histiocyte rich large B-cell lymphoma

Pathology (- xxxx) xxx(xxx), xxx

LY M P H O M A 2 0 2 0 : A N U P D AT E

Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to T-cell/histiocyte rich large B-cell lymphoma SYLVIA HARTMANN1,2, DENNIS A. EICHENAUER3,4 1 Dr Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany; 2 Reference and Consultation Center for Lymph Node and Lymphoma Pathology, Goethe 3

University, Frankfurt am Main, Germany; University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, Germany; 4German Hodgkin Study Group, University Hospital Cologne, Cologne, Germany

Summary Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an unusual subtype of Hodgkin lymphoma characterised by a distinct histopathological and clinical presentation. It mostly affects males and presents with localised disease and an indolent clinical course in the majority of cases. However, there are also patients with advanced NLPHL who frequently present with spleen and liver involvement, B-symptoms and a more aggressive clinical course. Different clinical presentations correlate with distinct histopathological characteristics. NLPHL can be divided into typical and variant histopathological growth patterns. The clinical course of most patients with a typical growth pattern is indolent whereas patients with a variant histology more often present with advanced stage disease and relapse occurs more frequently and earlier. Despite these differences, the prognosis after stage-adapted treatment is favourable for both patient groups. Some cases presenting with a variant histology show a histopathological and clinical overlap with T-cell/ histiocyte rich large B-cell lymphoma (THRLBCL). Although being considered as aggressive B-cell lymphoma, THRLBCL exhibits many features that are similar to NLPHL, indicating a close relationship with regard to pathogenesis. Both lymphoma entities derive from germinal centre B-cells, show ongoing somatic hypermutation, and resemble each other in terms of gene expression of tumour cells, genomic imbalances and mutation patterns. Key words: Nodular lymphocyte predominant Hodgkin Lymphoma; T-cell histiocyte rich large B-cell lymphoma; transformation; relapses; LP cells; histopathological growth patterns; genetics. Received 22 August, revised 11 October, accepted 14 October 2019 Available online: xxx

INTRODUCTION Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) was first described as a distinct subtype of Hodgkin lymphoma (HL), designated as ‘paragranuloma’ in the classification by Jackson and Parker in 1947.1 Later on, it was called ‘lymphocytic and histiocytic variant’ by Lukes and

Butler in 1966.2 In 1974, Lennert already distinguished between a nodular and a diffuse type of NLPHL.3 Although our knowledge about NLPHL has tremendously increased, observations made many years ago are still the basis for our current understanding of this disease.

DIAGNOSIS: HISTOPATHOLOGY, MOLECULAR PATHOGENESIS AND GENOMICS Histology of NLPHL Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of all HL cases.4,5 Due to its low incidence and its variable morphological aspects,6 it is frequently misdiagnosed. Particularly T-cell-rich forms of NLPHL are prone to be diagnosed as T-cell lymphoma. The malignant cells are called the lymphocyte predominant (LP) cells (Fig. 1), which show characteristic nuclear folding and resemble popcorn. There are various histopathological patterns of NLPHL that can be appreciated best in CD20 immunostaining, usually allowing one to distinguish neoplastic LP cells and reactive B cells from bystander T cells. The vast majority of NLPHL cases (z75%)7 show a typical nodular growth pattern characterised by large nodules underpinned by follicular and dendritic cell networks and composed of small reactive B cells, some epithelioid histiocytes and single scattered LP cells, which are mostly located within the Bcell-rich nodules. In cases with a pure nodular growth pattern, LP cells can sometimes be relatively small. Thus, it can be challenging to recognise them in CD20 immunostaining due to abundant CD20-positive reactive B cells. In these cases, the detection of T-cell rosettes surrounding the LP cells is helpful to establish the diagnosis.8 Fan et al.9 described six histopathological growth patterns (termed A–F). Patterns A and B show a typical B-cell-rich background infiltrate, whereas patterns C–F either show a diffuse infiltrate or nodules dominated by T-cell bystander cells (Fig. 2 and 3). Histopathological growth patterns in NLPHL not only reflect variants of one disease, but also differ with regard to their clinical presentation and course (see below). This concept is also reflected in work by Carbone et al.10 who suggest that NLPHL cases with LP

Print ISSN 0031-3025/Online ISSN 1465-3931 © 2019 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved. DOI: https://doi.org/10.1016/j.pathol.2019.10.003 Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

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age at diagnosis (37 years and 38 years) and the proportion of male patients (75% and 77.7%) in the GHSG and LYSA studies were also comparable.11,12 An association between a variant histology (growth pattern C–F according to Fan et al.)9 and more advanced disease at the initial NLPHL diagnosis has been demonstrated in several studies.7,13 A retrospective analysis from the GHSG including a total of 413 patients, indicated that 29.5% of patients with a variant histology had advanced stage disease at the time of initial NLPHL diagnosis. In contrast, only 14.6% of patients with a typical growth pattern (growth pattern A and B according to Fan et al.)9 presented with advanced stages.7 According to an analysis from the United Kingdom (UK) including 60 children and adolescents with NLPHL, 23% of patients with a variant histology presented with advanced stage disease whereas only 6% of patients with a typical growth pattern had advanced disease.13 A correlation between a variant histology and bone marrow involvement was also described in some reports.14,15 Hence, baseline characteristics of patients with a typical growth pattern and individuals with a variant histology appear to differ substantially. Histology of THRLBCL

cells localised within the B-cell nodules represent noninvasive neoplasias commonly presenting with early-stage disease and an indolent course. In contrast, in the frankly invasive variant patterns, LP cells have probably acquired the ability to invade and disseminate. NLPHL diagnosed in extranodal sites frequently presents with LP cells in a T-cell- and epithelioid histiocyte-rich background, lacking small reactive B cells. If only small biopsies from extranodal sites can be obtained, difficulties in distinguishing between NLPHL and T-cell/histiocyte rich large B-cell lymphoma (THRLBCL) can occur (Fig. 4 and 5, see below). In such cases, a lymph node excision should be considered whenever possible.

THRLBCL is traditionally considered an aggressive B-cell lymphoma and was first included as a separate entity in the 2008 World Health Organization (WHO) classification.16 In previous times THRLBCL represented a variant of diffuse large B-cell lymphoma (DLBCL) and the diagnostic criteria were only loosely defined. It is not surprising that cases of ordinary DLBCL with a T-cell-rich microenvironment were included in this category as well as cases of classical HL (cHL) with aberrant CD20 expression. Keeping this in mind, it is even more surprising that the clinical presentation of THRLBCL is rather homogenous,17 usually affecting middle-aged male patients, presenting with advanced stage disease with frequent involvement of spleen and liver. The histology of THRLBCL shows single scattered large blasts, which can have popcorn-like, but also centroblast-like or Hodgkin –Reed– Sternberg (HRS)-like nuclei.18 These blasts are found in an extensive background of histiocytes, which can have an epithelioid character admixed with reactive T-cells (Fig. 5). Usually there are no to very few reactive naïve B cells in the microenvironment, which can be highlighted by IgD-immunostaining, since the tumour cells of THRLBCL are IgD-negative in most cases.19 In the cases with a few residual small reactive B cells, the diagnosis is rather a variant pattern of NLPHL (pattern E according to Fan et al.9).

