Review

Nodular Lymphocyte Predominant Hodgkin Lymphoma: Biology, Diagnosis and Treatment Anupama Goel,1,2 Wen Fan,1,2 Amit A. Patel,1 Madhuri Devabhaktuni,1 Michael L. Grossbard1,2 Abstract Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an uncommon variant of classical Hodgkin lymphoma. It is characterized histologically by presence of lymphohistiocytic cells which have B-cell phenotype, are positive for CD19, CD20, CD45, CD79a, BOB.1, Oct.2, and negative for CD15 and CD30. Patients often present with early stage of disease and do not have classical B symptoms. The clinical behavior appears to mimic that of an indolent non-Hodgkin lymphoma more than that of classical Hodgkin disease. The purpose of the present report is to define the biology of NLPHL, review its clinical presentation, and summarize the available clinical data regarding treatment. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Hodgkin lymphoma, LP cell, NLPHL, Popcorn cell, Reed Sternberg cells

Introduction Hodgkin’s lymphoma accounts for approximately 8% of lymphoid malignancies.1 According to the World Health Organization (WHO) classification, Hodgkin lymphomas (HLs) are comprised of 2 disease entities based on the morphologic, genotypic, and phenotypic characteristics.1 Classical HL (cHL), the more common of the 2 entities, can be subdivided into 4 subtypes (nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted) and most practicing oncologists are comfortable with the management of this entity. In addition, many large clinical trials have defined the management for cHL. In contrast, the less common nodular lymphocyte predominant (LP) HL (NLPHL) comprises only 3% to 8% of all Hodgkin cases.2,3 Because of the relative rarity of this entity, there are limited prospective clinical trial data to guide management and most of our knowledge has been acquired through retrospective data analyses. As such, many oncologists remain uncomfortable with treating this entity.

Epidemiology Nodular LP HL is a predominantly male disease with a 3:1 male to female ratio in Caucasian and a 1.2:1 ratio in African American 1

Department of Hematology and Oncology, St Luke’s Roosevelt Hospital Center, New York, NY 2 Mt Sinai Health System Submitted: Oct 17, 2013; Revised: Jan 22, 2014; Accepted: Jan 23, 2014 Address for correspondence: Anupama Goel, MD, Department of Hematology and Oncology, St Luke’s Roosevelt Hospital Center, 1000 10th Ave, Suite 11C-02, New York, NY 10019 Fax: 212-523-2004; e-mail contact: [email protected]

2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.01.006

individuals. It exhibits bimodal age distribution curves—one peak in children and another in adults. In adults, the median age is similar to that of cHL, 30 to 35 years.4

Morphology and Immunophenotype The characteristic cells of NLPHL are LP or popcorn cells (formerly lymphohistiocytic cells [L&H cells]). Histologically, NLPHL shows a nodular growth pattern in most cases. However, in some cases, nodular and diffuse architectures might coexist. The nodules are composed of small lymphocytes and histiocytes with scattered LP cells, few plasma cells, and eosinophils. The LP cells have vesicular polylobulated nuclei and distinct, but small, usually peripheral nucleoli, without perinucleolar halos that are typically surrounded by small lymphocytes (Figs. 1 and 2). In contrast, the key morphologic feature of cHL is the presence of Hodgkin cells (mononucleated giant cell) or Reed-Sternberg cells (multinucleated giant cell) (H-RS cells) in the background of acute and chronic inflammatory cells—plasma cells, eosinophils, histiocytes, and T cells.5 The immunophenotype of NLPHL is significantly different from that of cHL (Table 1).6 LP cells of NLPHL characteristically express B cell-associated antigens—CD19, CD20, CD22, CD79a, and CD45 (Fig. 3). However, they lack CD15 and CD30 expression, a hallmark feature of cHL cells. NLPHL cells also express epithelial membrane antigen in 50% of cases, and transcription factors for B cell development, such as BOB.1 (Fig. 4), Oct.2, PAX5, BCL6, and germinal center marker, but are CD10-negative. The Reed-Sternberg cells of cHL typically express CD15 and CD30 and do not express CD45, J chain, B-cell antigens (CD20, CD79a, etc) or B-cell transcription factors (Oct.2, BOB.1) in most cases. H-RS cells are weakly positive for PAX5. The plasma

Clinical Lymphoma, Myeloma & Leukemia Month 2014

-1

NLPHL Update on Biology, Diagnosis, and Treatment Figure 1 Lymphocyte Predominant (Popcorn) Cells. (A) Low Power and (B) High Power Lymph Node Biopsy Displaying Characteristic Large Multilobated LP Cells With Small Vesicular, Polylobulated Nuclei, and Distinct Peripheral Nucleoli, Without Perinucleolar Halos (Arrows). Hematoxylin and Eosin Stain

Abbreviation: LP ¼ lymphocyte predominant.

cell-specific transcription factor MUM1 is inconsistently expressed in LP cells, whereas in cHL MUM1 is consistently positive in HRS cells with high staining intensity. LP cells are negative for Epstein Barr virus, however positivity can be seen in up to 40% of cHL cases. The background of NLPHL demonstrates an expanded meshwork of follicular dendritic cells, which could be highlighted by CD21 immunostains (Fig. 5). The background cells are composed of small lymphocytes and histiocytes. The lymphocytes are germinal center T-lymphocytes (CD4-positive [CD4þ]/CD57þ) and polyclonal small B lymphocytes with a mantle zone phenotype (immunoglobulin [Ig]MþIgDþ) (Fig. 6).7 The lymphocyte-rich variant of cHL (LRCHL) has some morphological similarities with NLPHL and often has a similar clinical presentation and disease course. LRCHL commonly demonstrates a nodular pattern; the nodules are composed of expanded mantle zone B cells (IgMþIgDþ) with eccentric regressed germinal centers without eosinophils, plasma cells, or neutrophils. The H-RS cells can be seen in the nodules or between the nodules. Immunophenotyping is needed to differentiate LRCHL from NLPHL;

the H-RS cells in the LRCHL are positive for CD15 and CD30, and negative for CD20 and CD45. It also is important to distinguish T-cell/histiocyte rich B-cell lymphoma (T/HRBCL), a variant of diffuse large B-cell lymphoma (DLBCL), from NLPHL because they both share similar morphology and immunophenotype. In NLPHL, tumor cells are characteristically LP cells, in a background meshwork of follicular dendritic cells, abundant small B cells, and mainly CD4þ/CD57þ follicular T cells forming rosettes. In T/HRBCL, most tumor cells resemble centroblasts and immunoblasts, with only some LP-like cells and only scarce RS-like cells in the background of absent follicular dendritic cells (FDC), rare small B lymphocytes, T cells (which are mainly CD8þ cytotoxic T cells), and histiocytes with rare formation of T-cell rosettes. NLPHL and T/HRBCL share many immunophenotypic features, with the exception that CD79a and BCL2 are more frequently expressed in T/HRBCL. Moreover, the transcription factor PU.1, which is necessary in early B cell differentiation, is reduced or absent in T/HRBCL, but variably expressed in NLPHL. In NLPHL, neoplastic cells inside FDC networks appear to have an increased expression of J chain and

