stress is known to trigger autophagy. The results suggest that therapies inhibiting autophagy may be effective for the treatment of malignant melanoma by depriving cells of an important energy source. Lazova R, Klump V, Pawelek J. Autophagy in cutaneous malignant melanoma.     

Neonatal giant congenital nevi with proliferative nodules: a clinicopathologic study and literature review of neonatal melanoma

BACKGROUND: Review of the literature reveals that congenital malignant melanoma is an exceptionally rare occurrence and has a generally poor prognosis when it does occur. However, benign proliferative melanocytic lesions are known to occur within giant congenital nevi (GCN). This entity is not well recognized and can be confused clinically and histologically with malignant change. OBSERVATIONS: We report 2 cases of GCN in neonates demonstrating benign proliferating nodules present at birth. An initial diagnosis of malignant melanoma was assumed in both cases. Careful histologic analysis, however, revealed these lesions to be benign, as did long-term follow-up of 3.5 years, with both patients remaining well with no evidence of melanoma. Review of the literature suggests that there are 2 clinical patterns of these benign nodules arising within GCNs: small (<1 cm) and large (>1 cm) dermal nodules with varying histologic patterns that we have attempted to categorize. CONCLUSIONS: Our cases illustrate the difficulty in accurate diagnosis of melanocytic lesions in the neonate. We recommend caution in making a diagnosis of malignant melanoma and highlight the possibility that benign lesions can be mistaken for melanoma in this age group. We encourage the acquisition of fixed histologic specimens for accurate diagnosis of melanocytic lesions.     

Colliding,colonizing or combining? Four cases illustrating the unique challenges presented by melanoma arising in conjunction with basal cell carcinoma

Biphasic lesions comprised of melanocytic and epithelial components are rare entities believed to arise either as a collision of 2 histologically distinct lesions in the same anatomic location or as a singular progenitor tumor differentiating along 2 differing lineages. Regardless of mechanism of origin, these tumors present unique challenges in pathologic interpretation and in determining appropriate measurements, which assigns subsequent prognosis to the patient. We present 4 tumors of melanoma co‐existing with basal cell carcinoma (BCC) and discuss relevant literature regarding these biphasic entities. Patients consisted of 3 males and 1 female, ranging in age from 62 to 93, with lesions located on the shoulder, frontal scalp, forearm and nose. Three of 4 lesions showed melanoma cells limited to BCC tumor lobules, without evidence of direct dermal invasion by melanoma cells, raising the question of whether or not these tumors should be classified as in situ or invasive melanoma. These cases highlight the complexity that such lesions pose to dermatopathologists, in terms of their uncertain origin and variable microscopic appearance. In the absence of data regarding outcomes for these tumors (given their rarity), it is important to utilize a case‐by‐case approach, with careful clinical correlation and appropriate use of ancillary techniques.     

Cellular fine structure in the invasive nodules of different histogenetic types of malignant melanoma

Ultrastructural studies were carried out on the invasive nodule of forty malignant melanomas. The findings support the concept that the fine structure of lentigo maligna melanoma is often characteristic, and differs from that of superficial spreading and nodular melanoma. The melanosomes in lentigo maligna melanoma are usually ellipsoidal and resemble those of normal melanocytes, whereas the melanosomes in superficial spreading and nodular melanoma are most often spheroidal and abnormal in appearance. Superficial spreading and nodular melanomas cannot be distinguished reliably by their ultrastructure. Melanosomal appearances could not be related to the presence of a pre-existing naevus or the depth of invasion of the tumour nodule.     

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

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

Cutaneous malignant melanoma associated with extensive pseudoepitheliomatous hyperplasia. Report of a case and discussion of the origin of pseudoepitheliomatous hyperplasia

We report a case of cutaneous malignant melanoma associated with extensive pseudoepitheliomatous hyperplasia. Pseudoepitheliomatous hyperplasia may mimic squamous cell carcinoma and may complicate the diagnosis of cutaneous melanoma. This diagnostic pitfall is important to both recognize and be cognizant of, so as to avoid diagnostic errors. The observation of the pseudoepitheliomatous hyperplasia, in this case with an extensive proliferation of eccrine ducts, provides further evidence that cutaneous pseudoepitheliomatous hyperplasia arises within the eccrine apparatus.     

