Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Hodgkin Lymphoma, Nodular Lymphocyte Predominant

  • Sylvia HartmannEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_3856-1



Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a subtype of Hodgkin lymphoma (HL) with distinct clinical, morphological, immunophenotypical, and molecular features.

Clinical Features

  • Incidence: HL has an incidence of 3:100,000 (Küppers et al. 2012). NLPHL constitutes between 5% and 16% of all HL cases (Saarinen et al. 2013), depending on locoregional differences.

  • Age: NLPHL affects patients of a broad age range. This includes pediatric patients from the age of approximately 5 years up to elderly patients around 80 years (Anagnostopoulos et al. 2000; Shankar et al. 2015). The median age is 40 years.

  • Sex: NLPHL shows an important predominance of the male gender with around 75% of patients being males (Anagnostopoulos et al. 2000). Male patients have a sixfold increased risk of relapse (Hartmann et al. 2013b).

  • Site: NLPHL affects primarily lymph nodes. Most frequently axillary, cervical, and inguinal lymph nodes are affected. Patients with advanced stages usually show involvement of the liver and spleen. The bone marrow may likewise be affected in advanced stages. In relapsed patients, NLPHL can also present with infiltrates in unusual extranodal locations like, e.g., the lung.

  • Treatment: Until recently, the treatment of NLPHL did not relevantly differ from classical HL. Involved field radiotherapy had the lowest risk of toxic effects in early stages of NLPHL (Eichenauer et al. 2015). In pediatric patients with stage I, some centers prefer a watch and wait strategy, as it was shown that only around 50% of the patients develop relapses without treatment when the lymphoma infiltrated lymph node was completely excised (Mauz-Korholz et al. 2007). In recent years, as targeted therapies have become available, treatment of NLPHL differs increasingly from classical HL since the tumor cells of NLPHL, the LP cells, are positive for CD20, have a preserved B-cell receptor (BCR) signaling, and lack CD30 expression. Therefore targeting CD20 and the BCR pathway seems promising in contrast to targeting CD30, which is usually not expressed in the LP cells. However, patients treated exclusively with rituximab presented a higher rate of relapses when compared with patients treated by radiotherapy (Eichenauer et al. 2011). Therefore combined modality approaches should be considered at least in patients with advanced disease (Shankar et al. 2017). As LP cells are mainly negative for PD-L1 (Chen et al. 2013), from an academic standpoint, checkpoint inhibitors are not likely to be effective in this patient population. However, clinical trials evaluating these novel drugs are so far missing.

  • Outcome: NLPHL is diagnosed in a localized stage in most patients and has an excellent prognosis. The overall survival in these localized stages is around 99% (Eichenauer et al. 2015) and is even better than in classical HL. However, NLPHL patients more frequently develop late relapses, which can occur even after 20 years (Al-Mansour et al. 2010; Biasoli et al. 2010). Usually, these can still very well be treated. However, a certain number of patients develop a transformation into a diffuse large B-cell lymphoma (DLBCL) in the relapse situation, which requires more aggressive treatment. Some patients are already initially diagnosed with a composite lymphoma of NLPHL and clonally related DLBCL (Hartmann et al. 2014b), which is particularly the case in patients with longer standing disease or with intraabdominal masses.


Lymph nodes affected by NLPHL are usually markedly enlarged with sizes ranging around 5 cm. This is probably related to the slowly growing nature of NLPHL. The cut surface is gray tan, and often already macroscopically a nodular aspect is observed.