Figure 2 Lymph Node Biopsy (A) Low Power and (B) High Power Lymph Node Biopsy Displaying Characteristic LP Cells in a Background of Small Lymphocytes and Follicular Dendritic Cells. Classic Rosette Formation Around the LP Cells can be Seen. Hematoxylin and Eosin Stain

Abbreviation: LP ¼ lymphocyte predominant.

2

-

Clinical Lymphoma, Myeloma & Leukemia Month 2014

Anupama Goel et al Table 1 Morphologic and Immunophenotypic Features of NLPHL Compared With cHL, LRCHL, T/H RBCL, and PTGC Feature

NLPHL

Pattern

Nodular (at least in part)

Tumor Cell

LP (popcorn cells)

Background

CD15 CD30 CD20 PAX5 CD45 EMA Oct.2 BOB.1 CD57þ

Small B lymphocytes, CD57 T-cells, histiocytes, and expanded FDC meshwork   þ þ þ þ/ þ þ T-Cells Increased

cHL

LRCHL

Diffuse, interfollicular, nodular RS cells and variants

Nodular or interfollicular RS cells and variants

Lymphocytes, histiocytes, eosinophils, plasma cells þ þ /þ þ (Weak)   /þ /Rare þ 

Predominantly small B lymphocytes, rarely or no eosinophils þ þ  þ (Weak)   /þ /Rare þ 

T/H RBCL Usually diffuse Centroblast, immunoblast, or RS-like cells T cells and histiocytes no small B cells or CD57þ T cells  /þ þ þ þ þ/ þ þ 

PTGC Well circumscribed nodules No LP cells present Small B lymphocytes replace germinal center with increased CD57 T cells e e e e e e e e Increased

Lymphocyte predominant cells that are positive for B-cell markers (CD20, PAX5, CD45, CD79a, BOB.1, and Oct.2, and negative for CD15, and CD30) within the background of a fully or partially nodular growth pattern. The background cells consist of small B cells, CD3þCD4þCD57þ T-cells, and CD21þ follicular dendritic cells. Abbreviations: cHL ¼ classical Hodgkin lymphoma; EMA ¼ epithelial membrane antigen; FDC ¼ follicular dendritic cells; LP ¼ lymphocyte predominant; LRCHL ¼ lymphocyte-rich classical Hodgkin lymphoma; NLPHL ¼ nodular lymphocyte predominant Hodgkin lymphoma; PTGC ¼ progressive transformation of germinal centers; RS ¼ Reed-Sternberg; T/H RBCL ¼ T-cell/histiocyte-rich B-cell lymphoma. Adapted with permission from Devita et al 9th edition.6

PU.1 compared with cells in the same tumors that appear outside of the meshwork and express more CD79a and BCL2. This subtle disparity between the phenotypes of tumor cells seems to reflect their relationship to the FDC meshworks. However, these immunophenotypic changes do not aid in differentiating between NLPHL and T/HRBCL with absolute certainty.8 According to the current WHO criteria, at least 1 nodule showing typical features of NLPHL is needed to make a diagnosis of NLPHL. Some clinicians believe that both of these tumors might be a biologic continuum of a similar process. Another condition that might resemble NLPHL and requires distinction is progressive transformation of germinal centers (PTGC). This is characterized by development of an asymptomatic persistent lymphadenopathy typically involving peripheral lymph

nodes. Histopathologically, it is characterized by the presence in a lymph node of 1 or more nodules, 3 to 5 times the size of a reactive follicle, with mantle zone small B cells infiltrating and expanding the residual germinal centers. Immunophenotypically, like NLPHL, the nodules of PTGC are composed of IgMþIgDþCD20þ small mantle zone B cells with increased CD4þCD57þ T cells; however, it does not have the LP cells or the T-cell rosette formation on morphology. PTGC might precede, follow, or occur concurrently with HL. Nevertheless, most patients do not develop NLPHL. It is not considered a premalignant condition.9

Biology Lymphocyte predominant cells and H-RS cells are derived from germinal center B cells.10-12 Both show somatically mutated Ig

Figure 3 CD20 Stain Shows Nodules of Small B Cells (Low Power) and LP Cells are Positive for CD20 (High Power). (A) Low Power. (B) High Power

Abbreviation: LP ¼ lymphocyte predominant.

Clinical Lymphoma, Myeloma & Leukemia Month 2014

-3

NLPHL Update on Biology, Diagnosis, and Treatment Figure 4 Lymphocyte Predominant Cells are Positive for BOB.1

Figure 6 Increased CD57 T-Cells in the Nodules

variable gene rearrangements. Ig expression is detected at the RNA and protein level in LP cells but not in H-RS cells. In cHL, the acquisition of somatic mutations by the tumor clone is at least partially independent of selection for antigen receptor expression whereas in NLPHL the tumor clone shows evidence of selection for antigen receptor expression. In addition, evidence of ongoing somatic hypermutation in the Ig variable regions is seen in NLPHL, but rarely in cHL.13 The H-RS cells show downregulation of B cellspecific transcription factors, likely contributing to the lost B-cell antigen expression by H-RS cells. Marafioti et al demonstrated that a number of B-cell signal transducing molecules are absent or decreased in H-RS cells, whereas they are largely preserved in LP cells and in non-Hodgkin B-cell lymphomas.14 Hence, it appears that NLPHL cells depend on the signals produced by the Ig receptor within the background of expanded B-cell follicles for their growth and survival. In contrast, H-RS cells of cHL appear to be independent of Ig receptor signaling and instead depend on alternative receptors like CD30 and CD40 for their growth and survival.