Clinical presentation (histopathological patterns)

Immunophenotype of tumour cells

Most patients with newly diagnosed NLPHL present with limited-stage disease. According to a large analysis from the German Hodgkin Study Group (GHSG) comprising 394 individuals with NLPHL who had first-line treatment within prospective studies, 63% of patients had early stage, 16% had intermediate stage and 21% had advanced stage disease at initial diagnosis.11 A similar distribution of stages was reported in an analysis from the Lymphoma Study Association (LYSA) including 366 NLPHL patients. Individuals with stage I/II disease accounted for 82.5% of patients, whereas only 17.5% of patients had stage III/IV disease.12 The median

The immunophenotype of the LP cells with expression of CD20, CD79a, CD19, PAX5, OCT2, EMA, CD75, BCL6 and HGAL shows a strong overlap with germinal centre B cells (Fig. 6). CD10 is the only marker that can be used to distinguish between germinal centre B cells which are CD10-positive and LP cells which are negative for this marker in virtually all cases. The immunophenotype of the LP cells is usually identical in typical and variant forms.16 In cases with the growth pattern C according to Fan et al.,9 IgD is expressed more frequently by the LP cells.19 Although subtle differences in the immunophenotype of

Lymphocyte predominant (LP) cells in their typical microenvironment. (A) Exemplary case showing clear activated T cells surrounding LP cells, which are typical for nodular lymphocyte predominant Hodgkin lymphoma96 (H&E). (B–D) Representative examples of LP cells with typical popcorn-like nuclei in high magnification (arrows, H&E).

Fig. 1

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

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Schematic representation of patterns in NLPHL according to Fan et al.9 (A,B) The nodular and B-cell-rich patterns are considered typical and are observed in 75% of the patients. (C–F) Variant patterns show more diffuse and T-cell-rich infiltrates.

Fig. 2

tumour cells of THRLCBL in comparison with the LP cells from NLPHL have been described, such as LSP1 expression and lack of PU.1 expression,20 there is no immunophenotypic marker allowing specific discrimination between both entities. Immunoglobulin gene rearrangements and somatic hypermutation Both the LP cells of NLPHL and the tumour cells of THRLBCL carry clonal immunoglobulin gene rearrangements.21,22 The presence of mutations of immunoglobulin heavy chain genes (4.0–14.5% for LP cells and 7.2–24.0% for tumour cells of THRLBCL) with ongoing somatic hypermutation suggest that both lymphomas are derived from germinal centre B cells.

Deregulated pathways In NLPHL, similarly to cHL, the tumour cells show various deregulated signalling pathways. They display an active JAKSTAT signalling pathway in around 50% of the cases due to mutations observed in SOCS1,23 a negative regulator of JAK2. Another pathway frequently deregulated in LP cells and the tumour cells of cHL, is the nuclear factor-kappaB (NF-kB) pathway.24 However, mutations in components of the NF-kB pathway that are frequently observed in cHL, e.g., mutations affecting the IkBa and TNFAIP3 genes, are only rarely seen in NLPHL.25 Little is known about the molecular pathogenesis of the tumour cells of THRLBCL. This is mostly due to the rarity of the disease. However, one previous study of comparative genomic hybridisation (CGH) reported more frequent genomic imbalances in NLPHL than in THRLBCL.26,27

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

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Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in extranodal localisation involving the liver. (A) H&E staining shows a mixed infiltrate consisting of abundant epithelioid histiocytes, some small lymphocytes and few lymphocyte predominant (LP) cells (highlighted by arrows) with hyperchromatic nuclei. (B) CD20-immunostaining highlights the LP cells (arrows) but hardly any B cells in the microenvironment. This is a typical manifestation of NLPHL in the liver. The morphology resembles closely T-cell/ histiocyte rich large B-cell lymphoma.

Fig. 4

Examples of typical and variant histology in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) (CD20 immunstaining). (A) Example of NLPHL pattern A according to Fan et al.9 Numerous small reactive B cells are found in this nodule. (B) Example of NLPHL pattern C according to Fan et al.9 A small condensed B-cell follicle is surrounded by large lymphocyte predominant (LP) cells in a CD20-negative background. (C) Example of NLPHL pattern E according to Fan et al.9 Completely diffuse growth pattern with few small reactive B cells admixed with LP cells. Fig. 3

Gene expression profiling of microdissected tumour cells in NLPHL and THRLBCL Since we had previously observed strong similarities in the gene expression profiling (GEP) of microdissected tumour cells from NLPHL and THRLBCL,24 we sought to identify

new markers with different expression patterns in the malignant cells of NLPHL and THRLBCL. We performed GEP of microdissected tumour cells in a larger series of NLPHL and THRLBCL cases as well as in THRLBCL-like NLPHL cases, applying a new generation of gene expression arrays.28 THRLBCL-like NLPHL has been described as a diffuse variant of NLPHL, containing at least one typical nodule of NLPHL,16 morphologically mimicking THRLBCL and more frequently presenting in advanced stages.7 As a result, no clearly separate clustering of the microdissected tumour cells from these different lymphoma entities could be shown in unsupervised hierarchical clustering. In contrast, a continuous branching of the different samples was observed.28 Furthermore, only a few genes with differences in terms of expression between the tumour cells of NLPHL and THRLBCL were identified. However, applying immunohistochemistry, expression of most of the differentially expressed genes (BAT3, HIGD1A, FAT10 and CXCL13) could be demonstrated in the tumour cells of NLPHL, THRLBCL-like NLPHL and THRLBCL, in varying number and intensity, indicating great similarity in the tumour cells of these lymphomas. Similar to GEP of the

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

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T-cell/histiocyte rich large B-cell lymphoma (THRLBCL) involving the spleen, previously described as micronodular THRLBCL of the spleen. This patient had nodular lymphocyte predominant Hodgkin lymphoma with variant histology one year prior. Relapse with the morphology of a THRLBCL. (A) Nodular infiltrate in the spleen with many epithelioid cells. Arrow highlighting one representative tumour cell with centroblast-like morphology (H&E). (B) CD79a immunostaining highlighting the scarce number of tumour cells in the abundant background of epithelioid histiocytes and T cells.

