Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging

INTRODUCTION — Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon category of Hodgkin lymphoma (HL). The pathobiology, pathologic features, clinical presentation, treatment, and prognosis distinguish NLPHL from other categories of HL, which are collectively referred to as classic HL (cHL).

In recognition of these distinctions, NLPHL was renamed "nodular lymphocyte-predominant B cell lymphoma" in the International Consensus Classification (ICC) of mature lymphoid neoplasms [1]. The 5th edition of the World Health Organization (WHO5) classification of hematolymphoid neoplasms maintained the name NLPHL [2].

The epidemiology, pathogenesis, clinical manifestations, pathology, diagnosis, and differential diagnosis of NLPHL are reviewed here.

Treatment and prognosis of NLPHL are discussed separately. (See "Treatment of nodular lymphocyte-predominant Hodgkin lymphoma".)

EPIDEMIOLOGY — NLPHL accounts for approximately 5 percent of patients diagnosed with Hodgkin lymphoma (HL) [3]. The incidence of NLPHL in the United States and Europe has been stable at approximately 8 to 9 cases per 10,000,000 people per year, but the incidence in children may be rising [4,5].

Approximately 75 percent of patients with NLPHL are male [4]. The age distribution has two peaks: one in children and one in adults, the latter with a median age of 30 to 40 years [6,7]. In the United States, NLPHL is more common among Black Americans than White Americans, which distinguishes it from classic HL (cHL) [4].

NLPHL occurs with higher than expected frequency among first-degree family members of patients with NLPHL, as demonstrated by an analysis of 692 patients with NLPHL and their 4280 first-degree relatives in the Finnish Cancer Registry [7]. NLPHL, cHL, and non-Hodgkin lymphoma (NHL) were diagnosed in 9, 15, and 35 first-degree relatives, respectively. Compared with age-, sex-, and race-matched individuals from a general population, relatives of patients with NLPHL had a higher rate of developing NLPHL (standardized incidence ratio [SIR] 19; 95% CI 8.8-36), cHL (SIR 5.3; 95% CI 3-8.8), and NHL (SIR 1.9; 95% CI 1.3-2.6); the incidence of cancer overall was not increased in family members (SIR 1.1; 95% CI 1.1-1.2).

PATHOGENESIS — The malignant cells of NLPHL are referred to here as lymphocyte predominant (LP) cells. For historical reasons and because of previous uncertainty about their nature, LP cells were formerly called lymphocytic-histiocytic variants by pathologists.

LP cells are derived from transformed germinal center B (GCB) cells, but the bulk of the tumor mass in NLPHL consists of abundant reactive (nonmalignant) cells that surround the LP cells. Although LP cells and the malignant Hodgkin/Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma (cHL) are both derived from GCB cells, LP cells are morphologically distinct, are not associated with production of proinflammatory cytokines, utilize different mechanisms to sustain growth and survival, and are surrounded by a different mixture of reactive cells than those that surround HRS cells in cHL. The pathogenesis of cHL is discussed separately. (See "Pathogenesis of Hodgkin lymphoma", section on 'Pathogenesis of cHL'.)

●LP cells, the malignant cells of NLPHL – The origin of LP cells from transformed GCB cells is demonstrated by the presence of productive immunoglobulin (Ig) rearrangements and somatic hypermutation of Ig genes [8-10]. LP cells (picture 1) are morphologically distinct from HRS cells of cHL (picture 2). (See 'LP cells' below.)

●Molecular/genetic findings – The genetic changes associated with NLPHL and how they contribute to the pathogenesis of NLPHL are not well characterized. Somatic hypermutation, which is a characteristic feature of GCB cells, may be misdirected (ie, off-target) in LP cells and contribute to some of the mutations associated with NLPHL. Like other GCB-derived tumors, rearrangements of BCL6 are present in a minority of cases [11]. In some cases, loss-of-function mutations in SOCS1 (a negative regulator of JAK-STAT signaling) can lead to hyperactivation of STAT6 [12]. In two cases of large cell transformation of NLPHL, next-generation sequencing (NGS) of LP cells reported mutations of SOCS1, JUNB (transcription factor JunB), DUSP2 (dual specificity protein phosphatase 2), and SGK1 (serum/glucocorticoid regulated kinase 1), but the roles of these mutations in the pathogenesis of NLPHL remain to be defined [13]. Chronic antigenic stimulation by the common bacterium, Moraxella catarrhalis, may play a role in the pathogenesis of NLPHL, based on identification of B cell receptors expressed by LP cells that specifically recognize Moraxella antigens in a subset of cases [14].

