Looking for familial nodular lymphocyte-predominant Hodgkin lymphoma
Authors: Michele Merli, Margherita Maffioli, Andrea Ferrario, Francesco Passamonti
Journal: American Journal of Hematology (2013)

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare distinct subtype of HL, generally characterized by a more indolent behavior than classical Hodgkin lymphoma (cHL), male preponderance, and a median age at diagnosis of 30–40 years 1. A recent large population-based study 2 reported that first-degree relatives of patients with NLPHL have a 19-fold risk of developing this disease, a 5.3-fold risk of cHL, and 1.9-fold risk of non-HL. To date, a single candidate predisposing mutation has been found by whole exome sequencing in a family with four NLPHL-affected cousins 3. This is a truncating germline deletion of 2 bp, resulting in frame-shift and premature stop codon at serine 819 in exon 13 of the Nuclear Protein, Ataxia-Teleangectasia gene located on chromosome 11q22. Moved by these intriguing findings, we reviewed our institutional database to search for familial clustering of NLPHL. We found two families each with two patients affected by HL (three of the four cases having NLPHL, one having cHL). The pedigrees of the two families are illustrated in Fig. 1a,b. Concerning Family 1, the proband (F1, II:1) is a 47-year-old man, who was diagnosed in December 2006 with stage IVB composite lymphoma (NLPHL and diffuse large B-cell lymphoma). He was treated with six cycles of R-CHOP14, followed by three courses of R-DHAP and autologous stem-cell transplantation, achieving complete remission without recurrence after 8 years of follow-up. In November 2012, his 48-year-old brother (F1, II:2) was diagnosed with NLPHL, stage IIIA. He was scheduled to receive six courses of ABVD and is currently on therapy. Regarding Family 2, the index case (F2, III:3) is a 24-year-old man, who was diagnosed in November 2012 with NLPHL, stage IIISA, now receiving six courses of ABVD. His personal history included testicular cancer (mixed germ cells neoplasm) diagnosed in 2008 and treated with monolateral orchiectomy. His paternal grandmother (F2, I:2) was diagnosed with advanced-stage cHL at the age of 74 years and died thereafter because of disease progression. Taking into account data from the Finnish registry 2 and the few available case-reports 3-6, the two families described in this report allow us to add some considerations. First, the obligate carrier of Family 2 (F2, II:2) is not affected by lymphoma (individual currently aged 57 years). This suggests a low penetrance of the potential predisposing gene mutation, or, alternatively, the co-existence of additional genetic or environmental factors modifying the genetic risk. Second, the earlier onset of disease in subsequent generations, as found in Family 2 (I:2, age 74 years; III:3, age 24 years), supports the concept of disease anticipation, as previously described in HL families 7. Third, the presence of two tumors in patient F2, III:3 is an original finding in the setting of NLPHL families and might suggest a role for mutations involved in DNA repair. In conclusion, recent findings on NLPHL families emphasize the importance of a thorough investigation of family history in patients with this subtype of HL and underline the importance of genotyping such cases to decipher the molecular basis of familial clustering. Michele Merli Margherita Maffioli Andrea Ferrario Francesco Passamonti Division of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi, Viale L. Borri 57, Varese Italy