PATOGENESI

Br J Haematol 1997 Nov;99(2):375-8

Poor prognosis in non-villous splenic marginal zone cell lymphoma is associated with p53 mutations.

Baldini L, Guffanti A, Cro L, Fracchiolla NS, Colombi M, Motta M, Maiolo AT, Neri A.

Laboratorio di Ematologia Sperimentale e Genetica Molecolare, Istituto di Scienze Mediche dell'Universita, Ospedale Maggiore IRCCS, Milano, Italy.

We have recently reported a series of 15 non-villous splenic marginal zone lymphoma patients, six of whom showed p53 mutations (40%). This molecular alteration did not correlate with any particular clinico-pathologic feature at diagnosis. After a median follow-up of 56 months, four cases evolved into aggressive fatal non-Hodgkin's lymphoma (NHL) and two had refractory progressive disease; interestingly, p53 mutations were demonstrated in five of these patients at diagnosis. As the patients with wild-type p53 presented responsive or indolent disease, this genetic alteration may be an early marker of aggressive transformation or refractoriness. p53 evaluation at diagnosis could be advisable in this particular subset of NHL.

Oncogene 1999 Nov 4;18(46):6271-7

Dysregulation of cyclin dependent kinase 6 expression in splenic marginal zone lymphoma through chromosome 7q translocations.

Corcoran MM, Mould SJ, Orchard JA, Ibbotson RE, Chapman RM, Boright AP, Platt C, Tsui LC, Scherer SW, Oscier DG.

Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.

The increased or inappropriate expression of genes with oncogenic properties through specific chromosome translocations is an important event in the pathogenesis of B-cell lymphoproliferative diseases. Recent studies have found deletions or translocations of chromosome 7q to be the most common cytogenetic abnormality observed in SLVL, a leukemic variant of SMZL, with the q21-q22 region being most frequently affected. In three patients with translocations between chromosomes 2 and 7, the cloning of the breakpoints at 7q21 revealed that each was located within a small region of DNA 3.6 kb upstream of the transcription start site of cyclin dependent kinase 6 (CDK6). In each case the translocation event was consistent with aberrant VJ recombination between the immunoglobulin light chain region (Ig kappa) on chromosome 2p12 and DNA sequences at 7q21, resembling the heptamer recombination site. The t(7;21) breakpoint in an additional patient with splenic marginal zone lymphoma (SMZL), resided 66 kb telomeric to the t(2;7) breakpoints juxtaposing CDK6 to an uncharacterized transcript. In two of the SLVL patient samples, the CDK6 protein was found to be markedly over expressed. These results suggest that dysregulation of CDK6 gene expression contributes to the pathogenesis of SLVL and SMZL.

Clinica e terapia. Clinicamente tutti i pazienti con SMZL, di età di solito avanzata, si presentano con splenomegalia (anche se possono esistere casi con modesta o nulla splenomegalia), variabilmente accompagnata da citopenia, dolori addominali, perdita di peso, ed altri sintomi e segni di minor rilevanza. E’ riscontrabile la presenza di gammopatia monoclonale. Il linfoma è nella stragrande maggioranza dei casi in stadio IV all’esordio per coinvolgimento del midollo e/o del sangue periferico, con linfocitosi (variabile, spesso con le caratteristiche citologiche del linfocita "villoso"). L’andamento clinico è indolente, e la sopravvivenza, anche senza terapia, protratta. Per molti anni i pazienti restano asintomatici e solo raramente si segnala evoluzione verso forme aggressive, talvolta caratterizzate dalla presenza di mutazioni del gene p53 [Baldini L, et al. Br J Haematol 99:375,1997]. La terapia di elezione, quando necessaria, è la splenectomia (o la irradiazione della milza). Quando la splenectomia non è indicata, o in corso di aggravamento della malattia, la fludarabina può costituire una valida alternativa [Berger F, et al. Blood 95:1950,2000].