●Cell signaling and cytokine production – Like normal GCB cells, growth and survival of LP cells appear to depend on signals produced by the Ig receptor and interactions with dendritic cells and follicular T cells within B cell follicles [15]. By contrast, HRS cells of cHL lack Ig receptor signaling and instead depend on signals transmitted by other receptors (eg, CD30 and CD40 or, in Epstein-Barr virus [EBV]-associated cases, the EBV-encoded protein LMP1) to activate the transcription factor nuclear factor kappa-B (NF-kB) [16,17].

LP cells are not a rich source of proinflammatory cytokines and chemokines, and as a result, systemic B symptoms (eg, fever, sweats, weight loss) are not typically associated with NLPHL. This contrasts with the broad array of inflammatory cytokines and chemokines produced by HRS cells of cHL, which have both local and systemic effects. (See "Pathogenesis of Hodgkin lymphoma", section on 'Cytokines/chemokines'.)

●Lymph node milieu – LP cells are typically found within expanded B cell follicles that are rich in follicular dendritic cells and CD4+, CD57+, PD1+ follicular helper T cells. Crosstalk between LP cells and the surrounding reactive cells differs from that of HRS cells despite their shared origins as transformed GCB cells.

Progressive transformation of germinal centers (PTGC) has been described in patients who later develop NLPHL, but the nature of the association of PTGC with NLPHL is uncertain [18]. (See 'Progressive transformation of germinal centers' below.)

●Epstein-Barr virus – EBV is rarely detected in NLPHL, whereas EBV is detected in many cases of cHL, particularly the mixed cellularity and lymphocyte depleted subtypes [3,19-21]. Rare cases of EBV-associated NLPHL generally have atypical features that are reminiscent of lymphocyte-rich cHL [22]. (See "Pathogenesis of Hodgkin lymphoma".)

CLINICAL MANIFESTATIONS — The following symptoms and signs were present at diagnosis in the two largest series of patients with NLPHL [23-25]:

●Lymphadenopathy – Lymphadenopathy (present in 100 percent of patients) tends to present as a chronic, asymptomatic lymphadenopathy involving peripheral lymph nodes (above or below the diaphragm) that are easily detected by physical examination [23-25]. In contrast, central lymph node involvement is less common, with a mediastinal mass present in only 2 to 7 percent of patients.

●Constitutional (B) symptoms – B symptoms (fever, drenching night sweats, weight loss) are uncommon at presentation (6 to 15 percent) [6]. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'B symptoms'.)

●Organomegaly – Organomegaly is uncommon, with spleen involvement in 8 percent and liver involvement in 2 to 3 percent [6,26].

●Bone marrow – Bone marrow involvement by NLPHL is rare; marrow involvement has been reported in 1 to 2 percent of cases [6,26,27].

In a study of 275 patients diagnosed with NLPHL, only seven patients with purely nodular NLPHL had bone marrow involvement [27]. Notably, patients with marrow involvement typically had prior clinical, laboratory, radiologic, or morphologic evidence of aggressive disease or hematologic abnormalities. At least some of these patients may have actually had T cell/histiocyte-rich B cell lymphoma (T/HRBCL; a variant of diffuse large B cell lymphoma), which commonly involves bone marrow and the spleen and may be difficult to distinguish from NLPHL. (See 'T cell/HRBCL' below.)

●Lung involvement – Lung involvement, which can be manifest as a pulmonary lymphoid infiltrate, has been reported in 1 to 4 percent of patients at presentation [6,26,28].

●Bone – Skeletal involvement was reported in 1 to 3 percent of patients [6,26].

Approximately 75 percent of patients with NLPHL present with early stage disease (ie, stages I or II) (table 1) [24].

PATHOLOGY — Histologic and immunophenotypic characteristics are the bases for distinguishing NLPHL (table 2) from classic Hodgkin lymphoma (cHL).

Morphology — In NLPHL, the lymph node architecture is totally or partially replaced by a nodular or mixed nodular and diffuse infiltrate composed predominantly of small lymphocytes, macrophages, and epithelioid histiocytes admixed with variable numbers of intermingled lymphocyte predominant (LP) cells [3].

