The intermediate filament peripherin is expressed in cutaneous melanocytic lesions

Peripherin is an intermediate filament involved in growth and development of the peripheral nervous system and is localized to neurons, some other cells derived from neural tube and neural crest, and some neuroendocrine cells (e.g. β cells of islets of Langerhans). Peripherin also has been demonstrated in neuroblastomas and cutaneous neuroendocrine (Merkel cell) carcinomas. The expression of peripherin by other cells derived from the neural crest is unknown. We evaluated by immunohistochemistry 74 cutaneous melanocytic lesions including primary invasive malignant melanoma (IMM), melanoma in situ (MIS), atypical nevus (nevus with architectural disorder and cytologic atypia of melanocytes) (AN), spindle and epithelioid cell nevus (Spit/nevus) (SN), blue nevus (BN), and common intradermal benign melanocytic nevus (BMN) for expression of peripherin. Peripherin was detected in a cytoplasmic distribution within tumor cells in 14/14 IMM and 8/10 MIS. For IMM, peripherin localised to both the intraepidermal and invasive dermal components. Peripherin was detected in 10/10 AN and 9/9 SN, being localized to the intraepidermal component and, focally, to the superficial dermal component of the lesions. The dendritic nevus cells in 15/15 BN also expressed peripherin. For most of the BMN, expression of peripherin was absent or limited to rare, scattered cells in the superficial portion of the lesions. Melanocytes in adjacent normal skin were not labeled in any of the lesions studied. These results indicate that expression of peripherin is common in both benign and malignant melanocytic lesions, but not in normal resting adult melanocytes. Among benign lesions, expression of peripherin in the dermal component is rare except in the dendritic cells of BN. These findings provide evidence that the expression of peripherin, a marker of neuronal differentiation, is maintained by IMM, MIS, and BN, but is lost in the normal maturational sequence of the dermal component of other melanocytic lesions.     

Relation of maximum diameters of plantar malignant melanoma to various prognostic factors and prognosis of patients

The following factors were investigated in 43 cases of plantar malignant melanoma: maximum diameters of primary lesions, Clark's subtypes, clinical stages, UICC's stages, Clark's levels of invasion, Breslow's tumor thickness, and prognosis of patients. Relation of maximum diameter of primary lesions to various prognostic factors and prognosis of the patients was analysed. It was revealed that there were no statistically significant relationships between maximum diameters and other various factors. In our series, however, all patients with plantar malignant melanoma less than 14 mm in diameter are alive without metastasis. Judging from our previous and present studies, the following two points are the most important for improving the prognosis of patients with plantar malignant melanoma: 1) Catching all pigmented lesions on the sole that are more than 7 mm in diameter and examining them histologically, if they have no possibility of being congenital melanocytic nevus or black heel. 2) Treating plantar malignant melanomas adequately before they become 14 mm in maximum diameter.     

Targetoid hemosiderotic nevus. A trauma-induced simulator of malignant melanoma

BACKGROUND: Simulators of malignant melanoma comprise a heterogenous group of melanocytic and nonmelanocytic lesions of the skin. Among frequent clinical mimickers of melanoma are injured melanocytic nevi. Any change in the clinical appearance of a pre-existing nevus should alert the clinician to exclude the possibility of malignant transformation in order to early identify a lesion at a stage when complete cure can still be achieved. OBJECTIVE: The purpose of this study was to present the clinical, dermoscopic and histopathologic findings of a series of acquired melanocytic nevi which abruptly developed a pigmented peripheral halo, presumably following minor trauma. METHODS: A series of 6 cases of acquired melanocytic nevi which suddenly developed a targetoid halo were included in the study. All lesions were evaluated by dermoscopy. Three cases were surgically removed at different stages of evolution and submitted to histopathologic examination. In all cases, follow-up was obtained. RESULTS: All the lesions arose on trauma-prone skin sites of young women. The sudden development of an asymptomatic, targetoid halo on a long-lasting, acquired exophytic nevus was the main presentation. Whereas the central nevus persisted, the ecchymotic halo ultimately disappeared. Histopathologic examination disclosed changes of the traumatized nevus in the central part, whereas the ring showed hemorrhage and hemosiderin deposits. Increased numbers of small vessels with hobnail characteristics were associated features. CONCLUSIONS: Targetoid hemosiderotic nevus is a distinctive clinicopathologic variant of traumatized acquired melanocytic nevus which should be included in the list of clinical simulators of melanoma.     