Fig. 5

tumour cells, GEP of microdissected histiocytes from NLPHL and THRLBCL revealed only a few differences.29 Thus, we hypothesised that NLPHL and THRLBCL represent closely related entities. Major differences in clinical behaviour might be due to the different composition of the microenvironment (see below). Genomic aberrations of microdissected tumour cells in NLPHL and THRLBCL Array CGH profiles of microdissected tumour cells of seven NLPHL, four THRLBCL-like NLPHL, six THRLBCL and four DLBCL transformed from NLPHL were obtained as previously published.30 Two regions on 2p16 and 2p11 were affected in both NLPHL and THRLBCL as well as in THRLBCL-like NLPHL.31 Therefore, the close relationship between NLPHL and THRLBCL observed in the GEP study could also be demonstrated on a genomic basis. One region on 9p11 was deleted in 6/7 NLPHL cases, 2/4 THRLBCLlike NLPHL and 3/4 DLBCL transformed from NLPHL, but not in THRLBCL. Therefore, transformation of NLPHL to THRLBCL or DLBCL may be related to different genomic aberrations.

Typical immunophenotype of nodular lymphocyte predominant Hodgkin lymphoma. Example of a case with lymphocyte predominant cells positive for (A) BCL6, (B) EMA, and (C) J-chain.

Fig. 6

Genomic mutations and translocations in NLPHL and THRLBCL BCL6 translocations have been described in approximately one-third of NLPHL cases,32,33 explaining the strong BCL6

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

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expression in LP cells in at least a subset of cases. Whether BCL6 translocations also occur in THRLBCL is unknown. Four cases of THRLBCL were described to have PAX5/IGH rearrangement.34 Whole genome sequencing of two composite lymphomas of clonally related NLPHL and DLBCL led to the identification of four frequently mutated genes: DUSP2, JUNB, SGK1 and SOCS1.35 In a first small cohort of NLPHL cases, these mutations occurred more frequently in cases with variant growth patterns,35 whereas this could not be confirmed in a different series of NLPHL cases.36 In the latter, only SOCS1 mutations were significantly more frequent in variant NLPHL and THRLBCL when compared with NLPHL cases with typical patterns. Overall, based on this targeted sequencing approach, the mutational spectrum of NLPHL and THRLBCL was relatively similar.

matrix.48 A high number of macrophages in the lymphoma microenvironment can thus facilitate the dissemination of tumour cells throughout the human body. Additionally, the content of CD4+ cells in THRLBCL is significantly decreased compared to typical NLPHL. Differences in the microenvironment between NLPHL and THRLBCL may depend either on the availability and functional status of CD4+ T cells and monocytes/macrophages at the time of initial lymphoma development, or on differences in the chemokine milieu secreted by the tumour cells and attracting the bystander cells. Single centre studies have shown that the ratio of absolute lymphocyte count/absolute monocyte count in the peripheral blood at diagnosis is an independent prognostic factor in patients with cHL as well as NLPHL.49,50

Microenvironment

Differential diagnosis between early NLPHL and progressively transformed germinal centres

The microenvironment of NLPHL is typically composed of B-cell-rich nodules, in which the LP tumour cells are located, surrounded by rosetting T cells. In the typical nodular patterns, LP cells are surrounded by rosetting PD1+ T cells (Fig. 7).37,38 In the variant patterns these rosetting follicular T helper cells are less frequently observed.38 Another typical feature observed in flow cytometry immunophenotypic analysis of NLPHL are CD4+ CD8+ double-positive T cells, which are rarely observed in other settings (Fig. 8).39,40 The frequency of this double-positive T-cell population ranges between 1 and 38% of all T cells. Furthermore, a high number of CD69+ T cells in NLPHL nodules has been demonstrated by flow cytometry.41 It has been suggested that the presence of CD69+ T-cells in the tumour cell areas of NLPHL has an immunosuppressive effect by producing TGF-b. The microenvironment of THRLBCL is dominated by a high content of macrophages and dendritic cells, which were in part shown to create a tumour tolerogenic environment.42 In cHL, a high macrophage content in the microenvironment has been shown to be an adverse prognostic factor.43–46 In a small NLPHL patient cohort, a high macrophage content in the tissue correlated with a lower complete remission rate.47 It has been shown that macrophages can degrade extracellular

PD1-positive rosetting T cells in nodular lymphocyte predominant Hodgkin lymphoma. Lymphocyte predominant cells are completely surrounded by PD1-positive T-cell rosettes (arrows, PD1-immunostaining).

Initial NLPHL cases need to be distinguished from progressively transformed germinal centres, which sometimes can very closely mimic an early NLPHL infiltrate. Most reliable in this differential diagnosis is the detection of rosettes of follicular T helper (TFH) cells, positive for PD1, which allow one to clearly detect LP cells, whereas in progressively transformed germinal centres only incomplete TFH rosettes around centroblasts are encountered.8 The shape of nodules can also be of diagnostic help, since NLPHL nodules more frequently present with irregular forms and a moth-eaten appearance. Demonstration of high numbers of IgG4positive plasma cells within the B-cell nodules can additionally help to rule out NLPHL, since IgG4-positive plasma cells are only rarely detected in the NLPHL microenviroenment.51 However, in very early infiltrates, the diagnosis can be challenging and a close follow-up of the patient may be considered.

Fig. 7

Fig. 8 FACS plot showing CD4/CD8 double-positive cells in a case of variant

nodular lymphocyte predominant Hodgkin lymphoma.

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

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NLPHL on familial basis and related to genetic syndromes Families with an accumulation of NLPHL cases have been observed.5,52,53 This accumulation of NLPHL could be related to a small germline deletion of the NPAT gene in some families and also sporadic cases.52 However, NLPHL has also been described to occur in patients with defects in the innate and adaptive immune system like Hermansky–Pudlak type 2 syndrome and autoimmune lymphoproliferative syndrome,54,55 indicating that dysregulation of the immune system importantly contributes to the pathogenesis of NLPHL. NLPHL cell line DEV The only cell line established from NLPHL so far is the DEV cell line, which was established by Poppema et al. from a patient with long standing disease in 1985.56,57 The DEV cell line expresses B-cell antigens like primary LP cells, but is also positive for CD30. It carries complex translocations involving chromosome 3 and the BCL6 locus.58 Furthermore, it was shown that the DEV cell line has downregulated the major histocompatibility (MHC) genes, due to a mutation in the start codon of B2M59 as well as a translocation involving the class II transactivator gene CIITA.60 Therefore, DEV cells have probably acquired MHC downregulation as mechanism of immune escape. Whereas in most cHL cell lines the proteins TARC and RANTES, responsible for the shaping of cHL-typical microenvironment, were identified, these proteins were not expressed in the DEV cell line.61 Generally, in the supernatants of the DEV cell lines only relatively few proteins were found, which did not explain the particular composition of the NLPHL microenvironment. PD-L1 expression in NLPHL In the era of checkpoint inhibition, much attention has been paid to the expression of PD-L1 in cHL. In contrast to the HRS cells of cHL, PD-L1 expression was observed in LP cells of NLPHL in some studies,62 whereas other studies could not find PD-L1 expression in LP cells.63 Although PDL1 expression by LP cells is probably heterogeneous among cases and with different antibodies, strong PD-L1 expression is always found on the epithelioid histiocytes, which can be numerous in close proximity to LP cells, particularly in cases with variant histology and Fan pattern E (Fig. 9).62 It has similarly been observed in cHL, that PD-L1+ tumour-associated macrophages are closely associated with the HRS cells, thus creating a microenvironmental niche and augmenting immune suppression.64

TREATMENT AND OUTCOME First-line treatment Patients with newly diagnosed NLPHL receive stageadapted first-line treatment (early stages: stage I/II disease without clinical risk factors; intermediate stages: stage I/II disease with at least one clinical risk factor; advanced stages: selected stage IIB disease with defined clinical risk factors, stage III/IV disease) usually consisting of radiotherapy (RT) alone, chemotherapy alone or combined-modality treatment (CMT).