LP cells — A key morphologic feature of NLPHL is the presence of LP cells (picture 1) (also called "popcorn cells" because the nucleus resembles an exploded popcorn kernel), which are the malignant component of NLPHL. LP cells are large and usually have a single large vesicular, polylobulated nucleus and distinct but small and usually peripheral nucleoli, without perinucleolar halos [29]. The presence of LP cells is required for the diagnosis of NLPHL, but cells with similar morphology can be seen in other disorders. (See 'Differential diagnosis' below.)

Background cells — NLPHL is characterized by scattered LP cells in a background of small B lymphocytes, follicular dendritic cells, and CD4+, CD57+, PD1+ follicular helper T lymphocytes, which often form rosettes around the LP cells [30]. By contrast, the histology of cHL is typically characterized by scattered Hodgkin/Reed-Sternberg (HRS) cells in a polymorphous background of acute and chronic inflammatory cells.

Growth pattern — Over 80 percent of cases of NLPHL have a distinctly nodular architecture. The nodular pattern is enhanced by stains for follicular dendritic cell markers (eg, CD21, CD23), which typically highlights expanded follicles that are rich in small resting B cells and LP cells (picture 3).

Variant growth patterns of NLPHL have been described that are often associated with higher-stage disease, greater incidence of recurrence, and worse overall outcome [31]. In some of these variants, a predominantly diffuse architecture is seen, and such cases may be difficult to distinguish from other entities, such as the lymphocyte-rich variant of cHL and T cell/histiocyte-rich B cell lymphoma [2]. In other instances, typical NLPHL acquires a diffuse growth pattern as part of a transformation to diffuse large B cell lymphoma (DLBCL) or T cell/histiocyte-rich B cell lymphoma (T/HRBCL) [32]. In cases of transformation to DLBCL, the mutational profile of the transformed tumor resembles that of germinal center B (GCB) subtype of DLBCL [33]. (See 'T cell/HRBCL' below.)

It is uncertain if purely diffuse cases of NLPHL exist [34]. In the World Health Organization (WHO) classification, it is recommended that diffuse cases that lack admixed follicular dendritic cells be classified as T/HRBCL rather than NLPHL [35]. (See 'Lymphocyte-rich classic HL' below.)

Immunophenotype — The characteristic immunophenotype of LP cells is an important aspect of distinguishing NLPHL from cHL.

LP cells express the B cell antigens (CD19, CD20, CD22, CD79a), CD45 (leukocyte common antigen), and the transcription factors BOB-1 and OCT-2; they do not express CD15 and they rarely express CD30 (picture 4) [3,36]. By contrast, HRS cells of cHL are typically CD15+, CD30+, CD45-, CD20- and usually lose expression of BOB-1 and/or OCT-2 (table 2). (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Nodular lymphocyte-predominant HL'.)

DIAGNOSIS — NLPHL may be suspected in a patient with chronic, asymptomatic peripheral lymphadenopathy.

Diagnosis requires demonstration of the characteristic morphologic and immunophenotypic features on a lymph node biopsy. We strongly encourage an excisional lymph node biopsy for the diagnosis of NLPHL, when possible. Distinguishing NLPHL from other conditions in the differential diagnosis relies on morphologic differences that may be difficult to appreciate in core biopsies and fine needle aspiration (FNA). Because NLPHL is an uncommon disease, it is most reliably diagnosed by an experienced hematopathologist.

The following features are components of the diagnosis of NLPHL (table 2) [3]:

●Histology – The presence of neoplastic lymphocyte predominant (LP) cells within the background of a fully or partially nodular growth pattern.

●Immunophenotype – LP cells are typically CD20+, CD45+, CD15-, and CD30-. An expanded set of markers, including epithelial membrane antigen (EMA) and other B cell markers, such as CD79a and the transcription factors BOB-1 and OCT-2, can be helpful in ambiguous cases.

●Cellular milieu – Background cells primarily consist of small B lymphocytes; CD3+, CD4+, CD57+, PD1+ follicular helper T cells; and CD21+, CD23+ follicular dendritic cells. Although flow cytometry is of limited utility in diagnosing NLPHL, background activated CD4+ T cells sometimes express low levels of CD8, which can be a clue to the presence of NLPHL.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of NLPHL includes both non-malignant and malignant causes of lymphadenopathy. It is particularly important to distinguish NLPHL from lymphomas with a distinctive prognosis and those that require different treatment (table 3). The importance of an excisional lymph node biopsy to distinguish NLPHL from other conditions in the differential diagnosis is discussed above. (See 'Diagnosis' above.)

