melanocytic tumors

Molecular biology

 kinase fusions in melanocytic tumors. (doi : 10.1038/labinvest.2016.122 )

CGH

Comparative genomic hybridization (CGH) have been used to perform genome-wide searches for patterns of aberrations that may be of help in the classification of melanocytic neoplasms. CGH can detect and map changes in DNA copy number in DNA samples including DNA extracted from archival specimens.

Whereas the vast majority of melanomas show chromosomal aberrations, the benign nevi mostly do not show aberrations.

Congenital nevi and blue nevi did not show aberrations at all.

A subset of Spitz nevi (about 20%) showed an isolated gain of chromosome 11p. The remainder of the Spitz nevi also did not show aberrations. This gain is because of the presence of multiple copies of an isochromosome 11p in the cells of these nevi. Remarkably, this aberration does not appear to be present in melanomas.

Spitz nevi can show significant histologic overlap with melanoma, leading to frequent misdiagnosis. The clearcut difference between the aberration patterns between nevi – no aberrations or presence of an isochromosome 11p –and melanoma – multiple chromosomal aberrations in over 95% of the cases – suggests that chromosomal analyses may be of assistance in the classification of lesions that are ambiguous by histopathology.

This aspect is of significant clinical relevance, because of the limitations of current techniques to classify reliably tumors that have overlapping histologic features.

Congenital nevi have an increased risk to progress to melanoma. However, during the first year of life, several types of melanocytic tumors can develop within congenital nevi, many of which are thought to be distinct from melanoma.

These tumors range widely in size, can grow very fast and ulcerate, and can be extremely difficult to classify histologically.

Although histologically these lesions simulate nodular melanoma, they tend to regress within a few months. Most of the cases did show chromosomal aberrations by CGH. However, different from melanoma, the aberrations involved only entire chromosomes.

In melanomas gains or losses of entire chromosomes do occur frequently, but in 95% of the cases are paralleled by gains or losses of chromosomal fragments.

Aberrations involving chromosomal fragments suggest abnormalities in handling double-stranded DNA breaks.

However, an aberration pattern with numerical chromosomal aberrations only is suggestive of a malfunction in chromosomal segregation, possibly within the mitotic spindle checkpoint.

A control group of bona fide melanomas that arose in congenital nevi showed a pattern indistinguishable from melanoma. Mutation analyses on genes operating at the spindle checkpoint are underway.

Yet another pattern of chromosomal aberrations arose when different types of melanomas were analysed.

When compared to the most frequent melanoma type – superficial spreading melanoma – melanomas on acral skin invariably showed gene amplifications.

Amplifications were defined as focused chromosomal regions with marked copy number increase (>2.5-fold of ploidy). Whereas all acral melanomas appeared to have at least one amplification, most had several, less than 15% of nonacral melanomas had amplifications.

Additional studies showed that the amplifications in acral melanomas arise very early in the progression, at or even before the in situ stage of the disease (see the section on field cells below). In contrast, the few nonacral melanomas that do display amplifications appear to have acquired them later during progression (unpublished data).

The amplified regions in acral melanomas frequently contain known oncogenes such as HRAS (Bastian et al., 2000a), cyclin D1 (Sauter et al., in press), CDK4, HTERT, but also involve regions without obvious candidate genes.

CGH

Analysis of DNA copy number changes using comparative genomic hybridization in melanocytic neoplasms has revealed distinct patterns of chromosomal aberrations between benign melanocytic nevi and melanoma.

Whereas the vast majority of melanoma expresses chromosomal aberrations, blue nevi, congenital nevi, and most Spitz nevi typically show no aberrations.

A subset of Spitz nevi shows an isolated gain of chromosome 11p, an aberration pattern not observed in melanoma. These Spitz nevi frequently harbor mutations in the HRAS gene located on this chromosomal arm.

Comparisons among melanoma types showed that melanomas of the palms, soles, and subungual sites can be distinguished by the presence of multiple gene amplifications that arise very early in their progression.

About 50% of these amplifications are found at the cyclin D1 locus. By contrast, amplifications are significantly less frequent in other cutaneous melanoma types and if present arise late in progression.

The frequent amplifications in melanomas on acral sites allowed the detection of single basal melanocytes with gene amplifications in the histologically normal appearing skin immediately adjacent to a melanoma.

These "field cells" represent subtle melanoma in situ and are likely to represent minimal residual disease that can lead to local recurrences if not excised with safety margins.

