Expression of p16/INK4a in Posttransplantation Lymphoproliferative Disorders

Abstract

It was recently demonstrated that classification of posttransplantation lymphoproliferative disorders (PT-LPDs) into morphological and molecular categories is clinically relevant. It was also reported that PT-LPD not associated with Epstein-Barr virus (EBV) had a more aggressive course than most lesions associated with EBV. Because the cyclin-dependent kinase inhibitor p16/INK4a has been reported to be frequently inactivated in high-grade lymphomas, we evaluated 17 PT-LPD to determine whether p16/ INK4a expression could be correlated to morphology, EBV detection, and a Ki-67 labeling index. We demonstrated that tumors with no p16/INK4a expression (n ‫؍‬ 8) had a predominantly monomorphic appearance, and most were EBV negative (respectively, 7/8 and 5/8), whereas lesions with p16/INK4a expression (n ‫؍‬ 9) were mostly polymorphic PT-LPD (6/9) (P ‫؍‬ 0.049) and associated with EBV (9/9) (P ‫؍‬ 0.015). In particular, strong p16/INK4a expression was observed in atypical immunoblasts and ReedSternberg-like cells. Furthermore, the proliferation index was significantly higher in tumors lacking p16/ INK4a expression than in other lesions (P ‫؍‬ 0.0008). Lymphoproliferative disorders (LPDs) are a major cause of morbidity in organ transplant recipients receiving immunosuppression, 1,2 varying between 1 and 12% of the graftees, for the most part according to the dose and duration of immunosuppressive therapy and the organ transplanted. 1,3-6 These tumors frequently involve extranodal sites and generally regress with reduction or withdrawal of immunosuppressive therapy, but some of them progress independently from the restoration of the immune system. It has been hypothesized that PT-LPDs arise from a polyclonal expansion of Epstein-Barr virus (EBV)-infected B cells and can evolve into a lymphoid tumor with the emergence of an oligoclonal or monoclonal dominant population. 7 PT-LPDs are usually classified into two subgroups, according to their appearance: polymorphic and monomorphic. 3 The latter closely resembles the diffuse large B-cell lymphoma (DLCL) of the Revised European American Lymphoma (REAL) classification. 8 Based on morphological and molecular analysis, Knowles et al 7 distinguished three main subgroups: 1) plasmacytic hyperplasia, 2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphomas, and 3) malignant lymphoma or multiple myeloma, with the latter group being more frequently associated with genetic alterations, such as the inactivation of tumor suppressor gene p53 and the activation of c-myc and N-ras oncogenes. Moreover, Chadburn et al 9 recently showed the clinical relevance of this classification, as no response to aggressive clinical intervention was more frequently seen in patients with the lesions from the last group than those with the other tumors. Some patients with PT-LPDs that are not associated with EBV have a shorter survival time than those with EBV-positive lesions. 10 Expansion of B cells after organ transplantation should involve an excessive activation of the cell cycle, as in man...

Metallochemistry of Neurodegeneration: Biological, Chemical and Genetic Aspects. By Henryk Kozlowski, David R. Brown, and Gianni Valensin.

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INK4a-ARF alterations in Barrett?s epithelium, intraepithelial neoplasia and Barrett?s adenocarcinoma

“…Aberrant methylation of the p16 INK4a promoter has been reported in carcinomas as well as in early preneoplastic lesions in the lung, stomach, oesophagus and pancreas [1,28]. We examined the status of p14 ARF and p16 INK4a simultaneously to analyse whether alterations in these genes may function as co-operative or alternative mechanisms in the pathogenesis of neoplastic transformation of Barrett's epithelium.…”

p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

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