Most patients with NLPHL present with peripheral lymphadenopathy. The numerous other causes of lymphadenopathy include infectious, autoimmune, benign, and malignant conditions. A general approach to the evaluation of lymphadenopathy in adults is presented separately. (See "Evaluation of peripheral lymphadenopathy in adults".)

Progressive transformation of germinal centers — Progressive transformation of germinal centers (PTGC) is an uncommon condition that is often associated with a chronic inflammatory or autoimmune disorder. It typically presents as unexplained, asymptomatic, persistent, or recurrent lymphadenopathy. Lymph node biopsy of PTGC is characterized by at least one enlarged follicle (ie, three to five times the size of a normal reactive follicle) showing a predominance of small mantle zone B cells that become admixed with, and eventually replace, the underlying germinal center [37,38]. While some patients with PTGC may later develop NLPHL or another lymphoma, PTGC is not considered to be a premalignant condition.

The absence of lymphocyte predominant (LP) cells distinguishes PTGC from NLPHL, but malignant LP cells may be missed on initial pathologic review. Biopsies interpreted as PTGC should be re-evaluated to make certain that a diagnosis of NLPHL is not missed.

T cell/HRBCL — T cell/histiocyte-rich B cell lymphoma (T/HRBCL) is a variant of diffuse large B cell lymphoma (DLBCL) that can be challenging to distinguish from NLPHL because of similar morphology and an identical immunophenotype; some experts consider these tumors to be part of a biologic continuum [34,39]. In support of this idea, T/HRBCL is associated with mutations in JUNB, DUSP2, SGK1, and SOCS1, the same genes that appear to be commonly mutated in NLPHL [40].

It is important to distinguish T/HRBCL from NLPHL because of their distinct natural histories and different treatment approaches. Because the growth pattern is difficult to ascertain in core needle biopsies, surgical lymph node biopsy may be needed. NLPHL usually presents as low-stage disease and follows an indolent course, whereas most cases of T/HRBCL present as high-stage disease and have poorer outcomes [41]. The key features that distinguish T/HRBCL from NLPHL are the growth pattern (table 3) and composition of the background cells [3]:

●Growth pattern – The growth pattern in T/HRBCL is diffuse, whereas the growth pattern in NLPHL is usually at least partially nodular [3,21]. Because the growth pattern is difficult to ascertain in core needle biopsies, lymph node biopsy may be necessary to arrive at a definitive diagnosis.

●Malignant cells – In both T/HRBCL and NLPHL, involved nodes contain scattered neoplastic CD20+ B cells within a reactive background. The neoplastic cells in T/HRBCL can resemble LP cells, but they may also appear like centroblasts, immunoblasts, or the Hodgkin/Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma (cHL).

●Background cells – The background cells in T/HRBCL differ from those of NLPHL. In T/HRBCL, the background cells are predominantly CD8+ cytotoxic T cells and macrophages, while follicular dendritic cells are absent. By contrast, the typical background of NLPHL consists primarily of small B lymphocytes; CD3+, CD4+, CD57+, PD1+ follicular helper T cells; and follicular dendritic cells.

The World Health Organization (WHO) classification system acknowledges that NLPHL occasionally transforms to a tumor identical in appearance and immunophenotype to T/HRBCL and recommends that such cases be diagnosed as T/HRBCL-like transformations [3]. Such transformation is associated with the loss of background dendritic cells.

Lymphocyte-rich classic HL — Lymphocyte-rich classic Hodgkin lymphoma (LRCHL) is a variant of cHL that can be difficult to distinguish from NLPHL [42]. Both conditions have similar clinical presentations, including predominantly early stage, nonbulky disease, and absence of B symptoms. Histologically, LRCHL contains characteristic HRS cells in a background of small lymphocytes with a predominantly nodular pattern although, occasionally, it can be diffuse. Typical LP cells are not seen.

In addition to the presence of characteristic HRS cells and the absence of LP cells, immunophenotypic differences help to distinguish LRCHL from NLPHL (table 3). LRCHL is also much more likely to be positive for Epstein-Barr virus (table 2). (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Immunophenotype'.)