Amelanotic conjunctival melanoma

Conjunctival melanoma is a rare condition of the eye pigment predominantly affecting white adults. We describe a 32-year-old white man with an amelanotic malignant melanoma of the conjunctiva that is not associated with primary acquired melanosis (PAM) or melanocytic nevus. The patient presented with a 2-year history of nonpigmented vascularized nodules of the right eye. Results of hematoxylin and eosin (H and E) staining of the lesion showed an invasive nodule with vertical spreading, invasion of the substantia propria corneae, and ulceration. S100 protein was expressed in the cells of the invasive nodule. HMB45 protein was highly positive in the melanoma cells. The de novo amelanotic malignant melanoma of the conjunctiva we describe is an extremely uncommon tumor mainly affecting white adults.     

Microinvasive lentigo maligna melanoma

Ninety-one skin biopsy specimens previously identified as lentigo maligna were examined for the presence of microinvasion, using the demonstration of S100 protein within atypical cells as the means for locating these superficial foci. In 14 cases, atypical melanocytes were identified, most often in the papillary dermis. The mean depth of invasion in this group was 0.23 mm with a range of 0.10 mm to 0.75 mm. In these cases, atypical cells were difficult if not impossible to identify in routinely processed sections, either because the invasive cell was a spindle cell variant and indistinguishable from a fibrohistiocytic cell, because the invasive cells were occasionally solitary or in small groups, or because there was an inflammatory infiltrate that obscured the tumor cells. Recent studies of lentigo maligna melanoma have revealed no better prognosis when compared to that of other forms of malignant melanoma after normalization for depth and body location. We therefore advocate close examination of lentigo maligna with the use of appropriate immunohistochemical techniques if there are areas of dermal fibrosis or inflammation that might obscure invasion.     

Neurotropic Melanoma. A variant of desmoplastic melanoma

In ten cases of neurotropic melanoma, patients presented with nodules composed of amelanotic, deeply infiltrating neuroid fascicles. Only four cases were clinically suggestive of melanoma. In eight of the tumors, a precursor lesion was found histologically and provided a major clue to the diagnosis. In seven cases, the dysplastic precursor was lentiginous, while a superficial spreading pattern was present in one. Initial surgery was often inadequate because of the difficulty in defining tumor margins and the lack of pigment. In seven of the tumors, S100 protein was demonstrated within the invasive spindle cell component by the immunoperoxidase method. This finding was negative in three cases, two of which showed positive staining of the precursor and nerve filaments, indicating that the absence of S100 protein cannot be used as an exclusion criterion for neurotropic melanoma.     

An unusual melanocytic lesion associated with eccrine duct fibroadenomatosis and syringoid features

The intimate association of nevomelanocytic nevi with eccrine ducts commonly seen in congenital nevi was emphasized by Mishima, who described as eccrine-centered nevi those lesions characterized by nevomelanocytic cells predominantly proliferating around and within the eccrine sweat duct walls. However, there were no changes in the overlying epidermis, dermis, or eccrine acrosyringeal or dermal duct proliferation in these lesions. We present the case of a 16-year-old boy with a 1-year-history of a 0.6-cm diameter single tan papule on the right heel, clinically thought to be a Spitz nevus. Histopathologic examination revealed a compound nevomelanocytic nevus associated with epidermal hyperplasia, thin anastomosing cords of acrosyringeal epithelium extending within the dermis, and eccrine ductal proliferation in a syringoma-like pattern associated with a dense fibrous stroma. Features that distinguish our case from eccrine-centered nevus are that the latter lacks epidermal and eccrine duct hyperplasia and a dense fibrous stroma. The location of the lesion on the heel in our case suggests the possibility that the pathologic changes observed could result from repetitive trauma.