Diagnosis

Figure 5 CD21 Stain Shows Expanded Meshwork of Follicular Dendritic Cells

4

-

Clinical Lymphoma, Myeloma & Leukemia Month 2014

Before the routine use of immunohistochemical studies, a number of lymphomas, including NLPHL, cHL, and certain nonHLs (NHLs), were easily confused. This is well demonstrated in a study from the European Task Force on Lymphomas (ETFL), in which clinical data and biopsy material were collected from 426 patients with presumed NLPHL based on the Rye classification system.2 After the biopsy specimens were meticulously reviewed using the stringent morphologic and immunophenotypic criteria of the REAL (Revised European e American Lymphoma classification) classification system (presence of atypical cells, LP or popcorn cells, absence of Reed-Sternberg cells, positive for CD20 and CD45, and negative for CD15 and CD30), 51% were confirmed to be NLPHL, and 27% were reclassified as lymphocyterich cHL. The findings of this study emphasize the importance of careful pathologic study of all new diagnoses of NLPHL including morphologic and immunophenotypic study (Table 1). Fan et al have further described different histopathological variants of NLPHL. A typical pattern includes a B-cell rich nodular pattern (pattern A) or a serpiginous interconnected pattern (pattern B), with predominately nodular growth and LP cells and nonneoplastic B cells in the nodules. Histological variants are described as prominent extranodular LP cells (pattern C), T-cell rich, B-cell depleted (pattern D), diffuse T-cell/histiocyte-rich pattern (pattern E), or diffuse moth-eaten pattern (pattern F).15 Recently, the German Hodgkin Study Group (GHSG) published the results of their analysis of prognostic significance of these histological variants. They reviewed the biopsies of 423 NLPHL patients from 9 different studies and classified them into 3 categories, typical NLPHL (n ¼ 308) presenting only with pattern A and/or B, histopathological variant (n ¼ 105) with at least 1 major or minor B, C, D, E, or F pattern, or tumor cell-rich cases with a high number tumor cells presenting as focal sheets. Their study demonstrated that the histological variant group had a higher stage at presentation (29.5% vs. 14.6%) and also a higher relapse rate at 5 years (18% vs. 6.5%). Based on this study, they have developed a prognostic score which includes histolopathological variants and clinical features (sex and albumin) in defining 3 risk groups. It is

Anupama Goel et al 83.3% in the early unfavorable stage, and 76.8% versus 77.8% in the advanced stages of NLPHL compared with cHL, respectively (Table 3). At a median follow-up of 50 months, overall survival (OS) was 96% versus 92% (P ¼ .0166) for NLPHL and cHL, respectively. There were statistically significant differences favoring NLPHL in terms of progressive disease (0.3% vs. 3.9%; P < .0001), mortality (4.6% vs. 9.6%; P ¼ .0004), and early relapses (0.8% vs. 3.2%; P ¼ .0037). However, there were more late relapses in NLPHL compared with cHL, 7.4% versus 4.7% (P ¼ .0226), respectively.

conceivable that this prognostic score might aid in the future to decide optimal treatment options for the patients, but presently its utility with respect to defining therapy is limited.16

Clinical Presentation Patients with NLPHL more often present with early stage disease that follows a more indolent course than cHL, and commonly present with asymptomatic, chronic lymphadenopathy involving peripheral lymph nodes—typically upper neck, epitrochlear, and inguinal lymph nodes. At presentation, 70% to 80% of patients have either stage I or stage II disease compared with 50% to 70% in cHL. Based on published studies, the average stage distribution of NLPHL is 49% for stage I, 24% for stage II, 20% for stage III, and 7% for stage IV. Classical B symptoms are present in approximately 6% to 15% of the cases. Liver and spleen involvement can be seen in approximately 3% to 8% of patients, bone marrow involvement in 1% to 2%, and rare lung and skeletal involvement in 1% to 4%.2,17-20 However, most of our knowledge for this rare disease comes from analysis of 2 seminal studies, the ETFL and the GHSG analysis.2,20 Of the total 219 cases of NLPHL in the ETFL study, 53% were stage I, 28% were stage II, 14% were stage III, and only 6% were stage IV compared with 115 cases of cHL, in which 46% were stage I, 24% stage II, 24% stage III, and 6% stage IV.2 Similarly, in the GHSG analysis of 394 NLPHL cases, 63% of patients were in early stage (stage I/II), 16% in the intermediate stage (stage III), and 23% in the advanced stage (stage IV) compared with 7904 cases of cHL and determined that 22% were in early stage, 39% in the intermediate stage, and 39% in the advanced stage (Table 2). Presence of B symptoms were equally distributed in the ETFL study; 10% of patients had NLPHL versus 11% of patients had cHL. However, in the GHSG analysis, the percentage of patients with B symptoms were much higher in the cHL group compared with NLPHL; 40% versus 9%, respectively. Overall, NLPHL appears to have a more indolent course and a better prognosis than its counterpart cHL, as observed in several large retrospective analysis studies.2,19,20 In the GHSG analysis, after first-line treatment, complete remission (CR) and near CR was 91.6% versus 85.9% in the early favorable stage, 85.7% versus

Treatment Considering the relatively low incidence of NLPHL, there are no randomized trials comparing stage-adapted treatment programs in these patients. The treatment options vary widely and include surgical excision alone, radiotherapy alone, combination radiation and chemotherapy, and monoclonal antibody therapy. One of the largest analyses was reported by Diehl et al, who evaluated 426 LP Hodgkin disease (LPHD) assessable cases from 17 different centers.2 The 8-year Hodgkin disease-specific survival in the LPHD group was 99%, 94%, 94%, and 41% for stage I, II, III, and IV disease, respectively. There were more relapses in the NLPHL group compared with the cHL group, 21% versus 17% respectively, though the difference was not statistically significant. Of these patients, 27% in the LPHD group had multiple relapses which were significantly more than the 5% of relapsing NLPHL. However, LPHD patients had significantly longer survival compared with cHL Hodgkin disease patients after relapse which was attributed partly to the younger average age of LPHD patients.