Epithelioid blue nevus: a rare variant of blue nevus not always associated with the Carney complex

Epithelioid blue nevus is a rare variant of blue nevus that has been recently described in patients with Carney complex. Some of the patients with Carney complex have multiple epithelioid blue nevi and a familial history of similar lesions is often recorded. Epithelioid blue nevus consists of an intradermal melanocytic nevus composed of polygonal epithelioid cells laden with melanin. Neoplastic cells show no maturation at the base of the lesion and, in contrast with the usual stromal changes in blue nevi, epithelioid blue nevus exhibits no fibrosis of the dermis. We have studied three cases of epithelioid blue nevus in three patients with no evidence of Carney complex. The lesions were solitary and there was no family history of similar lesions. Therefore, epithelioid blue nevus is a distinctive variant of blue nevus that may also appear as a sporadic lesion and is not always associated with Carney complex.     

Melanoma resembling spindle and epithelioid cell nevus

Three cases of malignant melanoma resembling spindle and epithelioid cell nevus histologically are presented. Lesions having histologic features of spindle and epithelioid cell nevus (Spitz nevus or juvenile melanoma) at or after puberty should be regarded with caution, particularly when they are heavily melanized. Such lesions are in a histologic "gray zone" and may be malignant.     

Desmoplastic malignant melanoma: a clinicopathologic analysis of 113 cases

Desmoplastic melanoma (DM) is a rare variant of spindle cell melanoma, which usually develops in sun-damaged skin of elderly patients. Often the lesion is nonpigmented and frequently mistaken for a nonmelanocytic proliferation, which delays diagnosis and treatment and therefore worsens the prognosis. The spindle shape of neoplastic melanocytes, the prominent desmoplasia, and the frequent neurotropism of neoplastic melanocytes are its most characteristic histopathological features. We have studied the clinicopathologic features of 113 cases of DM. The mean age of the patients was 71.1 years; 48% of the patients were males and 52% were females. The neoplasm was located on the head in 72% of the cases. Malignant melanoma was the initial clinical diagnosis in only 27% of the cases. Histopathologically, all lesions appeared as poorly demarcated neoplasms that involved the entire dermis and often extended into the subcutaneous tissue. The neoplasms were composed of ill-defined fascicles of spindle cells. Desmoplasia was defined as the presence of spindle cells associated with a fibrotic stroma. Fifty-one cases (45%) were classified as "pure DM" when the lesion was entirely desmoplastic, and 62 cases (55%) were considered as "combined DM" when a recognizable desmoplastic component was seen in an otherwise conventional malignant melanoma. In 81% of the cases, an atypical intraepidermal melanocytic component (in situ malignant melanoma) was identified, whereas in the remaining 19% of the cases the intraepidermal component was lacking. Seventy-one percent of the cases were histologically amelanotic, 23% showed a small amount of pigment, and only 6% were heavily pigmented. Neural involvement was identified in 40/113 cases (35%), predominantly in the thickest tumors. Lymphoid nodules, found in 42/113 cases (37%), were significantly more frequent in pure DM than in combined DM (53% vs 24%). The null hypothesis of homogeneity of the "pure" and "combined" subgroups should be rejected (P < 0.002). Solar elastosis, with variable intensity, was seen in 82% of the cases. Mean Breslow thickness was 4.1 mm (4.6/3.7 mm, in the pure/combined subgroups, respectively), median was 4.0 mm (4.0/3.0 mm); Breslow thickness ranged from 0.3 to 11.0 mm, with half of the cases thicker than 4 mm. Only 4% of the cases showed Clark level below IV. The predominant neoplastic cells consisted of spindle-shaped melanocytes in 85% of the cases, whereas the remaining 15% of the cases demonstrated round neoplastic cells forming the main mass of the neoplasm. The mitotic rate of the neoplastic cells was low in 72% of the cases, 23% had an intermediate mitotic rate, and 5% showed a high mitotic rate. On follow-up, 55/113 patients (49%) (with an average of 55 months) demonstrated persistence of the disease. About 4% had local recurrences, 2% of lymph node invasion, 9% systemic metastases, and 12% died from the disease (2 cases of pure DM and 5 cases of combined DM). Although a better prognosis has been postulated for DM when compared with conventional cutaneous malignant melanomas of the same thickness, in most cases, a DM is diagnosed only in established long-standing and thick melanomas. Therefore, dermatologists and dermatopathologists should be more aware of this clinicopathologic variant of cutaneous malignant melanoma.     