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in PDL1/OCT2 double staining: PD-L1 expression in epithelioid histiocytes (brown) in NLPHL creating a niche for lymphocyte predominant cells (OCT2-positive, red).

Fig. 9

Treatment of stage IA disease Unlike individuals with cHL, patients with stage IA NLPHL presenting without clinical risk factors are sufficiently treated with limited-field RT alone. Several studies compared treatment results with RT alone to those obtained with CMT in this patient group. A retrospective study from the GHSG included 49 patients who had extended-field RT alone, 108 patients who had involved-field RT alone and 72 patients who had CMT. The 8-year progression-free survival (PFS) and overall survival (OS) rates were 84.3% and 95.7% for extended-field RT alone, 91.9% and 99.0% for involved-field RT alone and 88.5% and 98.6% for CMT. Thus, outcomes were comparable for all approaches and the addition of chemotherapy to RT did not appear to be necessary in stage IA patients without clinical risk factors.65 Similarly, an analysis including a total of 113 patients with early-stage NLPHL who had been treated at a single institution in the US reported excellent results after RT alone with 10-year PFS and OS rates of 85% and 94%, respectively.66 In an attempt to reduce the treatment burden and the risk of late sequelae associated with RT, the GHSG conducted a phase II study evaluating single-agent anti-CD20 antibody treatment with rituximab. All 28 patients included in the study responded to treatment. However, the 3-year PFS rate was only 81.4% and thus significantly worse than with RT alone.67 Hence, limited-field RT represents the current standard of care for patients with stage IA NLPHL presenting without clinical risk factors at most institutions.68,69 In paediatric patients with involvement of a single lymph node, observation only after complete resection of the affected lymph node, as confirmed by positron emission tomography, was prospectively evaluated in 52 patients. The 5-year event-free survival rate was 77.1%. There were no deaths. Based on these data and similar results obtained from a retrospective study comprising 58 children with early-stage NLPHL, a watch and wait strategy after complete lymph node resection may be considered in paediatric patients with very limited disease, since the risk for the development of therapy-related late effects should be kept as low as possible especially in this

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

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patient group.70,71 Borchmann and colleagues at Memorial Sloan Kettering Cancer Center have reported on active surveillance in adults with NLPHL, suggesting that this approach is adequate in selected patients.72 Treatment of early stages except for stage IA without clinical risk factors and intermediate stages In patients with early-stage NLPHL other than stage IA without clinical risk factors, disease control after RT alone does not seem to be sufficient.66,73 Therefore, individuals with early-stage NLPHL other than stage IA without clinical risk factors are usually treated very similarly to cHL, i.e., with CMT. According to a retrospective study using the British Columbia Cancer Agency (BCCA) database, the 10-year PFS and OS rates after 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or ABVD-like chemotherapy followed by consolidation RT were 91% and 93%, respectively.73 A recent retrospective analysis from the GHSG including 251 patients with early-stage NLPHL revealed 8-year PFS and OS rates of 83.2% and 95.1% after 2 or 4 cycles of ABVD-based chemotherapy followed by consolidation RT. In 76 patients presenting with intermediate stages, 4 cycles of ABVD-based chemotherapy followed by consolidation RT resulted in 8-year PFS and OS rates of 85.2% and 98.6%, respectively.74 Thus, the outcome of NLPHL patients presenting with early stages other than stage IA without clinical risk factors and intermediate stages is excellent after HL-directed therapy. Therefore, the use of standard HL-directed approaches should be considered in these patient groups. Treatment of advanced stages Different treatment protocols have been investigated in patients with advanced NLPHL. A retrospective analysis using the BCCA database evaluated the outcome of 42 patients with newly diagnosed advanced NLPHL who had first-line treatment with ABVD or ABVD-like protocols. After a median observation time of 11.3 years, approximately 40% of patients had lymphoma recurrence with either NLPHL histology or histological transformation into aggressive B-cell non-Hodgkin lymphoma (B-NHL).75 Due to this high lymphoma recurrence rate, ABVD does not appear to represent the optimal regimen for newly diagnosed advanced NLPHL. The more aggressive BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) protocol has also been evaluated in patients with advanced NLPHL. A total of 144 patients treated within GHSG studies were analysed. The 8-year PFS and OS rates after BEACOPP-based chemotherapy optionally followed by localised RT to residual lymphoma were 76.2% and 87.4%, respectively.74 However, the question of whether all patients benefit from this intensive approach has not been answered to date and should be subject to future analyses. Promising results were recently obtained with the B-NHL-directed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) protocol. A retrospective single centre analysis including 14 patients with stage III/IV NLPHL reported a 10-year PFS estimate of 85.7%.76 However, additional studies including more patients are necessary before firm conclusions can be drawn. Another recent retrospective analysis from a single institution investigated the

possible role of active surveillance as initial management strategy in newly diagnosed NLPHL including patients with advanced stage disease. Although the 5-year PFS rate was worse than after any other treatment, OS was not impacted.72 Thus, there may be selected patients with newly diagnosed NLPHL who could be candidates for active surveillance as an initial management strategy; however, this approach should be used with caution since data on how to identify such patients are not available. Taken together, there is no accepted standard of care for the treatment of advanced NLPHL. Some patients may be sufficiently treated with less intensive approaches such as ABVD and R-CHOP, whereas high-risk patients possibly benefit from aggressive chemotherapy with escalated BEACOPP. Refined risk allocation systems incorporating parameters such as the histopathological growth pattern which was shown to have significant prognostic impact may be helpful to choose the optimal treatment for the individual patient.7 Relapses NLPHL patients with a variant histology at initial diagnosis have a higher risk of disease recurrence.7 In these patients, relapses also occur at an earlier time point than in patients with typical NLPHL.77 In most patients, the histopathological growth pattern at relapse is consistent with the one observed at initial diagnosis. However, a switch from a typical to a variant growth pattern and vice versa is found in a subset of patients. In patients who receive rituximab during first-line treatment, the diagnosis at disease recurrence can be challenging, since LP cells frequently downregulate the expression of CD20 at relapse. Therefore, at relapse one should always consider additional B-cell markers like PAX5 and OCT2 to detect the neoplastic clone, which otherwise can easily be missed (Fig. 10). It has also been observed that patients initially presenting with NLPHL show a picture of THRLBCL at relapse and vice versa.78 Transformation into aggressive B-cell lymphoma Transformation into a clonally related aggressive B-NHL is observed in NLPHL in contrast to cHL, where DLBCLs rarely occur after the initial diagnosis.79–81 Recent studies with long-term follow-up described transformation rates of up to 30% at 20 years.82,83 These transformations included both DLBCL and THRLBCL. Several studies have suggested that patients with transformation of NLPHL into DLBCL have a more favourable outcome compared to de novo DLBCL.79,80,82–84 However, one study did not confirm this observation.81 Patients with transformation into DLBCL often present in an advanced stage and with splenic involvement.82 Patients with sequential transformation of NLPHL into DLBCL more frequently have splenic involvement at the initial diagnosis of NLPHL compared to other NLPHL patients.82 On a histological basis, the LP cells of NLPHL cases with transformation more frequently have aberrant immunophenotypes with expression of CD10, CD30 or CD15. The immunophenotype is usually consistent in the LP cells and the tumour cells of DLBCL.85 Furthermore, these DLBCL cases frequently show a sheet-like growth pattern and blast infiltrates are sharply demarcated from surrounding tissue (Fig. 11). Cases only containing small sheets of blasts confined to NLPHL nodules should not be considered as transformation into DLBCL since the clinical