Stage I and II Disease The indolent nature and favorable prognosis of adult patients with early-stage NLPHL suggest that observation alone is a viable treatment option. This was demonstrated in 2 case series. In 1983, Miettinen et al published a case series of 51 patients diagnosed with NLPHL, mostly staged as clinical stage IA. Of these, 31 patients were treated with tumor excision followed by observation only. After a median follow-up of 7 years, the actuarial survival rates were

Table 2 Patient Characteristics: NLPHL and cHL Characteristic Patients Median Age, Years Male Sex, % Stage I/II, % Stage III, % Stage IV, % Early Favorable, % Early Unfavorable, % Advanced Stage, % Mediastinal Bulky Mass, % B Symptoms, %

ETFL

GHSG

NLPHL (n [ 219)

cHL (n [ 115)

NLPHL (n [ 394)

cHL (n [ 7904)

35 74 80 14 6 e e e 7 10

43 69 70 24 6 e e e 15 11

37 75 e e e 63 16 21 31 9

33 e e e e 29 39 39 55 40

The early favorable group includes stage I and II without risk factors; the early unfavorable group includes stage I and II with risk factors; and the advanced stage group includes stage IIB with risk factors, stage III, and IV. Risk factors include large mediastinal mass, > 3 nodal lesions, extranodal lesions, massive spleen, ESR > 50 mm without B symptoms, and ESR > 30 with symptoms. Abbreviations: cHL ¼ classical Hodgkin lymphoma; ESR ¼ ---; ETFL ¼ European Task Force on Lymphomas; GHSG ¼ German Hodgkin Study Group; NLPHL ¼ nodular lymphocyte predominant Hodgkin lymphoma.

Clinical Lymphoma, Myeloma & Leukemia Month 2014

-5

NLPHL Update on Biology, Diagnosis, and Treatment Table 3 German Hodgkin Study Group Response Analysis CR/nCR After First-Line Therapy Stage at Presentation

cHL (n [ 7904)

LPHL (n [ 394)

cHL

LPHL

22 39 39

63 16 21

85.8 83.3 77.8

91.6 85.7 76.8

Early Favorable Early Unfavorable Advanced Stage

Data are presented as percentages. Complete remission or nCR after first-line therapy for cHL versus LPHL based on stage classification. Abbreviations: cHL ¼ classical Hodgkin lymphoma; CR ¼ complete remission; LPHL ¼ lymphocyte predominant Hodgkin lymphoma; nCR ¼ near complete remission.

88% at 5 years and 70% at 10 years. Of these 31 patients, 7 had died with 1 death attributed to HL and 2 deaths to NHL.21 Another similar report by Hansmann et al support the idea of long-term survival after resection of early-stage disease with no further treatment.22 However, these observations must be interpreted cautiously because the accuracy of diagnosis was limited in the absence of immunophenotyping.

Locoregional Radiation Therapy

6

-

This strategy has been evaluated in few retrospective series for patients with early-stage NLPHL. Schlembach et al analyzed 36 cases of nonbulky stage IA (n ¼ 27) and IIA (n ¼ 9), supradiaphragmatic (n ¼ 27) or subdiaphragmatic (n ¼ 9) LPHD treated with radiation alone at M.D. Anderson Cancer Center from 1963 to 1995. Median dose to involved fields (IFs) was 40.0 Gy. After a median follow-up of 8.8 years (range, 3.0-34.4 years), 5-year relapse-free and OS rates for the 20 patients with stage IA LPHD treated with involved field (IF) radiation therapy (RT) (IFRT) or regional RT were 95% and 100%, respectively. The authors concluded that IFRT or regional RT might be adequate for stage IA LPHD.23 However, when compared with cHL in which most recurrences take place within 24 months, relapses in this study occurred relatively late, ranging from 2 years to 12.9 years. Among the 7 relapses, 5 occurred outside the radiation field. Wirth et al, from the Australian Radiation Oncology Lymphoma Group, reported another large retrospective analysis of 202 patients with stage I and II LPHL treated with radiotherapy alone between 1969 and 1995. Most of the patients had stage I disease with supradiaphragmatic involvement alone seen in 80% of patients. The median RT dose was 36 Gy and the RT fields included full mantle (n ¼ 52%), less than full mantle (n ¼ 24%), and inverted Y field (n ¼ 7%). After a median follow-up of 15 years, OS was 83% and freedom from progression was 82%, including 84% for patients with stage I disease and 73% for patients with stage II disease. In multivariate analysis, increased age (older than 45 years), presence of B symptoms, and number of involved sites (< 3 vs.  3) were found to be independent prognostic factors for OS. Causes of death at 15 years were LPHL in 3%, NHL in 2%, in-field malignancy in 2%, and in-field cardiopulmonary complications in 4% of patients. The authors concluded that RT might be potentially curative for patients with stage I and II LPHL and suggested that limited field RT might be used without loss of treatment efficacy.24 In another observational study by Chen et al, 93 of 113 patients were treated with radiation alone.25 Of these, 22% received limited radiation, 31% regional, and 41% received extended field (EF)

Clinical Lymphoma, Myeloma & Leukemia Month 2014

radiation. At 10 years, progression-free survival (PFS) was 89% and 72% and OS was 96% and 100% for stage I and II, respectively. However, at 15 years PFS was 76% and 50% for stage I and II, respectively, with OS of 89%. After adjusting for clinical stage and sex, the extent of RT was not significantly associated with PFS or OS. These studies support the fact that radiotherapy alone, with limited field RT, might lead to sustained disease control and provide long-term survival rates, albeit with a significant risk of late relapse.