Pigmented epithelioid melanocytoma: report of first Japanese cases previously diagnosed as cellular blue nevus

Background:  The term 'pigmented epithelioid melanocytoma (PEM)' was recently used for borderline melanocytic tumor/low-grade melanoma including cases previously diagnosed as human animal-type melanoma and epithelioid blue nevus. No Japanese cases have been reported.
Methods:  We reviewed 219 cases previously diagnosed as blue nevus in Japan. Common blue nevus was identified in 154 cases and cellular blue nevus in 65 cases.
Results:  We have found two Japanese cases of PEM previously diagnosed as cellular blue nevus. Two patients were female. The age at presentation was 32 and 28 years. Two lesions were on the buttock. Two cases fulfilled histological criteria proposed for PEM. There is no evidence of recurrence or metastases.
Conclusions:  PEM is a distinct melanocytic tumor and the unifying diagnostic term. PEM is present in Japanese, but these cases may be previously diagnosed as cellular blue nevus. Japanese pathologists should recognize a new concept of PEM, and when they make a diagnosis of PEM, they should be recommended sentinel lymph node sampling.     

Plexiform spitz nevus: an intradermal spitz nevus with plexiform growth pattern

Two cases of a distinctive variant of Spitz (spindle and epithelioid cell) nevus are described. One lesion developed on the lower leg of a 17-year-old boy and the other lesion on the back of a 52-year-old man. The microscopic appearance was characterized by a plexiform arrangement of bundles and lobules of enlarged spindle to epithelioid melanocytes throughout the superficial and deep dermis. Intraepidermal melanocytic proliferation was unappreciated. Some lobules were circumscribed by a thin rim of compressed fibrous tissue. In both cases a myxoid stroma was present. The cells had abundant eosinophilic cytoplasm with well-defined borders. The nuclei were enlarged, consistently ovoid and vesicular, with small nucleoli. Both cases contained scattered multinucleate giant cells similar to those observed in classical form of Spitz nevi. No melanin pigment was detectable by light microscopy. No mitoses were observed in one case and a rare mitosis was present in the other. Tumor cells were strongly immunoreactive for S-100, but not for HMB-45, desmin, and actin. The differential diagnosis of this distinctive tumor includes desmoplastic/neurotropic melanoma, plexiform spindle cell nevus, cellular blue nevus, plexiform neurofibroma, and cellular neurothekeoma. The designation of "plexiform Spitz nevus" is chosen to emphasize its distinctive plexiform growth pattern.     

De novo intraepidermal epithelioid melanocytic dysplasia as a marker of the atypical mole phenotype -- a clinical and pathological study of 75 patients

BACKGROUND: We encountered a distinctive pattern of dysplastic intraepidermal melanocytic proliferation, which defies classification as a dysplastic melanocytic nevus, but in which the morphologic features fall short of a diagnosis of melanoma in situ. We designate such lesions as de novo intraepidermal epithelioid melanocytic dysplasia. METHODS: From 75 patients, 82 skin biopsies were encountered that showed this distinctive morphology. Hematoxylin- and eosin-stained histologic sections were studied and the features were correlated with personal and family histories of dysplastic nevi and melanoma. RESULTS: The diagnosis of de novo melanocytic dysplasia was made in 27 male patients and 48 female patients (mean age: 44 years). The histologic hallmark was a pagetoid (single-cell) array of moderately to severely atypical epithelioid melanocytes within the epidermis. Seventy-three lesions were located on sun-exposed skin and nine on sun-protected skin. In 41 patients, there was an atypical mole phenotype, whereas 20 patients had a prior or subsequent diagnosis of melanoma with five of 16 patients questioned revealing a family history of melanoma. CONCLUSIONS: De novo intraepidermal epithelioid melanocytic dysplasia is a distinct entity associated with an atypical mole phenotype and a personal and/or family history of melanoma.     

“Malignant Spitz Nevus” in a 2-Year-Old Japanese Child

Smith et al. (1989) have reported a variant of Spitz's nevus with histological atypical features. Despite local lymph node metastases, further metastases were not observed. They proposed the name “malignant Spitz nevus” for this variant. A 2-year-old Japanese girl had a large nodule (27 × 17 mm) surrounded by an indurated erythema over the Achilles tendon. Histologically, it proved to be a melanocytic lesion resembling spindle cell and epithelioid cell nevus (Spitz's nevus) with unusual features; the tumor extended deep into the subcutis, and the mitotic figures deep into the tumor, together with prominent lymphatic vessel invasion by melanocytes. Thus the tumor was aptly termed “malignant Spitz nevus”. Flow cytometric analysis of the DNA content revealed a diploid pattern. The child is well 5 years after a wide resection of the tumor. The diploid pattern of the DNA content as well as the good prognosis could support the idea that “malignant Spitz nevus” fits within the spectrum of Spitz's nevus.     

