cyclin-d1 and Nevus--Epithelioid-and-Spindle-Cell

Spitzoid neoplasms may represent a difficult diagnosis in the practice of dermatopathology. We evaluated the concordance of the fluorescence in-situ hybridization (FISH) assay, histopathology, and dermoscopy in a group of adults and in a group of children with spitzoid neoplasms. The FISH assay, designed to detect the copy number of the RREB1 (6p25), MYB (6q23), and CCND1 (11q13) genes and of centromere 6 (Cep 6), was performed in a group of children and in a group of adults with a histopathologic diagnosis of spitzoid neoplasms. FISH data were compared with dermoscopy and histopathology. Fifteen spitzoid neoplasms were collected from 13 patients (five children and eight adults): nine lesions were histologically diagnosed as typical Spitz nevi; three lesions were melanomas and three were atypical Spitz nevi. The conventional FISH criteria were concordant with the clinical and histopathologic diagnosis of Spitz nevi in four adults and in three children. FISH criteria of the other neoplasms showed a concordance with the histopathologic diagnosis in three cases. Discordant results were obtained in five cases (two children, three adults). The FISH melanoma assay proved more reliable in spitzoid lesions found in adults than in children. This assay should be interpreted carefully in pediatric patients with Spitz nevi in the context of histological features as melanomas in the pediatric population may show distinct chromosomal aberrations.

Topics: Adolescent; Adult; Child; Child, Preschool; Cyclin D1; Cytogenetic Analysis; Diagnosis, Differential; DNA Copy Number Variations; DNA-Binding Proteins; Female; Humans; In Situ Hybridization, Fluorescence; Male; Melanocytes; Melanoma; Middle Aged; Nevus, Epithelioid and Spindle Cell; Proto-Oncogene Proteins c-myb; Skin Neoplasms; Transcription Factors; Young Adult

Spitz naevi are difficult to diagnose, because of significant overlap with melanomas. It has been recently demonstrated that the LSI RREB1(6p25)/LSI MYB(6q23)/LSI CCND1(11q13)/CEP6 fluorescence in-situ hybridization (FISH) assay is a reliable tool with which to distinguish benign naevi and melanomas. Little is known about its diagnostic usefulness in Spitz naevi.. We investigated 51 patients with Spitz naevi and long-term median follow-up (8.18 years) with the multicolour FISH probe. Control groups included 11 benign naevi and 14 melanomas. Spitz naevi from 32 (63%) patients did not show cytogenetic abnormalities (FISH-). In contrast, Spitz naevi from 19 (37%) patients showed changes in the investigated loci (FISH+). Spitz naevi with the FISH+ profile showed chromosome X polysomy in 14/18 (78%) patients. All Spitz naevi with the FISH- profile were disomic. All melanomas displayed a FISH+ profile, and 4/11 (36%) showed chromosome X polysomy. No differences in clinicopathological features were detected between Spitz naevi with and without genetic abnormalities.. The presence of gene copy number changes in Spitz naevi as detected by FISH is higher than expected, and Spitz naevi at the genetic level represent a heterogeneous group. The findings of similar cytogenetic alterations in Spitz naevi and melanomas suggest that there should be cautious interpretation of FISH analysis in this setting.

Topics: Adolescent; Adult; Biopsy; Child; Child, Preschool; Chromosome Aberrations; Chromosomes, Human, X; Cyclin D1; Diagnosis, Differential; DNA-Binding Proteins; Female; Follow-Up Studies; Gene Dosage; Humans; In Situ Hybridization, Fluorescence; Male; Melanoma; Middle Aged; Nevus, Epithelioid and Spindle Cell; Oncogene Proteins v-myb; Retrospective Studies; Skin; Skin Neoplasms; Transcription Factors; Young Adult