Generally, lymph nodes involved by NLPHL present an abundant microenvironment with only few LP cells, which usually represent less than 1% of the infiltrate (Küppers 2009). LP cells are relatively large cells with a high nuclear-cytoplasmic ratio and lobulated nuclei, which often resemble popcorn and are therefore sometimes also called popcorn cells (Fig. 1). In 2003, six different histopathological NLPHL growth patterns were described by Fan et al. (2003) (Fig. 2). These patterns include two variants (A and B) with nodular infiltrates composed mainly of small reactive B cells which contain scattered tumor cells. The other patterns (C–E) are characterized by a T-cell-rich background which can contain variable amounts of histiocytes (pattern E). Whereas in patterns C and D, the nodular structure is preserved, pattern E frequently has extensive areas with a purely diffuse infiltrate and a high histiocyte content and can therefore easily be confused with T-cell-/histiocyte-rich large B-cell lymphoma, particularly in fine needle biopsies. Finally, pattern F shows LP cells in a diffuse B-cell-rich background. Whereas these different patterns are difficult to recognize in HE staining, they become visible in the CD20 immunohistochemical staining which both highlights the neoplastic LP cells and reactive bystander B cells. Atypical patterns C–F more frequently present with an advanced stage and are at higher risk to develop a relapse (Hartmann et al. 2013b). NLPHL cases with pattern E according to Fan et al. (2003) usually have clinical features indistinguishable from T-cell-/histiocyte-rich large B-cell lymphoma (THRLBCL) (Hartmann et al. 2013a).
Fig. 1

LP cells of NLPHL are highlighted by arrows (HE staining, 400x)

Fig. 2

Six different NLPHL growth patterns as described by Fan et al. (2003). (a) Classical, B-cell-rich nodular pattern. (b) Serpiginous-interconnected pattern. (c) Prominent extranodular LP cells. (d) T-cell-rich nodular pattern. (e) Diffuse THRLBCL-like pattern. (f) Diffuse moth-eaten B-cell-rich pattern. CD20 immunostaining, 40x


LP cells have an immunophenotype comparable to germinal center (GC) B cells and express CD20, CD79a, CD19, PAX5, OCT2, and BCL6 (Küppers 2009). In contrast to GC B cells, they are usually negative for CD10 and weakly express BCL2 and MUM1. Approximately 1/3 of NLPHL shows IgD expression in the LP cells; these are particularly young male patients (Prakash et al. 2006). Apart from IgD expression in a subset of NLPHL and the usually observed absence of CD10 expression, there is no marker, which clearly differentiates between LP cells and reactive GC B cells. In contrast to Hodgkin-Reed-Sternberg cells of classical HL, LP cells are negative for CD30, CD15, and EBV in the vast majority of cases (Anagnostopoulos et al. 2000; Hartmann et al. 2014a; Huppmann et al. 2014). When double stainings are applied, it also becomes clear that CD30- and CD15-positive and EBV-infected cells do not represent the neoplastic population in most cases with positive cells (Hartmann et al. 2014a). However, there are cases which express CD30 or CD15 in the LP cells, and these cases are more frequently found among NLPHL with transformation into aggressive B-cell lymphoma (Hartmann et al. 2014b). Also very rare cases with EBV-infected LP cells exist (Anagnostopoulos et al. 2000; Huppmann et al. 2014). LP cells can be positive for HIGD1A, BAG6, FAT10, CXCL13, and ICOS in a subset of NLPHL cases (Hartmann et al. 2013a). Apart from ICOS and CXCL13, these markers are also expressed by germinal center (GC) B cells.

Despite the fact that there is no clearly discriminative marker between LP cells and GC B cells, OCT2 beautifully highlights the LP cells in the background of OCT2-weakly positive mantle zone B cells (Fig. 3). However, to make the diagnosis of NLPHL, an integration of immunohistochemical and morphologic parameters is required. This also extends to the presence of rosetting T cells around the neoplastic LP cells. Rosetting T cells are most frequently found in the nodular patterns (A and B according to Fan et al. (2003)) but can also occur in all other patterns at a lower frequency. Particularly in fine needle biopsies, the presence of rosetting T cells can help to delineate NLPHL from reactive conditions. Rosetting T cells are positive for CD3 and PD1 and can be positive for CXCL13, ICOS, and MUM1. A subpopulation of follicular T helper cells rosetting around LP cells if furthermore CD57-positive (Sattarzadeh et al. 2015), which is typical for NLPHL. In the cases with typical nodular NLPHL infiltrates, rosetting T cells are much more frequently observed than in NLPHL cases with atypical growth patterns and particularly the cases with T-cell-/histiocyte-rich large B-cell lymphoma-like areas (Churchill et al. 2010; Hartmann et al. 2013a). In the microenvironment of NLPHL, furthermore, a double-positive CD4+CD8+ T-cell population has been identified, which can help in establishing the diagnosis of NLPHL when flow cytometry is applied (Rahemtullah et al. 2006, 2008).
Fig. 3