Radiotherapy With and Without Chemotherapy Radiotherapy with or without chemotherapy has been examined in several studies for limited and advanced stages. In a retrospective analysis from M.D. Anderson Cancer Center, Wilder et al compared the OS and relapse-free survival outcomes in early-stage NLPHL patients treated with radiotherapy alone or with chemotherapy followed by RT.26 A total of 48 patients with stage I (n ¼ 30) and stage II (n ¼ 18) were followed for a median of 9.3 years. Thirty-seven patients received RT alone (median dose, 40 Gy) and 11 patients received chemotherapy with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) or NOVP (mitoxantrone, vincristine, vinblastine, and prednisone) for a median of 3 cycles, followed by RT. At 10 years, relapse-free survival and OS for RT alone compared with chemotherapy with radiation was 77% versus 88% (P ¼ .89), and 90% versus 100%, respectively. Addition of chemotherapy did not reduce the risk of recurrence outside of the radiation fields and did not improve relapse-free survival or OS rates in this small series. However, the number of patients are small and MOPP is not a therapy that would be offered by most practicing oncologists at present because of the risks of secondary leukemia and infertility. In another study, Feugier et al conducted a retrospective analysis of long-term outcomes of patients with NLPHL and cHL at clinical stages IA and IIA treated with brief anthracycline-based chemotherapies plus extended high-dose radiation.27 In this study, 42 patients had early-stage NLPHL, and all patients received 1 to 3 cycles of anthracycline-based chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), or EBVM (epirubucin, bleomycin, vinblastine, methotrexate, and methylprednisolone), and patients who achieved either CR or PR received EF RT up to 30 to 40 Gy. The 15-year HL mortality rates were low in patients with NLPHL (2.4%) and OS rate was 88%. Again, this study failed to define the relative contributions of chemotherapy and RT to outcome. Moreover, treatment was variable with some patients receiving only 1 cycle of ABVD or alternate chemotherapy. It also is possible that EBVM might not have efficacy similar to ABVD.

Anupama Goel et al Nogová et al reported a retrospective series of 131 cases of favorable clinical stage IA LPHL from 3 GHSG clinical trials; HD4, HD7, and HD10.19 In this series, 45 patients were treated with EF radiotherapy, 45 patients with IF radiation, and 41 patients received combined modality (CM) treatment (2-4 cycles of ABVD plus EF/IF radiotherapy). After a median follow-up of 43 months, a total of 129 of 131 patients (99%) achieved CR/complete response (unconfirmed): 98% after EF, 100% of patients after IF, and 98% after CM. The OS rates were 94%, 100%, and 96%, respectively, again questioning the role of systemic chemotherapy beyond radiation. In a recent publication, Savage et al questioned the approach for RT alone.28 These investigators collected data form the British Columbia Cancer Agency for 2 different eras, patients treated with RT alone (n ¼ 32, before 1993) and those treated with ABVD-like chemotherapy (n ¼ 42) or AVD (doxorubicin, vinblastine, dacarbazine) chemotherapy (n ¼ 14) for 2 cycles followed by RT (n ¼ 56, 1993-2011). In an era to era comparison, the 10-year time to progression was 76% versus 98% (P ¼ .0074), PFS 65% versus 91% (P ¼ .0024), and OS 84% versus 93% (P ¼ .074) for RT alone compared with chemotherapy with RT, respectively. Potential reasons for the poorer than expected outcome for the RT-alone cohort could be inclusion of patients dating back as far as 4 decades with the potential for pathological misdiagnosis and understaging due to the absence of modern staging modalities like computed tomograpy imaging. However, this study does provide a strong rationale for treating limited-stage NLPHL similar to cHL with CM; a short course of chemotherapy with radiation.

Stage III and IV Disease Most patients with NLPHL present at an early stage, with stage III or IV NLPHL being a rare entity. Most of the stage III and IV patients have disease that already has transformed to DLBCL. In the absence of data from prospective clinical trials, the treatment of advanced staged disease also is guided by retrospective studies. In most of the published reports, patients have been treated with MOPP or ABVD-like regimens. In the GHSG, complete and near complete response was 85% and 76% in patients with early unfavorable and advanced stage disease, respectively. At a median observation of 50 months, HL-specific freedom from treatment failure was 87% in early unfavorable patients and 77% for patients with advanced stage disease.

Appropriate Systemic Chemotherapy Regimen A literature review revealed that there have been no prospective series of specific regimens published for patients with NLPHL requiring systemic chemotherapy. As mentioned, radiation with and without chemotherapy using standard Hodgkin disease protocols can lead to complete responses in more than 95% of patients. However, this might not be the optimal approach for LPHD patients, secondary to associated significant later toxic effects, including secondary malignancies. In the ETFL study, at least as many patients died from secondary malignancies, as died of lymphoma itself.2 There are very limited data suggesting that an alkylating agentcontaining regimen might be the preferred therapy for treatment

of LPHL.19 In a study by Bodis et al, 16 patients received chemotherapy initially or at first relapse.19 Eight of 12 patients treated with MOPP or MOPP-like regimen as primary or salvage therapy sustained a durable complete response, compared with 2 of 6 patients treated with ABVD. It is, therefore, appropriate to consider initial regimens containing an alkylating agent, such as cyclophosphamide, vincristine, and prednisone, similar to the therapy for low-grade NHL. Recently, Shankar et al reported their experience with cyclophosphamide, vinblastine, and prednisone in children and adolescents with early stage NLPHL.29 Forty-five patients with early-stage disease were treated with this regimen as first-line therapy. Complete response or near complete response was observed in 80% of the patients with a 40-month freedom from treatment failure and OS of 75% and 100%, respectively. The addition of an anthracycline and/or bleomycin might not have an additive benefit and exposes the patient to unnecessary cardiac and pulmonary toxicities.

Role of Rituximab Since the classic LP cells of NLPHL express the CD20 B-cell surface antigen, rituximab (R) has been evaluated as a potential treatment option in at least 3 clinical trials for upfront treatment of patients with NLPHL and in 2 studies in relapsed disease (Table 4).30-34 The GHSG recently published their experience with R in patients with newly diagnosed stage IA NLPHL.30 In this phase II study, 28 patients with stage IA NLPHL received 4 weekly treatments of R 375 mg/m2. They reported an overall response rate of 100% with complete response rate in 85% of the patients. At a median follow-up of 43 months, OS was 100% with PFS of 96%, 85%, and 81% at 12, 24, and 36 months, respectively. There were 7 relapses and 2 patients developed secondary malignancy. All relapses were successfully salvaged, and there was no case of transformation to NHL seen in the patients included in this trial. These results appear to be only slightly inferior when compared with radiotherapy alone or combined radiotherapy and chemotherapy, and report fewer side effects. In a second study, only reported as an abstract, 19 patients with newly diagnosed NLPHL disease, stages I to III (stage 1 ¼ 9, stage II ¼ 7, and stage III ¼ 6 patients), were treated with R alone as their front-line treatment.31 Patients received R 375 mg/m2 weekly for 4 doses and then after protocol amendment, R followed by 4 doses of R maintenance (RM) every 6 months for 2 years. Ten patients received R alone and 9 received R and RM. The overall response rate was 100% after R induction alone. The median PFS was 50 months and 67 months, for R and R and RM, respectively. Ten patients progressed (5 each in the R and the R and RM arm) with 6 having biopsy proven transformation. Five of the transformed patients had stage III abdominal disease at presentation. The authors concluded that R alone is an active single-agent treatment option for patients with NLPHL with a median PFS of 5.6 years, and that abdominal involvement was associated with high risk of transformation. Another study reported only as an abstract by Fanale et al from M.D. Anderson Cancer Center showed excellent results with an R-containing alkylating agent-based regimen.32 In this observational study, a total of 15 patients received R-CHOP (R with