The differential diagnosis between Spitz naevus and spitzoid melanoma can be extremely difficult, or even impossible. In recent years, many attempts have been made to find specific histopathological or immunohistochemical markers, although none has proved successful. Because the prognosis and treatment of each are very different, it is important to distinguish between these entities. We evaluated the ability of the fluorescence in situ hybridization (FISH) assay-designed to detect the copy number of the RREB1 (6p25), MYB (6q23) and CCND1 (11q13) genes and of centromere 6 (Cep 6)-in order to distinguish between Spitz naevus and spitzoid melanoma.. We evaluated 12 spitzoid melanomas and six Spitz naevi from our records. The diagnosis of both conditions was based on previously described histopathological criteria. We obtained valuable results for FISH in eight spitzoid melanomas and five Spitz naevi. Chromosomal aberrations were detected in seven of the eight spitzoid melanomas (FISH-positive) and in none of the five Spitz naevi. The FISH-negative spitzoid melanoma was the least typical in its group.. FISH was able to distinguish between Spitz naevus and spitzoid melanoma, with a sensitivity of 87.5% and a specificity of 100%. Our findings suggest that FISH could prove a useful tool in the differential diagnosis between these entities.

Topics: Adult; Child; Chromosome Aberrations; Cyclin D1; Diagnosis, Differential; DNA-Binding Proteins; Female; Gene Dosage; Genes, myb; Humans; In Situ Hybridization, Fluorescence; Male; Melanoma; Middle Aged; Nevus, Epithelioid and Spindle Cell; Skin Neoplasms; Transcription Factors; Young Adult

We evaluated the usefulness of immunohistochemical examination for E-cadherin, p16, and cyclin D1 in discriminating melanoma from Spitz tumors. Immunoperoxidase staining was performed on formalin-fixed tissue specimens from 46 Spitz tumors and 42 concurrent melanoma specimens. The percentages of immunoreactive melanocytes in the epidermis and dermis were estimated semiquantitatively. Qualitatively abnormal immunoreactivity patterns were also tabulated. Dermal p16 immunoreactivity was the best quantitative discriminator: decreased nuclear immunoreactivity (<25% of dermal melanocytes) was 3-fold more likely in melanoma than in Spitz tumors (P = .004). Loss of both nuclear and cytoplasmic dermal p16 immunoreactivity was 8-fold more likely in melanoma (P = .01). Qualitative irregularities in the zonal distribution of E-cadherin immunoreactivity were 2-fold higher in melanoma (P = .01), but these were often focal or subtle. There was no statistically significant difference in cyclin D1 immunoreactivity. In atypical Spitz tumors, the dermal p16 immunoreactivity and frequency of qualitative E-cadherin abnormalities were intermediate between those of ordinary Spitz nevi and melanoma. Also, contrasting immunoreactivity patterns were helpful in determining Breslow thickness in specimens containing melanoma and contiguous dermal nevi.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cadherins; Chi-Square Distribution; Child; Child, Preschool; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Male; Melanoma; Middle Aged; Nevus, Epithelioid and Spindle Cell; Skin Neoplasms

We present the case of 10-year-old girl who have had from birth a plane tumor, of tan color, 3-4 mm of diameter, localized on the face on the cutaneous part of the superior lip. This tumor has been stabile until 8-year-old. Then, after repeated sunlight exposures, the lesion has become more stark, hemispheric in shape, has increased in size becoming about 5-6 mm, with irregular borders, and after an accidental traumatism it began to bleed. We have performed the electroexcision of the lesion for diagnostic and therapeutic purpose. The histopathologic exam distinguished typical images of Spitz nevus on some of the histological sections but also of melanocytary tumor with uncertain malignant potential on the others where atypical mitoses localized in the deeper component of the tumor are being noticed. The immunohistochemical assessment of the tumoral cells showed positivity for the melanocytic markers HMB45 and Melan A, within junctional intraepidermic nevic cells and in the nevic cells from superficial dermis, and also for CD44 protein (belonging to the adhesion molecules family). However, cyclin D1 was positive in rare nevic cells, and the proliferation rate of the tumor was small, with a proliferation index for Ki67 lesser than 5%. The correlation between histopathological and immunohistochemical data conducive to final diagnosis of Spitz nevus with uncertain malignant potential. The clinical evolution confirmed the histopathological diagnosis by the fact that the patient did not presented clinical signs of local recurrences or metastasis at three years after the excision of the tumor.