HMB-45 staining in benign and malignant melanocytic lesions. A reflection of cellular activation.

The antibody HMB-45 used as an immunohistochemical reagent has often been labeled as a marker for melanoma, even though some benign lesions have been noted to show positive staining reactions with this reagent. Biopsy specimens from 225 benign and malignant melanocytic lesions were examined after immunoperoxidase staining for S-100 protein and HMB-45. The lesions studied included common acquired nevi, spindle cell and epithelioid cell nevi (Spitz nevi), cellular blue nevi, deep penetrating nevi, congenital nevi, nevi from hormonally reactive areas (genital), malignant melanoma, and desmoplastic malignant melanoma. A positive reaction for HMB-45 was seen in the dermal component in a high percentage of each of these types of lesions except for the common acquired nevi and the desmoplastic malignant melanomas that were uniformly negative for HMB-45 in the dermal component. HMB-45 correlates with melanosome production and thus a melanocytic origin of HMB-45-positive cells. HMB-45 may correlate best with factors that stimulate melanocytic proliferation and production of melanosomes.     

Compound blue nevus: a variant of blue nevus with an additional junctional dendritic component. A clinical, histopathologic, and immunohistochemical study of six cases

We studied six cases of heavily pigmented melanocytic lesions with features of blue nevi within the dermis, but with an additional junctional dendritic component. This compound variant of blue nevus is an uncommon lesion that has not been previously identified as a distinct histologic entity. Immunoperoxidase staining for S100 protein and counterstaining with azure B distinguished the presence of melanocytes among numerous melanophages within the dermis. The compound variant of blue nevus can be distinguished histologically from combined blue nevus, pigmented spindle cell nevus, malignant melanoma, and melanosis due to a regressed malignant melanoma. The six lesions were from three men and three women whose ages ranged from 11 to 51 years (mean, 31 years). Three lesions were located on the trunk, two on the extremities, and one on the head. After a mean follow-up period of 47 months (range, 38 to 58 months), there was no evidence of recurrence.     

AgNOR (nucleolar organizer regions) staining in malignant melanoma.

Nucleolar organizer regions (NORs) are loops of ribosomal DNA seen in nuclei, which are demonstrable as black dots (AgNOR) in tissue sections by silver (Ag) colloid staining. The number of such AgNORs is correlated with cellular activity and is an indicator of the degree of malignancy. In this study, 76 melanocytic lesions were analyzed by AgNOR staining, and the clinical and histopathological characteristics of malignant melanoma and melanocytic nevi were considered. Although the AgNOR counts for melanocytic nevi were significantly different from those in malignant melanoma, an obvious overlap between them was detected. The number of AgNORs in melanocytic nevi per cell was usually 1 or 2. On the other hand, the number of AgNORs per malignant melanoma cell was variable. Morphologically, malignant melanoma cells often showed dispersal of AgNORs throughout the nucleus as well as multiple nucleoli containing clustered AgNORs, whereas melanocytic nevus cells tended to have a regular nucleolus with tightly clustered AgNORs. The correlation between AgNOR count and pathological staging was uncertain, but a slight correlation between AgNOR count and thickness of the primary lesion was obtained. However, the AgNOR count in malignant melanoma was not a prognostic factor for the disease. Therefore, the AgNOR method is difficult to use for differential diagnosis between benign pigmented lesions and malignant melanoma. Nonetheless, an AgNOR count of more than two per cell favors a diagnosis of malignant melanoma.     

Nevo de Spitz y otros tumores spitzoides en la infancia. Parte 1: aspectos clínicos,histológicos e inmunohistoquímicos

A Spitz nevus is a melanocytic neoplasm of epithelioid and/or spindle cells that usually appears in childhood. These lesions are by nature benign, but their features can sometimes make them difficult to distinguish from melanomas. Spitzoid melanocytic lesions have been grouped into 3 types in recent decades: Spitz nevi, atypical Spitz tumors, and spitzoid melanomas. Atypical Spitz tumors are spitzoid melanocytic proliferations that have atypical histopathologic features that are insufficient to support a diagnosis of melanoma. The malignant potential of these lesions is at present uncertain. This review examines the clinical, dermoscopic, and histopathologic features of this group of lesions.     