STAGING — Staging of NLPHL is based on clinical evaluation, laboratory studies, and positron emission tomography (PET)/computed tomography (CT) according to Lugano criteria (table 1). Bone marrow examination is not routinely performed unless there are unexplained cytopenias or other suspicion for marrow involvement.

Additional details of staging are provided separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

History and physical examination — The history should include documentation of constitutional (B) symptoms (fever, sweats, weight loss), and physical examination should evaluate all accessible lymph node stations, liver, and spleen.

Laboratory studies — The following laboratory studies should be obtained:

●Complete blood cell count with differential

●Serum chemistries – Chemistries should include serum electrolytes, glucose, renal and liver function tests, lactate dehydrogenase (LDH), and calcium

●Viral studies – HIV and viral hepatitis tests

PET/CT — PET/CT should be performed to document regions of lymph node and organ involvement [43,44].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging" and "Society guideline links: Management of Hodgkin lymphoma".)

SUMMARY

●Description – Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon subtype (approximately 5 percent) of Hodgkin lymphoma (HL). NLPHL differs importantly from the other subtypes of HL, which are referred to collectively as classic HL (cHL).

●Epidemiology – NLPHL accounts for approximately 5 percent of Hodgkin lymphoma. It has a bimodal age distribution (childhood and age 30 to 40 years), and it is more common in males than females. (See 'Epidemiology' above.)

●Pathogenesis – The malignant cells of NLPHL (named LP cells) are derived from germinal center B (GCB) cells. LP cells are typically found within expanded B cell follicles that are rich in follicular dendritic cells and a distinctive population of CD3+, CD4+, CD57+ T cells. LP cells appear to depend on immunoglobulin receptor signaling for growth and survival. (See 'Pathogenesis' above.)

●Clinical presentation – NLPHL generally presents as chronic, asymptomatic peripheral lymphadenopathy that is detectable by physical examination. Mediastinal, splenic, liver, and bone marrow involvement and constitutional (B) symptoms are uncommon. Most patients present with early-stage disease (ie, stage I or II). (See 'Clinical manifestations' above.)

●Pathology – A key morphologic feature of NLPHL is the presence of LP cells (picture 1) (also called popcorn cells, due to their microscopic appearance) with a characteristic immunophenotype, in the context of a fully or partially nodular growth pattern and with a background of predominantly small B lymphocytes, follicular helper T cells, and follicular dendritic cells. (See 'Pathology' above.)

●Diagnosis – NLPHL may be suspected in a patient with chronic, asymptomatic peripheral lymphadenopathy. (See 'Diagnosis' above.)

Diagnosis requires an excisional lymph node biopsy; core biopsies and fine needle aspiration are generally not sufficient to distinguish NLPHL from other disorders.

Diagnosis includes:

•Histology – LP cells within the background of a fully or partially nodular growth pattern.

•Immunophenotype – LP cells are typically CD20+, CD45+, CD15-, and CD30-.

Additional markers (eg, epithelial membrane antigen [EMA], CD79a, BOB-1, OCT-2) can be helpful in ambiguous cases.

•Cellular milieu – Background cells that primarily consist of small B lymphocytes, CD3+, CD4+, CD57+, PD1+ follicular helper T cells; and CD21+, CD23+ follicular dendritic cells.

●Differential diagnosis – The differential diagnosis includes nonmalignant and malignant causes of lymphadenopathy (table 3). The distinction between NLPHL and other conditions is best made by an experienced hematopathologist. (See 'Differential diagnosis' above.)

NLPHL should be distinguished from:

•Progressive transformation of germinal centers (see 'Progressive transformation of germinal centers' above)

•T cell/histiocyte-rich B cell lymphoma (see 'T cell/HRBCL' above)

•Lymphocyte-rich cHL (table 2) (see 'Lymphocyte-rich classic HL' above)  

●Staging – Staging is based on clinical evaluation, laboratory studies, and positron emission tomography (PET)/CT, according to Lugano criteria (table 1). Bone marrow examination is not routinely performed unless there are unexplained cytopenias or other suspicion of marrow involvement. (See 'Staging' above.)

ACKNOWLEDGMENT — UpToDate acknowledges the contributions of the late Peter M Mauch, MD, who was a previous author for this topic.