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

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The genetic events preceding transformation into DLBCL can vary considerably as shown in two cases of clonally related NLPHL and DLBCL.35 One of these DLBCLs had chromothripsis-like genomic changes, mutations in TP53 and ATM and a high mutational load (10-fold increased when compared with the other DLBCL derived from NLPHL). Treatment of relapsed NLPHL and histological transformation into aggressive B-NHL Treatment of lymphoma recurrence with NLPHL histology

Fig. 10 Relapse of nodular lymphocyte predominant Hodgkin lymphoma

shortly after rituximab administration. (A) Only very few CD20-positive B cells are encountered (CD20 immunostaining). Inset: Lymphocyte predominant (LP) cells are CD20-negative. (B) In contrast to CD20 immunostaining, LP cells can be detected in PAX5 immunostaining. Inset: PAX5-positive LP cells.

Fig. 11 Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) with transformation into diffuse large B-cell lymphoma (DLBCL) in the same lymph node. In the typical NLPHL area (right side, marked with #) abundant small reactive B cells are found in nodules whereas the DLBCL area (left side, marked with *) consists of large sheets of confluent blast cells (CD20 immunstaining).

behaviour of such cases does not differ from other NLPHL cases.7 Gene expression analysis of DLBCL transformed from NLPHL reveals a more prominent cytotoxic immune cell infiltrate when compared with conventional DLBCL.86

Due to the rarity of the disease, the optimal treatment of relapsed NLPHL is ill-defined. Several approaches including high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), conventional chemotherapy optionally combined with RT and/or anti-CD20 antibody treatment, single-agent anti-CD20 antibody treatment and localised RT have been evaluated and efficacy could be demonstrated.87– 92 The most appropriate approach for the individual patient should be chosen on the basis of different factors such as time to relapse, previous therapies, symptom burden and extent of disease at relapse. The largest analysis investigating high-dose chemotherapy followed by ASCT in relapsed NLPHL came from the European Society for Blood and Marrow Transplantation (EBMT), and included a total of 60 patients with NLPHL recurrence. The median time between NLPHL diagnosis and ASCT was only 21 months. At a median follow-up of 56 months, the 5-year PFS and OS estimates were 66% and 87%, respectively.87 Thus, high-dose chemotherapy followed by ASCT represents a highly active treatment option in relapsed NLPHL and should be discussed, especially in individuals with poor-risk characteristics such as a short time interval between the initial NLPHL diagnosis and disease recurrence. Conventional chemotherapy optionally combined with RT and/or anti-CD20 antibody treatment represented the secondline approach in 27 patients included in a recent GHSG analysis. The 5-year PFS and OS estimates were 68.0% and 77.8%.88 Good results with conventional chemotherapy as a salvage approach were also obtained from a retrospective study including children and adolescents with NLPHL recurrence or poor response to the initial treatment.93 Conventional chemotherapy optionally combined with RT and/or anti-CD20 antibody treatment therefore should be considered as salvage therapy in patients who had no or little chemotherapy as part of their first-line treatment. Limited-field RT alone can be discussed as second-line treatment in patients with localised disease at NLPHL recurrence who did not have RT to the affected site as part of their initial treatment.88 In contrast to other second-line approaches that were investigated only retrospectively, the role of single-agent anti-CD20 antibody treatment in relapsed NLPHL has also been evaluated prospectively in several smaller phase II studies. An older study evaluated the first-generation antiCD20 antibody rituximab given at the standard dose of 375 mg/m2 once a week for four consecutive weeks in 15 NLPHL patients with disease recurrence. The overall response rate (ORR) was 94%. At a median observation time of 63 months, the median time to progression was 33 months. Only one death occurred during follow-up.89 Similar results were obtained from a more recent study investigating the second-

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

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generation anti-CD20 antibody ofatumumab in 28 patients with relapsed NLPHL. The antibody was given once a week for eight consecutive weeks (week 1: 300 mg; week 2–8: 1000 mg). The ORR was 96%. At a median follow-up of 26 months, the 1-year and 2-year PFS estimates were 93% and 80%, respectively. No deaths were reported.90 Thus, singleagent anti-CD20 antibody treatment induces long-term disease control in a proportion of patients with relapsed NLPHL. Given the low toxicity of this approach, it should be discussed in patients with an indolent course of disease and a longer time interval between the initial diagnosis and NLPHL recurrence. Treatment of lymphoma recurrence with histological transformation into aggressive B-NHL Patients with a history of NLPHL who experience lymphoma recurrence with histological transformation into aggressive B-NHL often present with poor-risk characteristics such as a high International Prognostic Index (IPI) and a substantial symptom burden.82,94 Therefore, treatment of these patients is usually more aggressive than for patients who relapse with NLPHL histology. Patients who did not have chemotherapy as part of their treatment for NLPHL can be treated with R-CHOP or similar protocols.83,94,95 Highdose chemotherapy followed by ASCT represents the treatment of choice for patients who have already had chemotherapy as part of their treatment for NLPHL.82,94,95 The available retrospective studies evaluating the outcome of NLPHL patients who developed histological transformation into aggressive B-NHL reported 5-year PFS rates of approximately 60% and 10-year PFS rates of approximately 50%.82,94 The OS at 10 years was in excess of 50%.82 Hence, a proportion of NLPHL patients who have lymphoma recurrence with histological transformation into aggressive B-NHL can be salvaged with B-NHL-directed conventional chemotherapy or high-dose chemotherapy followed by ASCT.

