Nodular lymphocyte-predominant Hodgkin's disease associated with large- cell lymphoma: analysis of Ig gene rearrangements by V-J polymerase chain reaction

Abstract

The clonality of nodular lymphocyte-predominant Hodgkin's disease (NLPHD) and the relationship to composite or sequential large-cell lymphomas (LCLs) is poorly understood. Clonal Ig heavy-chain gene rearrangements (lgHGR) have infrequently been observed in NLPHD by Southern hybridization. The goals of this study were (1) to determine if IgHGR could be identified by polymerase chain reaction (PCR) techniques in the LCL associated with NLPHD; (2) to determine if the lgHGR identified in the LCL could also be found in the associated NLPHD; and (3) to determine if Epstein-Barr virus (EBV) played a role a role in histologic progression to LCL. Using consensus primers to conserved regions in the lgH variable (V) and joining (J) region genes, we analyzed formalin-fixed paraffin-embedded sections from the biopsies of 25 patients referred to the National Cancer Institute (NCI) registry for NLPHD and LCL using both single-step and seminested V-J PCR. The histologically aggressive component was further subclassified as frank LCL or as L&H-cell-rich, but not fulfilling criteria for LCL. Matched samples representing both NLPHD and aggressive components were available in 13 cases. In 12 cases, only one component was available (aggressive, n = 8; NLPHD, n = 4). In addition, we also amplified, with 32P labeling, 12 cases of NLPHD without associated LCL. Two clonal IgHGR were identified in 29 cases (7%) of typical NLPHD, both of which were associated with LCL containing a similar sized band by PCR. The clonal identity of the bands in the NLPHD and associated LCL was confirmed by sequencing the products in these two cases. Eight of 10 cases (80%) of LCL associated with NLPHD contained a clonal band by this technique. By contrast, none of the cases classified as L&H-cell- rich contained an IgHGR. The single-step and seminested PCR methods produced identical results. All clonal LCLs were studied for EBV sequences by in situ hybridization using the EBER1 probe, and were negative. We conclude that the LCLs associated with NLPHD are clonal B- cell malignancies. However, by these methods, the same clone can be identified in only a minority of cases of NLPHD and LCL. EBV does not appear to play a role in histologic progression. Moreover, our results suggest that many cases suspected of being LCL may actually represent NLPHD with increased numbers of L&H cells. In histologically equivocal cases, the diagnosis of LCL should be reserved for those cases in which a clonal B-cell neoplasm can be demonstrated.

Nodular lymphocyte predominant Hodgkin lymphoma and diffuse large B-cell lymphoma: a study of six cases concurrently involving the same site

“…11 Molecular studies have shown that DLBCL is clonally related to NLPHL. 20,21 Most cases appear histologically as conventional DLBCL, as in our cases. 11,19,22 However, cases of TCHRLBL have also been reported.…”

Nodular lymphocyte predominant Hodgkin lymphoma at atypical locations may be associated with increased numbers of large cells and a diffuse histologic component

“…NLPHL typically behaves in an indolent manner and is generally associated with excellent clinical outcomes; however, the presence of a diffuse histologic component is associated with recurrent disease [15] and progression to DLBCL is associated with poor clinical outcome [12]. NLPHL affects men twice as often as women, and involvement of the head and neck, axillary, and inguinal lymph nodes together account for between 90 and 100% of reported sites [8,15,18].…”

“…In contrast, 3-6% of NLPHL will develop aggressive disease in the form of diffuse large B-cell lymphoma (DLBCL). Molecular studies have confirmed a clonal relationship between the L&H cells of NLPHL and the neoplastic B-cells of DLBCL [8][9][10][11][12][13]. As such, it is generally accepted that the development of DLBCL in these cases represents a transformation of the underlying NLPHL.…”

Guidelines for the investigation and management of nodular lymphocyte predominant Hodgkin lymphoma

“…Higher rates of transformation (14%) were reported in a large series from the British Columbia Cancer Agency (BCCA) (Al-Mansour et al, 2010) with a median time to transformation of 8Á1 years. Molecular studies have conclusively demonstrated the clonal relationship between the two diseases (Greiner et al, 1996). Biopsy…”