Clinical Lymphoma, Myeloma & Leukemia Month 2014

-7

NLPHL Update on Biology, Diagnosis, and Treatment Table 4 Role of Rituximab Setting

Stage

n

Schedule of R

Results

Newly Diagnosed Eichenauer et al30

Stage IA

28

375 mg/m2 q. week for 4 doses

ORR/CR: 100/85% At a median follow up of 43 months, PFS 81%

Advani et al31

Stage I to III

19

375 mg/m2 q. week for 4 doses and later R maintenance with 4 weekly R every 6 months for 2 years

ORR: 100%; estimated PFS at 5 years: 51%

Fanale et al32

Stage I to IV

15

R-CHOP

ORR/CR: 100%/90%

Schulz et al33

Relapsed or refractory

15

375 mg/m2 q. week for 4 doses

ORR: 94% (8 patients with CR). At a median follow-up of 63 months, PFS, 33 months

Ekstrand et al34

Relapsed and newly diagnosed

22

375 mg/m2 q. week for 4 doses

ORR/CR: 100%/41%; median time to progression, 10.2 months

Relapsed

Abbreviations: ORR ¼ overall response rate; PFS ¼ progression-free survival; q. ¼ ---; R ¼ rituximab; R-CHOP ¼ rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone.

cyclophosphamide, doxorubicin, vincristine, prednisone) alone (4 stage I/II and 11 stage III/IV) and 5 patients received R-CHOP with IFRT. They reported an overall response rate of 100% with a complete response rate of 90%, and at a median follow-up of 42 months there have been no reported transformation or relapses. These limited data suggest that patients with advanced stage NLPHL might be best treated with regimens akin to low-grade Bcell lymphoma, R alone for patients with stage I disease, and R-CVP (rituximab, cyclophosphamide, vincristine and prednisone) or R-CHOP for patients with advanced-stage disease.

Relapsed/Refractory Disease

8

-

Late relapses are quite common in patients with LPHD compared with cHL. Despite a high initial response rate, including a significant complete response rate, LPHD continues to relapse continuously over time, with relapses frequently occurring beyond 5 years after initial treatment.2,19 Two phase II studies have been published that explore R therapy for patients with recurrent disease. Rehwald et al from the GHSG evaluated 14 patients with relapsed/refractory NLPHL treated with weekly R at doses of 375 mg/m2 for 4 weeks. The median time since initial diagnosis was 9 years and the median number of relapses was 2. All patients had received at least 1 previous cytoreductive chemotherapy regimen and/or radiotherapy, including autologous peripheral stem cell transplantation in 2 patients. The overall response rate was 86%, with 8 CRs and 4 partial remissions. Two patients had progressive disease. Of the 12 responders, 9 remained in remission after 12 months and the median duration of response was not reached at 20 months.35 In a follow-up report in 15 patients, published in 2008, the overall response rate was 94% with 8 CRs. At a median follow-up of 63 months, median time to progression was 33 months, and OS had not been reached.33 In another study, Ekstrand et al evaluated 22 patients with CD20þ LPHD treated with R 375 mg/m2 weekly for 4 weeks.34 Of these 22 patients, 10 had relapsed disease and 12 patients had previously untreated disease. The overall response rate was 100% with CR in 41%, CRu in 5%, and PR in 54%. With a median follow-up of 13 months, 9 patients had relapsed, and estimated

Clinical Lymphoma, Myeloma & Leukemia Month 2014

median freedom from progression was 10.2 months. Patients with relapsed disease had responses similar to those of untreated patients. In both of these trials, R was well tolerated with toxicity limited to minimal, transient infusional reactions. This evidence demonstrates the role of R as a potential treatment option for patients with relapsed/refractory NLPHL. Rituximab therapy can provide long-term remission in some patient but not in all. As such, high-dose therapy also remains a treatment consideration. Karuturi et al recently published their experience on autologous stem cell transplant (ASCT) after highdose chemotherapy in 26 patients with relapsed NLPHL. At the time of relapse 18 (70%) patients had histology consistent with NLPHL and 8 (33%) patients had transformed to large-cell lymphoma.36 Median time to transplantation from diagnosis was 35 months, and the most commonly used conditioning regimen was BEAM-R (carmustine, etoposide, cytarabine, melphalan, and R). At a median follow-up of 5 years, they reported event free survival (EFS) and OS of 61% and 73% in patients with NLPHL and 87% EFS and 87% OS in patients with large-cell lymphoma at the time of transplantation. Similarly, Jackson et al reported a median failure-free survival of 39.2 months in 8 patients with NLPHL who received ASCT.37 These 2 studies suggest ASCT as a reasonable and potential curative option in patients with relapsed or refractory NLPHL.

Transformation to DLBCL Studies have reported histological transformation rates of NLPHL to DLBCL ranging from 0% to 10%. One of the earlier studies from the Nebraska Lymphoma Study Group reported 21 cases of DLBCL arising either concurrently with NLPHL (n ¼ 7) or sequential to the diagnosis of NLPHL (n ¼ 14). In their study, the median time to development of DLBCL was only 1 year (range, 0.5-24 years) and patients had a median OS of 35 months after transformation.38 A clinical registry was launched from 1973 to 2003 in France to determine the histologic transformation rate of NLPHL to DLBCL and to assess long-term outcomes.39 All patients underwent biopsy at the time of relapse. They identified 164 patients with NLPHL,

