Home > E. Pathology by systems > Skin > proliferative nodule in congenital melanocytic nevus
proliferative nodule in congenital melanocytic nevus
Thursday 25 February 2010
Proliferative nodules are present in a significant proportion of large CMN. They occur congenitally or present as new pigmented papules within the nevus in infancy and early childhood.
Proliferative nodules have distinctive histomorphologic features compared with the adjacent areas of CMN.
Atypical Proliferative nodules have more cellular variability and enlargement and an abrupt interface with adjacent areas of the benign CMN.
Histologic maturation and regression of Proliferative nodules occurs in CMN subjected to sequential biopsies over time.
Immunochemistry
Immunohistochemical analysis of melanocytic markers, cell cycle/proliferative markers, and apoptotic and anti-apoptotic markers indicate that CMN and PNs share more similarities than differences, and both differ in distinct ways from malignant melanoma.
Proliferative nodules differ from the surrounding CMN in their significantly more frequent expression of c-kit and the inverse staining correlation between p21 and p53. C-kit may be a useful marker for their recognition.
Atypical PNs may differ from ordinary PNs in their more frequent expression of Mib1, p53, and bcl-2 and their less frequent expression of p21.
Proliferative, pro-apoptotic, and anti-apoptotic processes are involved in Proliferative nodules growth and regression and that PNs represent a distinctive clonal population within CMN.
Whether p53 mutation is present remains to be elucidated. Since none of the cases in our series demonstrated transformation to malignant melanoma or other neoplasms, the identification of markers for malignant transformation in CMN will require further investigation.
Although their clinical and pathologic features seem ominous, proliferative nodules (PNs) typically are benign and may regress, although atypical features cause greater concern.
Both CMN and proliferative nodules had similar expression of melanocytic, lymphocytic, and most cell-cycle/proliferative and apoptotic markers, including Mib-1, p16, p21, p27, c-Myc, Bax, CD95, and bcl-2.
A greater proportion of PNs than CMN are reactive for p53 (67% vs. 30%, P @<@ 0.0098) and c-kit (97% vs. 3%, P @<@ 0.0001).
p53 and p21 expression in CMN and all types of PNs were inversely correlated.
When ordinary and atypical PNs were compared, the atypical PNs more frequently expressed p53, Mib-1, Bax, and bcl-2, but less frequently expressed p21.
The c-kit expression in nearly all PNs and its absence in nearly all CMN is potentially useful for recognition of PN, suggests a delayed melanocytic maturation process in proliferative nodules, and may be likely indicative of their benign nature.
p53 reactivity in concert with a lack of p21 up-regulation by immunohistochemistry suggests that a p53 mutation may be present in PN, although the immunohistochemical findings alone cannot exclude possible overexpression of wild-type p53.
CGH
The numerical aberrations in the atypical nodular proliferations position them in the spectrum between benign melanocytic nevi that tend to have no chromosomal aberrations and outright melanoma in which both numerical and structural aberrations are the rule.
The aberration pattern in the atypical nodular proliferations points toward a malfunction in chromosomal segregation, possibly within the mitotic spindle checkpoint.
A only case with histological features described as proliferative neurocristic hamartoma showed multiple chromosomal aberrations that involved chromosome fragments, and was genomically indistinguishable from melanoma. This patient was alive and free of any signs of malignancy after 15 years.
These lesions may in fact be neoplasms rather than hamartomas. However, more cases of this extremely rare entity need to be studied to place it within the spectrum of tumors associated with congenital nevi.
There are frequent chromosomal aberrations in atypical nodular proliferations arising in congenital nevi. These aberrations differ from those seen in melanoma in the type of aberrations (numerical aberrations in atypical nodular proliferations versus structural aberrations in melanoma) and the pattern of chromosomes involved (losses of chromosome 7 in atypical nodular proliferations, and frequent losses of chromosomes 9 and 10 in melanoma).
These data indicate fundamental differences compared with melanoma, consistent with the generally benign behavior of these lesions. Genomic analysis may help in the classification of ambiguous cases.
