IGH-Mediated Translocations, Recurrent in Classic Hodgkin Lymphoma, Frequently Correlate with an Aggressive Behavior

Genetic studies of classic Hodgkin lymphoma (cHL) are hampered by a low content of neoplastic Reed-Stenberg cells (RSCs) in tumor mass. Therefore, cytogenetic features of cHL remain poorly characterized. Previous interphase FISH (iFISH) studies, however, suggest that RSCs which carry 'crippling' IGH mutations and lost B cell phenotype, are recurrently featured by t(IGH)-related rearrangements (PMID: 17079453, 18940474).

Recently, we have identified 14q32/IGH aberrations in karyotypes of two patients with nodular sclerosis HL (NSHL) analyzed at time of relapse. The first case showed the classic follicular lymphoma-associated t(14;18)(q32;q21)/IGH-BCL2 rearrangement which correlated with expression of the BCL2 protein (as demonstrated by immunohistochemistry). The second case revealed inv(14)(q11q32)/IGH-CEPBE, originally identified in B cell acute lymphoblastic leukemia. To identify additional cHL cases with 14q32/IGH aberrations and check whether these rearrangements correlate with clinical outcome, we screened by RSC-focused iFISH: (i) 46 relapsed cHL, (ii) 40 cHL with a long-term remission, and (iii) 60 prospective cases. Altogether, IGH rearrangements were detected in 28 patients, including 17 representing the former group (35.4%), four cases representing the second group (10%) and seven prospective cases (11.6%). FISH pattern of LSI IGH suggested a reciprocal t(14q32/IGH) in 20 cases, nonreciprocal t(14q32/IGH) in four cases, inv(14q32/IGH) or ins(14q32/IGH) in three cases and interstitial del(14q32/IGH) in one case. Twenty six cases were further analyzed by iFISH with break-apart (BA) assays for BCL2, BCL3, BCL6 and MYC. In three cases with a presumed inv(14)/ins(14), CEPBE BA was applied. Altogether, we have identified the IGH-BCL2 rearrangement in two cases, including the index case with t(14;18), and the IGH-CEPBE rearrangement in the case with inv(14). All the remaining cases showed a non-rearranged status of the examined loci. The cases were additionally examined with the JAK2/PDLs (9p24) probes; amplification of signals was observed in six cases (21.5%) and FISH pattern suggestive of the PDLs rearrangement was found in two cases (7%). The majority of patients (18/28) with t(14q32/IGH) were diagnosed with NSHL. There were 18 male and 10 female patients in age ranging from 18 to 91 years (mean 50). Patients presented with both early (10/26) and advanced (16/26) stage (two not staged). All were treated with chemotherapy with or without radiotherapy, except for two patients who were subjected to a palliative treatment. After induction therapy, complete and partial remission was achieved in 17 and 5 patients, respectively. Thirteen patients are alive (11 without disease and 2 with disease); 13 patients died, including 11 whose death was related with a disease, and two are lost for follow up. In summary, we confirmed that chromosomal aberrations involving 14q32/IGH occur recurrently in cHL. These rearrangements rarely target BCL2 and CEPBE, and do not affect BCL3, BCL6 and MYC, the oncogenes frequently affected in B-NHL. Interestingly, 17 out of 21 (81%) patients with t(14q32/IGH) and long follow up showed an aggressive behavior. Our study allows a new insight into the pathogenesis of cHL and might help in further stratification of cHL patients.