Abstract
Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite sharing the name and similar morphological features with cutaneous melanoma (CM), it is an entirely different neoplasia with a particular genetic background and clinical behavior. CDKN2A is a gene located at chromosome 9p21, encoding for P16INK4a and P14(ARF) proteins, whose role as a tumor suppressor has been clearly defined in many malignant tumors. CDKN2A frequently presents germline mutations in familial CM and epigenetic downregulation in a considerable percentage of sporadic CM. It has been hypothesized that CDKN2A alterations are early events in CM development, playing a central role in the malignant transformation of melanocytes. Alterations of the CDKN2A gene reduce the expression of P16INK4a in most CM subtypes. Immunohistochemical evaluation of P16INK4a is currently used, in association with Ki67 and HMB45, in pathology practice to discriminate between dysplastic nevi and melanoma. On the other hand, CKDN2A is rarely mutated in UM, and the immunohistochemical expression of P16INK4a has only been reported in small case series. We tested P16INK4a expression on paraffin-embedded tissue sections from 9 tissue microarrays (TMAs), built with 2 mm cores derived from 133 uveal melanoma FFPE blocks, collected from 1990 to 2018, and from selected paraffin-blocks of 3 UM liver metastases. The immunohistochemical expression of P16INK4a was assessed with a visual evaluation by light microscopy and then with a digital approach. Both approaches, with an acceptable concordance rate, revealed P16INK4a expression in a large proportion of UM cases and all liver metastases, opening new possibilities of using it in the differential diagnosis between cutaneous and uveal melanoma metastases in cases of unknown primary tumor or patients with two different primary melanomas.
Highlights
Uveal melanoma (UM) is rare ocular neoplasia with a steady incidence rate in Europe (5–7 cases per million) [1]
We found P16INK4a positivity at immunostaining in 98 out of 127 cases of primary UM tumors and in 3 out of 3 metastases
Uveal melanoma is a rare neoplasia characterized by unpredictable behavior, and, despite the illusory success of local therapies, more than 50% of patients develop metastases within 5 years from diagnosis [31]
Summary
Uveal melanoma (UM) is rare ocular neoplasia with a steady incidence rate in Europe (5–7 cases per million) [1]. P16INK4a Expression in Uveal Melanoma melanoma (CM), UM is characterized by a distinct genetic profile and unique biological and clinical behaviors [3]. About 20% of UM present the L129G-activating mutation in the CYSLTR2 gene, or the D630Y mutation in the PLCB4 gene, both acting in the same pathway of GNAQ and GNA11. GNAQ, GNA11, CYSLTR2, and PLCB4 somatic mutations are crucial in early UM development but are not related to metastatic behavior or a bad prognosis [6]. These mutations are currently considered as precursor events in UM development, with the need for a “second hit” to complete the malignant transformation [7]
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