CONCLUSIONS NLPHL is a very specific lymphoma entity that differs from most other lymphomas by its clinical presentation and specific histological picture. Although basic biological principles of this lymphoma are only partly understood, treatment is highly effective leading to a high rate of longterm remissions and a generally very favourable prognosis. Future aims are to completely understand the pathogenetic mechanisms leading to the development of this lymphoma. Acknowledgments: SH is supported by the Deutsche Forschungsgemeinschaft (grant HA6145/3-1). Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Prof Dr Sylvia Hartmann, Dr Senckenberg Institute of Pathology, Goethe University Frankfurt am Main, TheodorStern-Kai 7, 60590, Frankfurt am Main, Germany. E-mail: s.hartmann@ em.uni-frankfurt.de

References 1. Jackson H Jr, Parker F Jr. Hodgkin’s Disease and Allied Disorders. New York: Oxford University Press, 1947.

Pathology (xxxx), xxx(xxx), -

2. Lukes RJ, Butler JJ. The pathology and nomenclature of Hodgkin’s disease. Cancer Res 1966; 26: 1063–83. 3. Lennert K, Mohri N. Histological classification and occurrence of Hodgkin’s disease. (German.) Internist (Berl) 1974; 15: 57–65. 4. 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. Blood 2000; 96: 1889–99. 5. Saarinen S, Pukkala E, Vahteristo P, et al. High familial risk in nodular lymphocyte-predominant Hodgkin lymphoma. J Clin Oncol 2013; 31: 938–43. 6. Hansmann ML, Stein H, Dallenbach F, et al. Diffuse lymphocytepredominant Hodgkin’s disease (diffuse paragranuloma). A variant of the B-cell-derived nodular type. Am J Pathol 1991; 138: 29–36. 7. Hartmann S, Eichenauer DA, Plutschow A, et al. 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. 8. Hartmann S, Winkelmann R, Metcalf RA, et al. Immunoarchitectural patterns of progressive transformation of germinal centers with and without nodular lymphocyte-predominant Hodgkin lymphoma. Hum Pathol 2015; 46: 1655–61. 9. Fan Z, Natkunam Y, Bair E, et al. Characterization of variant patterns of nodular lymphocyte predominant hodgkin lymphoma with immunohistologic and clinical correlation. Am J Surg Pathol 2003; 27: 1346–56. 10. Carbone A, Spina M, Gloghini A, et al. Nodular lymphocyte predominant Hodgkin lymphoma with non-invasive or early invasive growth pattern suggests an early step of the disease with a highly favorable outcome. Am J Hematol 2013; 88: 161–2. 11. Nogova L, Reineke T, Brillant C, et al. Lymphocyte-predominant and classical Hodgkin’s lymphoma: a comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol 2008; 26: 434–9. 12. Lazarovici J, Dartigues P, Brice P, et al. Nodular lymphocyte predominant Hodgkin lymphoma: a Lymphoma Study Association retrospective study. Haematologica 2015; 100: 1579–86. 13. Shankar AG, Kirkwood AA, Hall GW, et al. Childhood and adolescent nodular lymphocyte predominant Hodgkin lymphoma – a review of clinical outcome based on the histological variants. Br J Haematol 2015; 171: 254–62. 14. Panjwani P, Epari S, Sengar M, et al. Bone marrow involvement in nodular lymphocyte predominant Hodgkin lymphoma occurs in tumors with a variant pattern. Leuk Lymphoma 2015; 56: 236–8. 15. Agbay R, Loghavi S, Zuo Z, et al. Bone marrow involvement in patients with nodular lymphocyte predominant hodgkin lymphoma. Am J Surg Pathol 2018; 42: 492–9. 16. Swerdlow S, Campo E, Harris N, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC Press, 2008; 317–34. 17. Achten R, Verhoef G, Vanuytsel L, et al. T-cell/histiocyte-rich large Bcell lymphoma: a distinct clinicopathologic entity. J Clin Oncol 2002; 20: 1269–77. 18. Lim MS, Beaty M, Sorbara L, et al. T-cell/histiocyte-rich large B-cell lymphoma: a heterogeneous entity with derivation from germinal center B cells. Am J Surg Pathol 2002; 26: 1458–66. 19. Prakash S, Fountaine T, Raffeld M, et al. IgD positive L&H cells identify a unique subset of nodular lymphocyte predominant Hodgkin lymphoma. Am J Surg Pathol 2006; 30: 585–92. 20. Marafioti T, Mancini C, Ascani S, et al. Leukocyte-specific phosphoprotein-1 and PU.1: two useful markers for distinguishing Tcell-rich B-cell lymphoma from lymphocyte-predominant Hodgkin’s disease. Haematologica 2004; 89: 957–64. 21. Braeuninger A, Küppers R, Strickler JG, et al. Hodgkin and ReedSternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci USA 1997; 94: 9337–42. 22. Bräuninger A, Küppers R, Spieker T, et al. Molecular analysis of single B cells from T cell-rich B-cell lymphoma shows the derivation of the tumor cells from mutating germinal center B cells and exemplifies means by which immunoglobulin genes are modified in germinal center B cells. Blood 1999; 93: 2679–87. 23. Mottok A, Renne C, Willenbrock K, et al. Somatic hypermutation of SOCS1 in lymphocyte-predominant Hodgkin lymphoma is accompanied by high JAK2 expression and activation of STAT6. Blood 2007; 110: 3387–90. 24. Brune V, Tiacci E, Pfeil I, et al. Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med 2008; 205: 2251–68. 25. Schumacher MA, Schmitz R, Brune V, et al. Mutations in the genes coding for the NF-{kappa}B regulating factors I{kappa}B{alpha} and

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

NLPHL: PATHOLOGY, CLINICAL COURSE AND THRLBCL

26. 27.

28.

29.

30. 31.

32.

33.

34.

35. 36. 37.

38.

39.

40. 41. 42.

43. 44. 45. 46.

47.