'Tubular' epithelioid cell nevus: a new variant of Spitz's nevus

The term Spitz's nevus refers to a large spectrum of nevi composed of spindle and/or epithelioid cells. We report on a hitherto undescribed tubular variant of a dermal epithelioid nevus, characterized by aggregates composed exclusively of cuboidal cells with the prominent feature of tubular or microcystic structures, Immunohistochemically, the epithelioid cells expressed melanocytic markers (S-100, NKI/C3) lacking markers for cytokeratin or carcinoembryonic antigen. The three-dimensional analysis of the lesions by confocal laser scanning microscopy revealed the structural configuration of tubular or microcystic empty spaces bordered by cuboidal nevus cells. This rare variant of epithelioid nevus is another example for the remarkable diversity of Spitz's nevi.     

Focal Regression‐Like Changes in Dysplastic Back Nevi :A Diagnostic Pitfall for Malignant Melanoma

The spectrum of melanocytic proliferations ranges from banal to overtly malignant. Borderline melanocytic lesions which bridge these two extremes pose a challenge, as their biological nature remains undefined. We set out to evaluate the utility of the sentinel lymph node biopsy in such lesions. Our compendium was defined by 11 cases of borderline melanocytic proliferations whereby sentinel node sampling was conducted. There were three severely atypical dermal‐epidermal melanocytic proliferations manifesting borderline features with nevoid melanoma (calf, shoulder, knee), three arising in association with a deep penetrating nevus (chest, shoulder, and arm), three atypical Spitz's tumors (helix, calf, arm, back), and two atypical pigment‐synthesizing melanocytic tumors, resembling equine melanotic disease in one and cellular blue nevus in another (buttock, calf, arm). The patient population comprised seven males and five females ranging in age from age 9–36 (mean: 25 years). At least one positive sentinel lymph node was uncovered in seven of the cases with a positive sentinel lymph observed in all but one case of deep penetrating nevus and atypical Spitz's tumor. The identification of sentinel lymph node positivity in seven of the twelve cases (58%) validates the role of sentinel lymph node biopsy in the setting of borderline melanocytic proliferations.     

Giant congenital nevus with progressive sclerodermoid reaction in a newborn

Giant congenital melanocytic nevi are a rare occurrence in the pediatric population. The risk of malignant transformation associated with these lesions has been well established; however, the management strategies for giant congenital nevi remain controversial. We report an unusual sclerodermoid reaction in a giant congenital nevus in a 6-week-old Caucasian girl. Given its abnormal clinical appearance, the entire lesion was excised. The histology was consistent with an atypical compound/sclerosing spindle and epithelioid cell congenital nevus. No evidence of malignant change was seen histologically. The incidence of malignant transformation in giant congenital nevi has been difficult to calculate. Review of the literature yields an incidence of between 4 and 9%, favoring surgical excision of these lesions where possible. Atypical presentations of giant congenital nevi are rare, and we have found no other reported cases with a stromal change similar to that seen in our patient. We hypothesize that this change may represent an atypical host reaction to the nevus cells.     

Animal‐type melanoma – tumor cell invasion of dermal lymphatics and molecular identification of lymph node metastasis

Animal‐type melanoma (ATM) represents a rare subtype within the wide spectrum of melanocytic tumors. Clinically, ATM lesions appear as sharply demarcated, brown, black and dark blue pigmented nodules, which show grey‐white surface elements on dermatoscopy. The tumor is restricted to the dermis and arranged in irregular fascicles, which are composed of spindle‐shaped and epithelioid melanocytes. Moderate tumor cell pleomorphism, mitoses and apoptotic cells all suggest a malignant process. Abundant, finely dispersed melanin pigment within tumor cells as well as numerous melanophages are strongly suggestive of ATM. Even though locoregional lymph node metastases are frequently found at diagnosis, the course of ATM is generally benign. Specific molecular changes may be detected in melanocytes from lesions and lymph nodes on fluorescence in situ hybridization (FISH). Such findings strongly indicate the malignant potential of ATM. The peculiar biology of ATM, as a moderately malignant tumor, is reflected in a new histopathological classification within the spectrum of dermal borderline melanocytic tumors (BMT).