Topics: Antigens, Neoplasm; Biomarkers, Tumor; Child; Cyclin D1; Diagnosis, Differential; Female; Humans; Hyaluronan Receptors; Ki-67 Antigen; MART-1 Antigen; Melanoma; Melanoma-Specific Antigens; Neoplasm Proteins; Nevus, Epithelioid and Spindle Cell; Skin Neoplasms

Spitz nevi are benign melanocytic nevi that overlap histopathologically with melanoma. We previously found copy number increases of chromosome 11p frequently paralleled by mutations in the HRAS oncogene mapping to this region. In this study, we explored mechanisms that inhibit proliferation in the presence of HRAS activation. We analyzed MAP-kinase activation using immunohistochemistry for phospho-ERK, cyclin D1, and microphthalmia transcription factor expression in 17 Spitz nevi with and 18 Spitz nevi without 11p copy number increase. We found relatively high levels of phospho-ERK and cyclin D1 expression suggesting MAP-kinase pathway activation in both groups of Spitz nevi. However, Spitz nevi with 11p copy number increases showed significantly higher levels of cyclin D1 expression and lower levels of microphthalmia transcription factor expression suggesting stronger MAP-kinase pathway activation in this group. Contrasting this apparent activation, the proliferation rate as assessed by Mib1 expression was low in both groups. An analysis of cell-cycle inhibitory proteins including p16, p21, and p27 showed that the majority of Spitz nevus cells expressed high levels of p16, with cells of the cases that had increased copy number of 11p expressing significantly higher levels than those of Spitz nevi with normal copy number of 11p. We propose that in benign nevi with constitutive activation of the MAP-kinase pathway, p16 functions as an essential mediator of oncogene-induced senescence preventing progression to melanoma.

Topics: Calibration; Cell Cycle; Cell Division; Cyclin D1; Disease Progression; DNA-Binding Proteins; Enzyme Activation; Humans; Immunohistochemistry; MAP Kinase Signaling System; Melanoma; Microphthalmia-Associated Transcription Factor; Mitogen-Activated Protein Kinases; Nevus, Epithelioid and Spindle Cell; Transcription Factors

The morphologic distinction between Spitz nevus and malignant melanoma can be difficult. Because cyclin D1 has been reported to be overexpressed in malignant melanomas, but not in common acquired nevi, we hypothesized that cyclin D1 might be a useful marker to distinguish Spitz nevi from malignant melanoma. Thus, we assessed for cyclin D1 expression in 11 Spitz nevi (10 compound and 1 intradermal) and 9 malignant melanomas (4 Clark stages I-III and 5 Clark stages IV-V) using an immunohistochemical method and routinely fixed and processed tissues. The cyclin D1 results were arbitrarily divided into three groups: 0% to 10%, >10% to 25%, and >25%. We confirmed the observations reported previously by others that cyclin D1 is expressed in malignant melanomas but not in common acquired nevi. Unexpectedly, a relatively high number of cyclin D1-positive cells (i.e., >10%) was also found in all cases of Spitz nevus. However, unlike malignant melanoma, the cyclin D1 positivity in Spitz nevi was present in a zonal pattern. In other words, the number of cyclin D1-positive cells decreased as the lesion extended more deeply, with the number of positive cells in the reticular dermis being less than that in the papillary dermis. Fluorescence in situ hybridization methods were used to assess amplification of 11q13, the locus harboring the cyclin D1 gene, in four cases of Spitz nevus; all were disomic. Using the antibody MIB-1, we compared cyclin D1 expression to the proliferation rate in Spitz nevi. Despite the high cyclin D1 positivity, all Spitz nevi had a relatively low number of MIB-1-positive cells (mean=3.2%), which was significantly lower than that of malignant melanomas (mean=15.3%) (p < 0.001). Thus, unlike malignant melanoma, there appears to be a dissociation between cyclin D1 overexpression and cell proliferation in Spitz nevi.

Topics: Carrier Proteins; Cell Cycle Proteins; Cyclin D1; Diagnosis, Differential; DNA-Binding Proteins; E2F Transcription Factors; Humans; Immunohistochemistry; Ki-67 Antigen; Melanoma; Nevus; Nevus, Epithelioid and Spindle Cell; Retinoblastoma-Binding Protein 1; Skin; Skin Neoplasms; Transcription Factor DP1; Transcription Factors