p16 Expression Is Lost in Severely Atypical Cellular Blue Nevi and Melanoma Compared to Conventional, Mildly, and Moderately Atypical Cellular Blue Nevi
Background. Significant decreases in p16 expression have been shown to occur in melanoma compared to Spitz tumors, and loss of p16 staining has been found to correlate with melanoma tumor progression. However, comparison of p16 between atypical cellular blue nevi (CBN) and melanoma has not been reported previously. Methods. p16 immunohistochemical staining was evaluated in 14 atypical CBN, 8 conventional and atypical melanocytic nevi, and 16 melanomas, including 4 malignant CBN. p16 staining intensity was graded on a scale of 0–3 and the percentage of melanocytes stained with p16 was determined. Results. p16 staining was significantly higher in all CBN as a group when compared to melanomas ( ) and malignant CBN ( ). Higher p16 expression was also seen in mildly ( ) and moderately atypical ( ), but not severely atypical, CBN compared to melanomas. Conclusions. p16 immunohistochemical expression is higher in mildly and moderately atypical CBN compared to severely atypical CBN and melanomas. In conjunction with additional markers and histology, p16 staining may be useful in confirming the benign nature of these tumors, but is not useful in distinguishing severely atypical CBN from malignant cases, consistent with the overlapping histologic features between these tumors. 1. Introduction Distinguishing atypical and unusual variants of melanocytic nevi from melanoma by routine histologic examination can be difficult in some cases [1–3]. In particular, differentiating atypical cellular blue nevi (CBN) from melanoma (including melanoma arising in or mimicking a cellular blue nevus, the so-called “malignant cellular blue nevus”) can pose a significant diagnostic problem [1], and it has been shown that even experienced dermatopathologists often disagree in differentiating CBN, especially atypical CBN, from melanoma [4]. Like melanoma, CBN often lack maturation, can have dermal mitotic figures, extend deeply in the dermis, and may have perineural and even intralymphatic involvement [5]. Immunohistochemistry is a useful tool in the diagnosis of some cases of melanoma, and markers such as S-100, HMB-45, Melan-A, MITF, and the proliferation marker Ki-67 are often used. Ki-67, in particular, has been found useful to distinguish benign from malignant melanocytic lesions [6], but additional markers would clearly be beneficial. p16 is one of the proteins that regulates the G1/S checkpoint of the cell cycle, and it is the product of the tumor suppressor gene CDKN2 [7]. Since loss of p16 expression has been documented to occur in melanoma [8], p16 may be a potential
References
[1]
D. J. Ruiter, M. C. R. F. van Dijk, and C. M. Ferrier, “Current diagnostic problems in melanoma pathology,” Seminars in Cutaneous Medicine and Surgery, vol. 22, no. 1, pp. 33–41, 2003.
[2]
L. Brochez, E. Verhaeghe, E. Grosshans et al., “Inter-observer variation in the histopathological diagnosis of clinically suspicious pigmented skin lesions,” Journal of Pathology, vol. 196, no. 4, pp. 459–466, 2002.
[3]
W. L. Tom, J. W. Hsu, L. F. Eichenfield, and S. F. Friedlander, “Pediatric “sTUMP” lesions: evaluation and management of difficult atypical Spitzoid lesions in children,” Journal of the American Academy of Dermatology, vol. 64, no. 3, pp. 559–572, 2011.
[4]
R. L. Barnhill, Z. Argenyi, M. Berwick et al., “Atypical cellular blue nevi (cellular blue nevi with atypical features): lack of consensus for diagnosis and distinction from cellular blue nevi and malignant melanoma (“malignant blue nevus”),” The American Journal of Surgical Pathology, vol. 32, no. 1, pp. 36–44, 2008.
[5]
R. Murali, S. W. McCarthy, and R. A. Scolyer, “Blue nevi and related lesions: a review highlighting atypical and newly described variants, distinguishing features and diagnostic pitfalls,” Advances in Anatomic Pathology, vol. 16, no. 6, pp. 365–382, 2009.
[6]
S. J. Ohsie, G. P. Sarantopoulos, A. J. Cochran, and S. W. Binder, “Immunohistochemical characteristics of melanoma,” Journal of Cutaneous Pathology, vol. 35, no. 5, pp. 433–444, 2008.
[7]
L. Talve, I. Sauroja, Y. Collan, et al., “Loss of expression of the p16INK4A/CDKN2 gene in cutaneous malignant melanoma correlates with tumor cell proliferation and invasive stage,” International Journal of Cancer, vol. 74, pp. 255–259, 1997.
[8]
B. C. Soares de Sá, M. L. Fugimori, K. D. C. Braga Ribeiro, J. P. Duprat Neto, R. I. Neves, and G. Landman, “Proteins involved in pRb and p53 pathways are differentially expressed in thin and thick superficial spreading melanomas,” Melanoma Research, vol. 19, no. 3, pp. 135–141, 2009.
