Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas

Abstract

Large congenital melanocytic nevi (CMN) are at an increased risk of developing melanoma. Several forms of secondary proliferations can arise in congenital nevi on rare occasions. Although some of these closely resemble melanoma both clinically and histologically, metastasis is rare. We used comparative genomic hybridization to analyze chromosomal aberrations in different types of proliferations arising in CMN and compared them to typical congenital nevi, clear-cut melanomas arising in congenital nevi, as well as primary cutaneous melanomas that were not associated with a CMN. Cases of CMN and CMN with secondary proliferations were assigned to six groups according to the predominant histological pattern: group I, bland congenital nevi (n = 6); group II, congenital nevi with foci of increased cellularity (n = 4); group III, CMN with a proliferation simulating superficial spreading melanoma in situ (n = 3); group IV, CMN with a proliferation simulating nodular melanoma (n = 9); group V, proliferating neurocristic hamartoma (n = 1); and group VI, melanoma arising in congenital nevus (n = 6). No aberrations were found in groups I to III, whereas seven of nine cases of group IV, and one of one case of group V, showed aberrations. In group IV six of seven cases with aberrations (86%) showed numerical aberrations of whole chromosomes exclusively. This pattern differed significantly from the findings in melanoma that arose within CMN (n = 6), group VI, or independent of CMN (n = 122) in which only 5% showed numerical changes only. The single case in group V showed aberrations similar to melanoma. The finding of frequent numerical chromosomal aberrations in atypical nodular proliferations arising in CMN identifies these as clonal neoplasms with a genomic instability consistent with a mitotic spindle checkpoint defect. This difference compared to the aberration pattern found in melanoma might explain their more benign clinical behavior and may be of diagnostic value in ambiguous cases.

Figure 1.

Histopathology of cases in groups II to V. A: Photomicrograph of case CN12, representative for cases of group II. In the center of the superficial dermis there is focus of increased cellularity in an otherwise bland superficial congenital nevus. B: Case CN14, representative of group III, showing a junctional melanocytic proliferation with melanocytes disposed in irregular nests and solitary units, simulating superficial spreading melanoma. This case additionally shows marked desmoplasia and irregularly configured nests of melanocytes in the dermis. Scanning magnification and close up of case D62, representative of cases in group IV (C, D), and case CN10, the only case in group V (E, F). The images show a large, sharply demarcated dermal nodule (C) with increased cellularity and marked angiogenesis (D). A large dermal nodule (E) with areas of increased cellularity and a hemangiopericytoma-like vascular pattern (F, left), and areas with spindle-shaped cells in a myxoid stroma (F, right).

Figure 2.

Copy number changes in a congenital nevus (A, C) and a melanoma arising therein (B, D). Top: Higher power fields of the nevus part and the melanoma of case CN31. Bottom: A dual-color FISH with probes for chromosomes 9p21 (red) and chromosome 9q34.1 (green). The melanocytes in the nevus (C) have equal copy numbers of red and green signals whereas the cells in the melanoma part (D) have lost one or both copies of 9p21.