Typical NLPHL growth pattern in Oct2 staining, highlighting the LP cells by a strong nuclear and weak cytoplasmic staining and showing a weaker nuclear staining in all reactive B cells. (a) 50x, (b) 300x

Molecular Features

The LP cells of NLPHL show mutated immunoglobulin genes with an intraclonal diversity of mutations, known as ongoing somatic hypermutation (Braeuninger et al. 1997). This indicates that they derive from GC B cells. BCL6 is probably the most important deregulated gene in NLPHL, which acts as an oncogene. LP cells are strongly BCL6-positive in all NLPHL cases (Carbone et al. 1998; Hartmann et al. 2014b). In approximately 1/3 of NLPHL cases, the LP cells present translocations affecting the BCL6 locus (Wlodarska et al. 2003). The translocation partners include immunoglobulin (IG) and non-IG genes (Renné et al. 2005). Further cases present genomic gains of the BCL6 locus (Bakhirev et al. 2014). Moreover, like in classical HL, genomic gains of the REL locus have been found in LP cells, which, however, correlated only in few cases with nuclear REL protein expression (Hartmann et al. 2015a). Somatic mutations of PIM1, RhoH/TTF, MYC, PAX5, SOCS1, DUSP2, JUNB, and SGK1 have been observed in the LP cells (Hartmann et al. 2016; Liso et al. 2006; Mottok et al. 2007). PIM1, RhoH/TTF, MYC, PAX5, and SOCS1 were shown to be targets of aberrant somatic hypermutation in LP cells. For SOCS1 even an intraclonal diversity of individual mutations with a stepwise accumulation of mutations was observed in line with ongoing somatic hypermutation in LP cells. In contrast, mutations of DUSP2, JUNB, and SGK1 occurred only in part in RGYW motifs, but these were not significantly enriched, indicating that other mechanisms apart from aberrant somatic hypermutation contribute to the mutational landscape of LP cells. Application of a specific SGK1 inhibitor could induce a high rate of apoptotic cells in the NLPHL cell line DEV, which strongly expresses SGK1 (Hartmann et al. 2016). It was furthermore observed that chromothripsis can occur in the transformation into DLBCL (Hartmann et al. 2016). Related to the defects in the SOCS1 gene, LP cells have an active JAK-STAT signaling. Furthermore, NF-kappaB signaling is constitutively active in LP cells (Brune et al. 2008).

Familial cases of NLPHL have been described. In one Finnish series, these could be correlated to germline NPAT mutations (Saarinen et al. 2011).

Differential Diagnosis

Various differential diagnoses to NLPHL exist. The first and most important as well as most difficult differential diagnosis to the histopathological NLPHL variants C–E is THRLBCL. Since the immunophenotype of the LP cells in NLPHL is usually identical to the one observed in the tumor cells of THRLBCL, the diagnosis of NLPHL and THRLBCL depends very much on the composition and distribution of microenvironmental cells, in particular reactive B cells, T cells, and histiocytes/epithelioid cells. Whereas in NLPHL pattern E, according to Fan et al. (2003), the criterium for the diagnosis of NLPHL is the presence of at least one typical NLPHL nodule, the immunophenotype of the tumor cells and the microenvironment, which is rich in histiocyte and epithelioid cells, can be indistinguishable from THRLBCL. In contrast, in the NLPHL variants C and D according to Fan et al. (2003), the microenvironment is dominated by T cells with variable amounts of B cells, small numbers of histiocytes, and usually some retained nodularity. Thus, these NLPHL variants can usually be well differentiated from THRLBCL, although the immunophenotype of the tumor cells may be identical.