Anupama Goel et al and at a median follow-up of 9.5 years, 66 patients developed disease recurrence. Most of the recurrences were NLPHL. However, 19 patients had DLBCL with a 10-year transformation rate of 12%. Median time to transformation was 4.7 years, and histological transformation was the first relapse in 68% of cases (13 of 19 patients). All patients were treated with a curative intent. Nine patients received high-dose chemotherapy with subsequent ASCT, and 10 patients received different chemotherapy regimens. The OS rate at 10 years was 60%. The analysis did not identify any clinical features that were associated with high risk of recurrence, and OS was not affected whether patients received ASCT or nonmyeloablative therapy. At the 2012 American Society of Hematology meeting, 2 abstracts were presented that reported on the outcomes of patients who had transformed to DLBCL from NLPHL. The Mayo Clinic lymphoma database identified 222 patients with a diagnosis of NLPHL between 1970 and 2010.40 At a median follow-up of 20 years, 17 patients (7.7%) developed transformation to DLBCL. The median time to transformation was 35 months, with transformation diagnosed at first relapse in 12 patients (70.6%). The remaining 5 patients developed 1 or more NLPHL relapses before transformation. Most patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CHOP-like regimens and 2 underwent ASCT. The OS rate was 76.4% at 5 years, calculated from the time of transformation. Xing et al presented outcomes of 42 patients with advanced stage NLPHL.41 Relapses were seen in 20 patients (48%); 12 patients (60%) had NLPHL and 8 (40%) aggressive NHL at the time of relapse. Median time to relapse was 5.4 years and they reported the risk of transformation as 12%, 15%, 20%, and 30% at 5, 10, 15, and 20 years, respectively. In their study, spleen involvement and initial mass size of > 5 cm were identified as risk factors for transformation.

Conclusion In general, the prognosis for NLPHL patients appears to be better than its counterpart, classical Hodgkin disease. This might be partly explained by early stage of presentation, absence of B symptoms, absence of bulky disease, and better response rates with salvage therapy after relapse. The clinical behavior of NLPHL appears to mimic that of an indolent NHL more than that of cHL. The published literature supports the use of radiation alone for early favorable stage NLPHL and the combination of RT and chemotherapy or chemotherapy alone for early unfavorable and advanced-stage NLPHL. However, the optimal treatment of NLPHL remains far from certain and there also are data to endorse the use of single-agent R for the treatment of advanced-stage disease. NLPHL is an indolent disorder and decades of follow-up are needed to assess disease control, risk of transformation, and late effects, especially secondary malignancies. Based on the slow growth of NLPHL and its tendency to relapse after radiation, a watch-and-wait strategy also might be feasible and is being evaluated in a European multicenter trial. Clinicians need to be aware of the unique features of this disease entity and its biology to deliver optimal treatment to their patients. Published clinical trials validate that this is a disease different from cHL which needs to be managed in different ways.

Acknowledgments Support for this research project was provided by Team Continuum Hematologic Malignancies Center, Continuum Cancer Centers of New York.

Disclosure The authors have stated that they have no conflicts of interest.

References 1. Swerdlow SH, Campo E, Harris NL, et al, eds. World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008. 2. Diehl V, Sextro M, Franklin J, et al. Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin’s disease and lymphocyte-rich classical Hodgkin’s disease: report from the European Task Force on Lymphoma project on lymphocyte-predominant Hodgkin’s disease. J Clin Oncol 1999; 17: 776-83. 3. Anagnostopoulos I, Hansmann ML, Franssila K, et al. European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. http://www.ncbi.nlm. nih.gov/pubmed/10961891. Blood 2000; 96:1889-99. 4. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006; 107:265-76. 5. Thomas RK, Re D, Wolf J, Diehl V. Part 1: Hodgkin’s lymphoma e molecular biology of Hodgkin and Reed-Sternberg cells. Lancet Oncol 2004; 5:11-8. 6. DeVita VT, Jr, Lawrence TS, Rosenberg SA, DePinho RA, Weinberg RA. Devita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology. 9th ed. New York, NY: Lippincot Williams & Wilkins; 2011. 7. Burns BF, Colby TV, Dorfman RF. Differential diagnostic features of nodular L & H Hodgkin’s disease, including progressive transformation of germinal centers. Am J Surg Pathol 1984; 8:253-61. 8. Boudova L, Torlakovic E, Delabie J, et al. Nodular lymphocyte-predominant Hodgkin’s lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte predominant hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma. Blood 2003; 102:3753-8. 9. Hicks J, Flaitz C. Progressive transformation of germinal centers: review of histopathologic and clinical features. Int J Pediatr Otorhinolaryngol 2002; 65:195-202. 10. Braeuninger A, Küppers R, Strickler JG, Wacker HH, Rajewsky K, Hansmann ML. Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A 1997; 94:9337-42. 11. Marafioti T, Hummel M, Anagnostopoulos I, et al. Origin of nodular lymphocytepredominant Hodgkin’s disease from a clonal expansion of highly mutated germinal-center B cells. N Engl J Med 1997; 337:453-8. 12. Ohno T, Stribley JA, Wu G, Hinrichs SH, Weisenburger DD, Chan WC. Clonality in nodular lymphocyte-predominant Hodgkin’s disease. N Engl J Med 1997; 337:459-65. 13. Liso A, Capello D, Marafioti T, et al. Aberrant somatic hypermutation in tumor cells of nodular-lymphocyte-predominant and classic Hodgkin lymphoma. Blood 2006; 108:1013-20. 14. Marafioti T, Pozzobon M, Hansmann ML, Delsol G, Pileri SA, Mason DY. Expression of intracellular signaling molecules in classical and lymphocyte predominance Hodgkin disease. Blood 2004; 103:188-93. 15. Fan Z, Natkunam Y, Bair E, Tibshirani R, Warnke RA. Characterization of variant patterns of nodular lymphocyte predominant Hodgkin lymphoma with immunohistological and clinical correlation. Am J Surg Pathol 2003; 27:1346-56. 16. Hartmann S, Eichenauer DA, Plutschow A, Mottok A, Bob R. The prognostic impact of variant histology in nodular lymphocyte predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG). Blood 2013; 122:4246-52. 17. Mauch PM, Kalish LA, Kadin M, Coleman CN, Osteen R, Hellman S. Patterns for presentation of Hodgkin disease. Implications for etiology and pathogenesis. Cancer 1993; 71:2062-71. 18. Pappa VI, Norton AJ, Gupta RK, Wilson AM, Rohatiner AZ, Lister TA. Nodular type of lymphocyte-predominant Hodgkin’s disease. A clinical study of 50 cases. Ann Oncol 1995; 6:559-65. 19. Bodis S, Kraus MD, Pinkus G, et al. Clinical presentation and outcome in lymphocyte-predominant Hodgkin’s disease. J Clin Oncol 1997; 15:3060-6. 20. Nogová L, Reineke T, Eich HT, et al. Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte predominant Hodgkin’s lymphoma: a retrospective analysis from the German Hodgkin Study Group (GHSG). Ann Oncol 2005; 16:1683-7. 21. Miettinen M, Franssila KO, Saxén E. Hodgkin’s disease, lymphocytepredominance nodular. Increased risk of subsequent non-Hodgkin’s lymphomas. Cancer 1983; 51:2293-300. 22. Hansmann ML, Zwingers T, Böske A, Löffler H, Lennert K. Clinical features of nodular paragranuloma (Hodgkin’s disease, lymphocyte predominance type, nodular). J Cancer Res Clin Oncol 1984; 108:321-30.