A20 are uncommon in nodular lymphocyte-predominant Hodgkin lymphoma. Haematologica 2010; 95: 153–7. Franke S, Wlodarska I, Maes B, et al. Lymphocyte predominance Hodgkin disease is characterized by recurrent genomic imbalances. Blood 2001; 97: 1845–53. Franke S, Wlodarska I, Maes B, et al. Comparative genomic hybridization pattern distinguishes T-cell/histiocyte-rich B-cell lymphoma from nodular lymphocyte predominance Hodgkin’s lymphoma. Am J Pathol 2002; 161: 1861–7. Hartmann S, Doring C, Jakobus C, et al. Nodular lymphocyte predominant hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma – endpoints of a spectrum of one disease? PLoS One 2013; 8: e78812. Hartmann S, Tousseyn T, Doring C, et al. Macrophages in T cell/histiocyte rich large B cell lymphoma strongly express metal-binding proteins and show a bi-activated phenotype. Int J Cancer 2013; 133: 2609–18. Steidl C, Telenius A, Shah SP, et al. Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood 2010; 116: 418–27. Hartmann S, Doring C, Vucic E, et al. Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma. Br J Haematol 2015; 169: 415–22. Wlodarska I, Nooyen P, Maes B, et al. Frequent occurrence of BCL6 rearrangements in nodular lymphocyte predominance Hodgkin lymphoma but not in classical Hodgkin lymphoma. Blood 2003; 101: 706–10. Renné C, Martin-Subero JI, Hansmann ML, et al. Molecular cytogenetic analyses of immunoglobulin loci in nodular lymphocyte predominant Hodgkin’s lymphoma reveal a recurrent IGH-BCL6 juxtaposition. J Mol Diagn 2005; 7: 352–6. Poppe B, De Paepe P, Michaux L, et al. PAX5/IGH rearrangement is a recurrent finding in a subset of aggressive B-NHL with complex chromosomal rearrangements. Genes Chromosomes Cancer 2005; 44: 218–23. Hartmann S, Schuhmacher B, Rausch T, et al. Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma. Leukemia 2016; 30: 844–53. Schuhmacher B, Bein J, Rausch T, et al. JUNB, DUSP2, SGK1, SOCS1 and CREBBP are frequently mutated in T-cell/histiocyte-rich large Bcell lymphoma. Haematologica 2019; 104: 330–7. Nam-Cha SH, Roncador G, Sanchez-Verde L, et al. PD-1, a follicular Tcell marker useful for recognizing nodular lymphocyte-predominant Hodgkin lymphoma. Am J Surg Pathol 2008; 32: 1252–7. Churchill HR, Roncador G, Warnke RA, et al. Programmed death 1 expression in variant immunoarchitectural patterns of nodular lymphocyte predominant Hodgkin lymphoma: comparison with CD57 and lymphomas in the differential diagnosis. Hum Pathol 2010; 41: 1726–34. Rahemtullah A, Reichard KK, Preffer FI, et al. A double-positive CD4+CD8+ T-cell population is commonly found in nodular lymphocyte predominant Hodgkin lymphoma. Am J Clin Pathol 2006; 126: 805–14. Rahemtullah A, Harris NL, Dorn ME, et al. Beyond the lymphocyte predominant cell: CD4+CD8+ T-cells in nodular lymphocyte predominant Hodgkin lymphoma. Leuk Lymphoma 2008; 49: 1870–8. Visser L, Rutgers B, Diepstra A, et al. Characterization of the microenvironment of nodular lymphocyte predominant Hodgkin lymphoma. Int J Mol Sci 2016; 17: 2127. Van Loo P, Tousseyn T, Vanhentenrijk V, et al. T cell/histiocyte rich large B-cell lymphoma shows transcriptional features suggestive of a tolerogenic host immune response. Haematologica 2009; 95: 440– 8. Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 2010; 362: 875–85. Tan KL, Scott DW, Hong F, et al. Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial. Blood 2012; 120: 3280–7. Tzankov A, Matter MS, Dirnhofer S. Refined prognostic role of CD68positive tumor macrophages in the context of the cellular micromilieu of classical Hodgkin lymphoma. Pathobiology 2010; 77: 301–8. Kamper P, Bendix K, Hamilton-Dutoit S, et al. Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin’s lymphoma. Haematologica 2011; 96: 269–76. Eladl AE, Satou A, Elsayed AA, et al. Nodular lymphocyte predominant Hodgkin lymphoma: Clincopathological study of 25 cases from Japan with a reappraisal of tissue associated macrophages. Pathol Int 2015; 65: 652–60.

11

48. Van Goethem E, Poincloux R, Gauffre F, et al. Matrix architecture dictates three-dimensional migration modes of human macrophages: differential involvement of proteases and podosome-like structures. J Immunol 2010; 184: 1049–61. 49. Porrata LF, Ristow K, Colgan JP, et al. Peripheral blood lymphocyte/ monocyte ratio at diagnosis and survival in classical Hodgkin’s lymphoma. Haematologica 2012; 97: 262–9. 50. Porrata LF, Ristow K, Habermann TM, et al. Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in nodular lymphocyte-predominant Hodgkin lymphoma. Br J Haematol 2012; 157: 321–30. 51. Kiil K, Bein J, Schuhmacher B, et al. A high number of IgG4-positive plasma cells rules out nodular lymphocyte predominant Hodgkin lymphoma. Virchows Arch 2018; 473: 759–64. 52. Saarinen S, Aavikko M, Aittomaki K, et al. Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma. Blood 2011; 118: 493–8. 53. Merli M, Maffioli M, Ferrario A, et al. Looking for familial nodular lymphocyte-predominant Hodgkin lymphoma. Am J Hematol 2013; 88: 719–20. 54. Lorenzi L, Tabellini G, Vermi W, et al. Occurrence of nodular lymphocyte-predominant hodgkin lymphoma in hermansky-pudlak type 2 syndrome is associated to natural killer and natural killer T cell defects. PLoS One 2013; 8: e80131. 55. van den Berg A, Maggio E, Diepstra A, et al. Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma. Blood 2002; 99: 1492–4. 56. Poppema S, De Jong B, Atmosoerodjo J, et al. Morphologic, immunologic, enzymehistochemical and chromosomal analysis of a cell line derived from Hodgkin’s disease. Evidence for a B-cell origin of Sternberg-Reed cells. Cancer 1985; 55: 683–90. 57. Poppema S, Visser L, De Jong B, et al. The typical Reed-Sternberg phenotype and Ig gene rearrangement of Hodgkin’s disease derived cell line ZO indicating a B cell origin. Recent Results Cancer Res 1989; 117: 67–74. 58. Atayar C, Kok K, Kluiver J, et al. BCL6 alternative breakpoint region break and homozygous deletion of 17q24 in the nodular lymphocyte predominance type of Hodgkin’s lymphoma-derived cell line DEV. Hum Pathol 2006; 37: 675–83. 59. Liu Y, Abdul Razak FR, Terpstra M, et al. The mutational landscape of Hodgkin lymphoma cell lines determined by whole-exome sequencing. Leukemia 2014; 28: 2248–51. 60. Mottok A, Woolcock B, Chan FC, et al. Genomic alterations in CIITA are frequent in primary mediastinal large B cell lymphoma and are associated with diminished MHC class II expression. Cell Rep 2015; 13: 1418–31. 61. Ma Y, Visser L, Roelofsen H, et al. Proteomics analysis of Hodgkin lymphoma: identification of new players involved in the cross-talk between HRS cells and infiltrating lymphocytes. Blood 2008; 111: 2339–46. 62. Panjwani PK, Charu V, DeLisser M, et al. Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes. Hum Pathol 2018; 71: 91–9. 63. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 2013; 19: 3462–73. 64. Carey CD, Gusenleitner D, Lipschitz M, et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for ReedSternberg cells in Hodgkin lymphoma. Blood 2017; 130: 2420–30. 65. Eichenauer DA, Plutschow A, Fuchs M, et al. Long-term course of patients with stage IA nodular lymphocyte-predominant hodgkin lymphoma: a report from the German Hodgkin Study Group. J Clin Oncol 2015; 33: 2857–62. 66. Chen RC, Chin MS, Ng AK, et al. Early-stage, lymphocyte-predominant Hodgkin’s lymphoma: patient outcomes from a large, single-institution series with long follow-up. J Clin Oncol 2010; 28: 136–41. 67. Eichenauer DA, Fuchs M, Pluetschow A, et al. Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood 2011; 118: 4363–5. 68. Eichenauer DA, Aleman BMP, Andre M, et al. Hodgkin lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and followup. Ann Oncol 2018: 29. iv19–29. 69. Brockelmann PJ, Eichenauer DA, Jakob T, et al. Hodgkin lymphoma in adults. Dtsch Arztebl Int 2018; 115: 535–40. 70. Appel BE, Chen L, Buxton AB, et al. Minimal treatment of lowrisk, pediatric lymphocyte-predominant Hodgkin lymphoma: a report from the Children’s Oncology Group. J Clin Oncol 2016; 34: 2372– 9. 71. Mauz-Korholz C, Gorde-Grosjean S, Hasenclever D, et al. Resection alone in 58 children with limited stage, lymphocyte-predominant

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003

12

72. 73.