Another differential diagnosis to NLPHL represents classical HL with a preserved B-cell phenotype. Many of these cases show EBV-infected tumor cells, and thus NLPHL can be excluded. In cases which do not show one of the typical Fan growth patterns (Fan et al. 2003) and which do not present an immunophenotype typical for NLPHL, classical HL as differential diagnosis to NLPHL must be excluded. Whereas in NLPHL LP cells can sometimes show a positivity for either CD30 or CD15, in Hodgkin-Reed-Sternberg (HRS), cells in classical HL are frequently positive for both CD30 and CD15. In CD20-positive classical HL cases, CD20 is frequently only weakly and variably expressed by the HRS cells, and other B-cell markers are lacking. LP cells in NLPHL sometimes present a slightly downregulated CD20 (and can even be CD20-negative in relapses after rituximab therapy), but other B-cell markers usually remain expressed (Tedoldi et al. 2007). OCT2 and BOB.1 are usually strongly and homogeneously expressed in the LP cells, whereas the majority of classical HL cases show absence or a weak and heterogeneous labeling of HRS cells by OCT2 and BOB.1 (Stein et al. 2001). Another transcription factor, which is usually expressed in LP cells of NLPHL, but absent in HRS cells of classical HL, is PU.1 (Torlakovic et al. 2001). PU.1 regulates the expression of immunoglobulin and other genes that are important for B-cell development. Consistently, IgD expression and a preferential kappa light chain restriction can be observed in the LP cells of NLPHL, but not in the HRS cells of classical HL (Prakash et al. 2006; Schmid et al. 1991).

On the other hand, various types of peripheral T-cell lymphomas presenting Hodgkin-like B cells are a differential diagnosis to NLPHL (Quintanilla-Martinez et al. 1999), particularly in elderly patients. Hodgkin-like blastoid B cells usually show a preserved B-cell phenotype, but they most frequently are EBV-infected (Nicolae et al. 2013). Whereas rosetting T cells in NLPHL present a follicular T helper (TFH) cell phenotype with expression of PD1, CD57, ICOS, CXCL13, and sometimes MUM1 or BCL6, they are almost always CD10-negative. In contrast, a strong CD10 expression in rosetting T cells is usually indicative of the presence of a follicular T-cell lymphoma (Moroch et al. 2012). These can show an NLPHL-like growth pattern, but in most cases the Hodgkin-like blasts do not show the typical popcorn-like morphology of LP cells and are usually positive for EBV and both CD30 and CD15 (Nicolae et al. 2013). Furthermore, the NLPHL-like growth pattern cannot be classified as one of the typical Fan patterns.

Progressive transformation of GC (PTGC) is another differential diagnosis, which applies to cases with initial involvement of a lymph node by NLPHL. Early manifestations of NLPHL can be associated with PTGC. Therefore, lymph nodes with PTGC should be totally embedded and carefully studied. Sometimes evolving NLPHL is found in only one or two nodules, whereas all other nodules correspond to typical PTGC nodules. PTGC also follows a constant mechanism which creates typical morphologic patterns, allowing a differentiation from early NLPHL (Hartmann et al. 2015b). Another helpful feature is the presence of rosetting T cells in NLPHL, which do not occur in PTGC. However, double-positive CD4+CD8+ T cells, which are observed in NLPHL, also occur in PTGC (Rahemtullah et al. 2008).

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Authors and Affiliations

  1. 1.Dr. Senckenberg Institute of PathologyUniversity Hospital of Goethe University Frankfurt/MainFrankfurt/MainGermany