See also
congenital melanocytic nevus
References
Proliferative nodules in congenital melanocytic nevi: a clinicopathologic and immunohistochemical analysis. Herron MD, Vanderhooft SL, Smock K, Zhou H, Leachman SA, Coffin C. Am J Surg Pathol. 2004 Aug;28(8):1017-25. PMID: 15252307
Neoplasms arising in congenital giant nevi: morphologic study of seven cases and a review of the literature. Hendrickson MR, Ross JC. Am J Surg Pathol. 1981 Mar;5(2):109-35. PMID: 6261595
Rhodes AR: Melanocytic precursors of cutaneous melanoma. Estimated risks and guidelines for management. Med Clin North Am 1986, 70:3-37
Sahin S, Levin L, Kopf AW, Rao BK, Triola M, Koenig K, Huang C, Bart R: Risk of melanoma in medium-sized congenital melanocytic nevi: a follow-up study. J Am Acad Dermatol 1998, 39:428-433
Swerdlow AJ, English JS, Qiao Z: The risk of melanoma in patients with congenital nevi: a cohort study. J Am Acad Dermatol 1995, 32:595-599
Ruiz-Maldonado R, Tamayo L, Laterza AM, Duran C: Giant pigmented nevi: clinical, histopathologic, and therapeutic considerations. J Pediatr 1992, 120:906-911
Quaba AA, Wallace AF: The incidence of malignant melanoma (0 to 15 years of age) arising in “large” congenital nevocellular nevi. Plast Reconstr Surg 1986, 78:174-181
Gari LM, Rivers JK, Kopf AW: Melanomas arising in large congenital nevocytic nevi: a prospective study. Pediatr Dermatol 1988, 5:151-158
Egan CL, Oliveria SA, Elenitsas R, Hanson J, Halpern AC: Cutaneous melanoma risk and phenotypic changes in large congenital nevi: a follow-up study of 46 patients. J Am Acad Dermatol 1998, 39:923-932
Bittencourt FV, Marghoob AA, Kopf AW, Koenig KL, Bart RS: Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis. Pediatrics 2000, 106:736-741
DeDavid M, Orlow SJ, Provost N, Marghoob AA, Rao BK, Huang CL, Wasti Q, Kopf AW, Bart RS: A study of large congenital melanocytic nevi and associated malignant melanomas: review of cases in the New York University egistry and the world literature. J Am Acad Dermatol 1997, 36:409-416
Marghoob AA, Schoenbach SP, Kopf AW, Orlow SJ, Nossa R, Bart RS: Large congenital melanocytic nevi and the risk for the development of malignant melanoma. A prospective study. Arch Dermatol 1996, 132:170-175
Clark WH, Elder DE, Guerry D: Dysplastic nevi and malignant melanoma. Farmer ER Hood AF eds. Pathology of the Skin ed 1 1990:pp 729-735 McGraw-Hill, New York .
Bastian BC, LeBoit PE, Hamm H, Bröcker EB, Pinkel D: Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. Cancer Res 1998, 58:2170-2175
Bastian BC, Kashani-Sabet M, Hamm H, Godfrey T, Moore DH, II, Bröcker EB, LeBoit PE, Pinkel D: Gene amplifications characterize acral melanoma and permit the detection of occult cells in the surrounding skin. Cancer Res 2000, 60:1968-1973
Bastian BC, Wesselmann U, Pinkel D, LeBoit PE: Molecular cytogenetic analysis of Spitz nevi show clear differences to melanoma. J Invest Dermatol 1999, 113:1065-1069
Mancianti ML, Clark WH, Hayes FA, Herlyn M: Malignant melanoma simulants arising in congenital melanocytic nevi do not show experimental evidence for a malignant phenotype. Am J Pathol 1990, 136:817-829
Lengauer C, Kinzler KW, Vogelstein G: Genetic instabilities in human cancers. Nature 1998, 396:643-649
Lengauer C, Kinzler KW, Vogelstein B: Genetic instability in colorectal cancers. Nature 1997, 386:623-627
Mitelman F: Catalog of Chromosome Aberrations in Cancer ed 5 1994. Wiley-Liss, New York .
Shah JV, Cleveland DW: Waiting for anaphase: Mad2 and the spindle assembly checkpoint. Cell 2000, 103:997-1000
Schar P: Spontaneous DNA damage, genome instability, and cancer—when DNA replication escapes control. Cell 2001, 104:329-332
Myung K, Chen C, Kolodner RD: Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae. Nature 2001, 411:1073-1076
Myung K, Datta A, Chen C, Kolodner RD: SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination. Nat Genet 2001, 27:113-116
Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100:57-70 [PubMed]
Amon A: The spindle checkpoint. Curr Opin Genet Dev 1999, 9:69-75 [PubMed]
25. Kadonaga JN, Barkovich AJ, Edwards MS, Frieden IJ: Neurocutaneous melanosis in association with the Dandy-Walker complex. Pediatr Dermatol 1992, 9:37-43
ISCN (1995): Report of the Standing Commitee on Human Cytogenetic Nomenclature. An International System for Human Cytogenetic Nomenclature. 1995. S. Karger, Basel .