74.

75.

76. 77. 78.

79.

80. 81.

82. 83.

84.

HARTMANN

AND

EICHENAUER

Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma. Cancer 2007; 110: 179–85. Borchmann S, Joffe E, Moskowitz CH, et al. Active surveillance for nodular lymphocyte-predominant Hodgkin lymphoma. Blood 2019; 133: 2121–9. Savage KJ, Skinnider B, Al-Mansour M, et al. Treating limited-stage nodular lymphocyte predominant Hodgkin lymphoma similarly to classical Hodgkin lymphoma with ABVD may improve outcome. Blood 2011; 118: 4585–90. Eichenauer DA, Plütschow A, Fuchs M, et al. Long-term outcome of patients with nodular lymphocyte-predominant Hodgkin lymphoma treated within the randomized HD7-HD15 trials: an analysis from the German Hodgkin Study Group. Haematologica 2017; 102: 275. Xing KH, Connors JM, Lai A, et al. Advanced-stage nodular lymphocyte predominant Hodgkin lymphoma compared with classical Hodgkin lymphoma: a matched pair outcome analysis. Blood 2014; 123: 3567–73. Fanale MA, Cheah CY, Rich A, et al. Encouraging activity for R-CHOP in advanced stage nodular lymphocyte-predominant Hodgkin lymphoma. Blood 2017; 130: 472–7. Hartmann S, Plutschow A, Mottok A, et al. The time to relapse correlates with the histopathological growth pattern in nodular lymphocyte predominant Hodgkin lymphoma. Am J Hematol 2019; 94: 1208–13. Rudiger T, Gascoyne RD, Jaffe ES, et al. Workshop on the relationship between nodular lymphocyte predominant Hodgkin’s lymphoma and T cell/histiocyte-rich B cell lymphoma. Ann Oncol 2002; 13 (Suppl 1): 44–51. Sundeen JT, Cossman J, Jaffe ES. Lymphocyte predominant Hodgkin’s disease nodular subtype with coexistent “large cell lymphoma”. Histological progression or composite malignancy? Am J Surg Pathol 1988; 12: 599–606. Hansmann ML, Stein H, Fellbaum C, et al. Nodular paragranuloma can transform into high-grade malignant lymphoma of B type. Hum Pathol 1989; 20: 1169–75. Huang JZ, Weisenburger DD, Vose JM, et al. 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. Al-Mansour M, Connors JM, Gascoyne RD, et al. Transformation to aggressive lymphoma in nodular lymphocyte-predominant Hodgkin’s lymphoma. J Clin Oncol 2010; 28: 793–9. Biasoli I, Stamatoullas A, Meignin V, et al. Nodular, lymphocytepredominant 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. Cotta CV, Coleman JF, Li S, et al. Nodular lymphocyte predominant Hodgkin lymphoma and diffuse large B-cell lymphoma: a study of six cases concurrently involving the same site. Histopathology 2011; 59: 1194–203.

Pathology (xxxx), xxx(xxx), -

85. Hartmann S, Eray M, Doring C, et al. Diffuse large B cell lymphoma derived from nodular lymphocyte predominant Hodgkin lymphoma presents with variable histopathology. BMC Cancer 2014; 14: 332. 86. Schuhmacher B, Rengstl B, Doring C, et al. A strong host response and lack of MYC expression are characteristic for diffuse large B cell lymphoma transformed from nodular lymphocyte predominant Hodgkin lymphoma. Oncotarget 2016; 7: 72197–210. 87. Akhtar S, Montoto S, Boumendil A, et al. High dose chemotherapy and autologous stem cell transplantation in nodular lymphocyte-predominant Hodgkin lymphoma: a retrospective study by the European Society for Blood and Marrow Transplantation – Lymphoma Working Party. Am J Hematol 2018; 93: 40–6. 88. Eichenauer DA, Plutschow A, Schroder L, et al. Relapsed and refractory nodular lymphocyte-predominant Hodgkin lymphoma: an analysis from the German Hodgkin Study Group. Blood 2018; 132: 1519– 25. 89. Schulz H, Rehwald U, Morschhauser F, et al. Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG). Blood 2008; 111: 109–11. 90. Eichenauer DA, Goergen H, Plutschow A, et al. Ofatumumab in relapsed nodular lymphocyte-predominant Hodgkin lymphoma: results of a phase II study from the German Hodgkin study group. Leukemia 2016; 30: 1425–7. 91. Haas RL, Girinsky T, Aleman BM, et al. Low-dose involved-field radiotherapy as alternative treatment of nodular lymphocyte predominance Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 2009; 74: 1199–202. 92. Karuturi M, Hosing C, Fanale M, et al. High-dose chemotherapy and autologous stem cell transplantation for nodular lymphocytepredominant Hodgkin lymphoma. Biol Blood Marrow Transplant 2013; 19: 991–4. 93. Shankar AG, Kirkwood AA, Depani S, et al. Relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents – a report from the United Kingdom’s Children’s Cancer and Leukaemia Study Group. Br J Haematol 2016; 173: 421–31. 94. Eyre TA, Gatter K, Collins GP, et al. Incidence, management, and outcome of high-grade transformation of nodular lymphocyte predominant Hodgkin lymphoma: long-term outcomes from a 30-year experience. Am J Hematol 2015; 90: E103–10. 95. Kenderian SS, Habermann TM, Macon WR, et al. Large B-cell transformation in nodular lymphocyte-predominant Hodgkin lymphoma: 40-year experience from a single institution. Blood 2016; 127: 1960– 6. 96. Nathwani BN, Vornanen M, Winkelmann R, et al. Intranodular clusters of activated cells with T follicular helper phenotype in nodular lymphocyte predominant Hodgkin lymphoma: a pilot study of 32 cases from Finland. Hum Pathol 2013; 44: 1737–46.

Please cite this article as: Hartmann S, Eichenauer DA, Nodular lymphocyte predominant Hodgkin lymphoma: pathology, clinical course and relation to Tcell/histiocyte rich large B-cell lymphoma, Pathology, https://doi.org/10.1016/j.pathol.2019.10.003