The high frequency of chromosomal aberrations in melanomas and their relative absence in nevi could indicate that melanocytes of melanomas went through telomeric crisis, whereas melanocytes in nevi did not.

Such a scenario would suggest that replicative senescence is a tumor-suppressive mechanism in melanocytic neoplasia. It might also explain part of the phenomenon of regression commonly seen in melanoma.

Localization

 cutaneous melanocytic tumors
 meningeal
 choridal

See also

 Tumors

Open references

 A review of kinase fusions in melanocytic tumors. Lab Invest, 2017. doi : 10.1038/labinvest.2016.122. http://www.nature.com/labinvest/journal/v97/n2/full/labinvest2016122a html

References

 Understanding the progression of melanocytic neoplasia using genomic analysis: from fields to cancer. Bastian BC. Oncogene. 2003 May 19;22(20):3081-6. PMID: 12789284

References (CGH, cytogenetics)

 Murphy MJ, Jen M, Chang MW, Grant-Kels JM, Makkar H. Molecular diagnosis of a benign proliferative nodule developing in a congenital melanocytic nevus in a 3-month-old infant. J Am Acad Dermatol. 2008;59:518–523.

 Bauer J, Bastian BC. Distinguishing melanocytic nevi from melanoma by DNA copy number changes: comparative genomic hybridization as a research and diagnostic tool. Dermatologic Therapy. 2006;19:40–49.

 Bastian BC, Olshen AB, LeBoit PE, Pinkel D. Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol. 2003;163:1765–1770.

 Bastian BC. Understanding the progression of melanocytic neoplasia using genomic analysis: from fields to cancer. Oncogene. 2003;22:3081–3086.

 Bastian BC, Xiong J, Frieden IJ, Williams ML, Chou P, Busam K, Pinkel D, LeBoit PE. Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas. Am J Pathol. 2002;161(4):1163–1169.

 Kallioniemi A, Kallioniemi OP, Piper J, Isola J, Waldman F, Gray JW, Pinkel D. Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer. 1994;10:231–243.

 Carlson JA, Ross JS, Sliminski A, Linette G, Mysliborski J, Hill J, Mihm M. Molecular diagnostics in melanoma. J Am Acad Dermatol. 2005;52:743–775.

References (Morphology)

 Lodha S, Saggar S, Celebi JT, Silvers DN. Discordance in the histopathologic diagnosis of difficult melanocytic neoplasms in the clinical setting. J Cutan Pathol. 2008;35:349–352.

 Wechsler J, Bastuji-Garin S, Spatz A, et al. Reliability of the histopathologic diagnosis of malignant melanoma in childhood. Arch Dermatol. 2002;138:625–628.

 Morton DL, Thompson JF, Cochran AJ, et al. Sentinel node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355(13):1307–1317.

 Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242:302–313.

 Pacella SJ, Lowe L, Bradford C, Marcus BC, Johnson T, Rees R. The utility of sentinel lymph node biopsy in head and neck melanoma in the pediatric population. Plast Reconstr Surg.

 Roaten JB, Partrick DA, Bensard D, Pearlman N, Gonzalez R, Fitzpatrick J, McCarter MD. Survival in sentinel lymph node-positive pediatric melanoma. J Pediatr Surg. 2005;40:988–992.

 Shah NC, Gerstle JT, Stuart M, Winter C, Pappo A. Use of sentinel lymph node biopsy and high-dose interferon in pediatric patients with high-risk melanoma: the Hospital for Sick Children experience. J Pediatr Hematol Oncol. 2006;28(8):496–500.

 Dewar DJ, Newell B, Green MA, Topping AP, Powell BWEM, Cook MG. The microanatomic location of metastatic melanoma in sentinel lymph nodes predicts nonsentinel lymph node involvement. J Clin Oncol. 2004;22:3345–3349.

 Zaharopoulos P, Hudnall SD. Nevus-cell aggregates in lymph nodes: fine-needle aspiration cytologic findings and resulting diagnostic difficulties. Diagn Cytopathol. 2004;31:180–184.

 Biddle DA, Evans HL, Kemp BL, El-Naggar AK, Harvell JD, White WL, Iskandar SS, Prieto VG. Intraparenchymal nevus cell aggregates in lymph nodes: a possible diagnostic pitfall with malignant melanoma and carcinoma. Am J Surg Pathol. 2003;27(5):673–681.