[9]
Y.-L. Wang, H. Uhara, Y. Yamazaki, T. Nikaido, and T. Saida, “Immunohistochemical detection of CDK4 and p16INK4 proteins in cutaneous malignant melanoma,” British Journal of Dermatology, vol. 134, no. 2, pp. 269–275, 1996.
[10]
A. Sanki, W. Li, M. Colman, R. Z. Karim, J. F. Thompson, and R. A. Scolyer, “Reduced expression of p16 and p27 is correlated with tumour progression in cutaneous melanoma,” Pathology, vol. 39, no. 6, pp. 551–557, 2007.
[11]
N. C. Demirkan, Z. Kesen, B. Akdag, L. Larue, and V. Delmas, “The effect of the sun on expression of β-catenin, p16 and cyclin d1 proteins in melanocytic lesions,” Clinical and Experimental Dermatology, vol. 32, no. 6, pp. 733–739, 2007.
[12]
J. O. Funk, P. I. Schiller, M. T. Barrett, D. J. Wong, P. Kind, and C. A. Sander, “p16INK4A expression is frequently decreased and associated with 9p21 loss of heterozygosity in sporadic melanoma,” Journal of Cutaneous Pathology, vol. 25, no. 6, pp. 291–296, 1998.
[13]
D. Mihic-Probst, C. D. Mnich, P. A. Oberholzer et al., “p16 expression in primary malignant melanoma is associated with prognosis and lymph node status,” International Journal of Cancer, vol. 118, no. 9, pp. 2262–2268, 2006.
[14]
C. Stefanaki, K. Stefanaki, C. Antoniou et al., “G1 cell cycle regulators in congenital melanocytic nevi. Comparison with acquired nevi and melanomas,” Journal of Cutaneous Pathology, vol. 35, no. 9, pp. 799–808, 2008.
[15]
P. Zoroquiain, B. F. Fernandes, S. González, et al., “p16INK4A expression in benign and malignant melanocytic conjunctival lesions,” International Journal of Surgical Pathology, vol. 20, pp. 240–245, 2012.
[16]
B. A. B. de Andrade, J. E. León, R. Carlos, W. Delgado-Aza？ero, A. Mosqueda-Taylor, and O. P. de Almeida, “Immunohistochemical expression of p16, p21, p27 and cyclin D1 in oral nevi and melanoma,” Head and Neck Pathology, vol. 6, no. 3, pp. 297–304, 2012.
[17]
E. George, N. L. Polissar, and M. Wick, “Immunohistochemical evaluation of p16INK4A, E-Cadherin, and cyclin D1 expression in melanoma and Spitz tumors,” The American Journal of Clinical Pathology, vol. 133, no. 3, pp. 370–379, 2010.
[18]
R. Al Dhaybi, M. Agoumi, I. Gagné, C. McCuaig, J. Powell, and V. Kokta, “p16 expression: a marker of differentiation between childhood malignant melanomas and Spitz nevi,” Journal of the American Academy of Dermatology, vol. 65, no. 2, pp. 357–363, 2011.
[19]
N. J. Hilliard, D. Krahl, and K. Sellheyer, “p16 Expression differentiates between desmoplastic Spitz nevus and desmoplastic melanoma,” Journal of Cutaneous Pathology, vol. 36, no. 7, pp. 753–759, 2009.
[20]
P. Ghiorzo, B. Villaggio, A. R. Sementa et al., “Expression and localization of mutant p16 proteins in melanocytic lesions from familial melanoma patients,” Human Pathology, vol. 35, no. 1, pp. 25–33, 2004.
[21]
S. J. Pavey, M. C. Cummings, D. C. Whiteman et al., “Loss of p16 expression is associated with histological features of melanoma invasion,” Melanoma Research, vol. 12, no. 6, pp. 539–547, 2002.
[22]
R. Z. Karim, W. Li, A. Sanki et al., “Reduced p16 and increased cyclin D1 and pRb expression are correlated with progression in cutaneous melanocytic tumors,” International Journal of Surgical Pathology, vol. 17, no. 5, pp. 361–367, 2009.
[23]
R. Keller-Melchior, R. Schmidt, and M. Piepkorn, “Expression of the tumor suppressor gene product p16(INK4) in benign and malignant melanocytic lesions,” Journal of Investigative Dermatology, vol. 110, no. 6, pp. 932–938, 1998.
[24]
S. R. Alonso, P. Ortiz, M. Pollán et al., “Progression in cutaneous malignant melanoma is associated with distinct expression profiles: a tissue microarray-based study,” The American Journal of Pathology, vol. 164, no. 1, pp. 193–203, 2004.
[25]
J. A. Reed, F. Loganzo Jr., C. R. Shea et al., “Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression,” Cancer Research, vol. 55, no. 13, pp. 2713–2718, 1995.
[26]
O. Straume, L. Sviland, and L. A. Akslen, “Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma,” Clinical Cancer Research, vol. 6, no. 5, pp. 1845–1853, 2000.