Clinical Lymphoma, Myeloma & Leukemia Month 2014

-9

NLPHL Update on Biology, Diagnosis, and Treatment 23. Schlembach PJ, Wilder RB, Jones D, et al. Radiotherapy alone for lymphocytepredominant Hodgkin’s disease. Cancer J 2002; 8:377-83. 24. Wirth A, Yuen K, Barton M, et al. Long term outcome after radiotherapy alone for lymphocyte predominant Hodgkin’s lymphoma: a retrospective multicenter study of the Australian Radiation Oncology Lymphoma Group. Cancer 2005; 104:1221-9. 25. Chen RC, Chin MS, Ng AK, et al. Early stage, lymphocyte predominant Hodgkin’s lymphoma: patient outcomes form a large, single institution series with long follow up. J Clin Oncol 2009; 28:136-41. 26. Wilder RB, Schlembcach PJ, Jones D, et al. European Organization for Research and Treatment of Cancer and Groupe d’Etude des Lymphomes de l’Adulte very favorable and favorable, lymphocyte-predominant Hodgkin disease. Cancer 2002; 94:1731-8. 27. Feugier P, Labouyrie E, Djeridane M, et al. Comparison of initial characteristics and long term outcome of patients with lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma at clinical stages IA and IIA prospectively treated by brief anthracycline based chemotherapies plus extended high dose irradiation. Blood 2004; 104:2675-81. 28. Savage KG, Skinnider B, Al Mansour M, Sehn LH, Gascoyne RD, Connors JM. Treating limited stage nodular lymphocyte predominant hodgkin lymphoma similarly to classical Hodgkin lymphoma with ABVD may improve outcome. Blood 2011; 118:4585-90. 29. Shankar A, Hall GW, Gorde-Grosjean S, Hasenclever D, Leblanc T. Treatment outcome after low intensity chemotherapy [CVP] in children and adolescents with early stage nodular lymphocyte predominant Hodgkin’s lymphoma - an Anglo-French collaborative report. Eur J Cancer 2012; 48: 1700-6. 30. Eichenauer D, Fuchs M, Pluetschow A, Klimmm B, Halbsguth T, Boll B. Phase 2 study of rituximab in newly diagnosed stage I A nodular lymphocyte predominant Hodgkin lymphoma: a report from German Hodgkin Study Group. Blood 2011; 118:4363-5. 31. Advani R, Horning SJ, Hoppe R, Daadi S, Allen J, Natkunam Y. Front line therapy of nodular lymphocyte predomiant Hodgkin lymphoma with rituximab. The Stanford University experience. ASH Annual Meeting 2011 (abstract 2686).

10

-

Clinical Lymphoma, Myeloma & Leukemia Month 2014

32. Fanale MA, Lai CM, McLaughlin, Romaguera JE, Fayad L. Outcome of nodular lymphocyte predominant Hodgkin’s lymphoma (NLPHL) patients treated with R-CHOP. ASH Annual Meeting 2010 (abstract 2812). 33. Schulz H, Rehwald U, Morschhauser F, Elter T, Driessen C, Rudiger T. Rituximab in relapsed lymphocyte predominant Hodgkin’s lymphoma: long-term results of a phase 2 trial by the German Hodgkin Study Group (GHSG). Blood 2008; 111:109-11. 34. Ekstrand BC, Lucas JB, Horowitz SM, Fan Z, Breslin S. Rituximab in lymphocyte predominant Hodgkin disease: results of a phase 2 trial. Blood 2003; 101:4285-9. 35. Rehwald U, Schulz H, Reiser M. Treatment of relapsed CD 20þ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase II trial of the German Hodgkin Lymphoma Study Group. Blood 2003; 101:420-4. 36. Karuturi M, Hosing C, Fanale M, et al. High dose chemotherapy and autologous stem cell transplantation for nodular lymphocyte predominant Hodgkin lymphoma. Biol Blood Marrow Transplant 2013; 19:991-4. 37. Jackson C, Sirohi B, Cunnningham D, Horwich A, Thomas K, Wotherspoon A. Lymphocyte-predominant Hodgkin lymphomaeclinical features and treatment outcomes from a 30-year experience. Ann Oncol 2010; 21:2061-8. 38. Huang JZ, Weisenburger DD, Vose JM, Greiner TC, Aoun P. Diffuse large B-cell lymphoma arising in nodular lymphocyte predominant Hodgkin lymphoma: a report of 21 cases from the Nebraska Lymphoma Study Group. Leuk Lymphoma 2004; 45:1551-7. 39. Biasoli I, Stamatoullas A, Meignin V, et al. Nodular, lymphocyte-predominant Hodgkin lymphoma: a long-term study and analysis of transformation to diffuse large B-cell lymphoma in a cohort of 164 patients from the Adult Lymphoma Study Group. Cancer 2010; 116:631-9. 40. Sirop SJ, Habermann TM, Macon WR, Ristow KM, Ansell SM, Colgan JP. Diffuse large B cell transformation in nodular lymphocyte predominant Hodgkin lymphoma: incidence, risk factors and outcomes after a forty year experience from a single institution. ASH Annual Meeting 2012 (abstract 1525). 41. Xing KH, Connors JM, Mansour MA, Gascoyne RD. The outcome of advanced stage nodular lymphocyte predominant Hodgkin’s lymphoma (NLPHL) compared to classical Hodgkin Lymphoma (CHL): a matched pair analysis. ASH Annual Meeting 2012 (abstract 1531).