Nodular Lymphocyte Predominant Hodgkin Lymphoma: A Rare Subtype with Distinct Clinicopathological Features

Shreya Bramhe¹, Seema Rao^1*, Shashi Dhawan¹

¹Department of Histopathology, Sir Ganga Gam Hospital, New Delhi

Abstract

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma (HL) characterized by a distinct morphology, an older median age at onset, less incidence of mediastinal involvement, more frequent relapse and better prognosis as compared to Classical-HL (CHL). In contrast to CHL, the tumor cell (LP cell) of NLPHL almost always retains its B cell phenotype and is a CD30 non-expresser. Due to its rarity, only a handful of studies on this entity are available in the literature. We present a short case series of 10 cases of NLPHL diagnosed in our institute over 10 years. A total of 10 cases of NLPHL were retrospectively accessed, re-evaluated and classified further, based on various morphological patterns and immunophenotypic expression. Morphological patterns were correlated with overall the prognosis. Our study showed peripheral lymph node localization and overall good outcome in these cases. We also came across two unique cases, one was of NLPHL with Rosai-Dorfman disease (RDD) and another was of composite lymphoma showing components of NLPHL and Diffuse Large B cell Lymphoma (DLBCL).

Keywords: NLPHL, Nodular lymphocyte predominant Hodgkin lymphoma, NLPHL with special cases, NLPHL case series, NLPHL case series with special cases

Seven cases showed pure morphologic patterns, including pattern A and pattern C in 3 cases each, and pattern E in 1 case (Figures 1a-1f). Three cases showed mixed patterns (Table 1), with pattern C being the predominant pattern in 2 cases and pattern A in 1 case.

On IHC, CD20 consistently highlighted the LP cells in all the cases (10/10). CD3 positive T-cells were forming collarette around the neoplastic LP cells and were consistently found in all cases. The majority of the cases were CD30 (8/10 cases) and CD15 (9/10 cases) negative. However, an occasional case showed few tumor cells expressing weak staining for CD30 and CD15. Other IHC markers (PAX5, EMA and BCL6) also proved to be contributing to the diagnosis of NLPHL. Thus the IHC profile in all the cases was consistent with the diagnosis of NLPHL. Details of the IHC used are mentioned in Table 2. Bone marrow biopsy report was available in 4 cases that didn’t show any disease.

S= Strong, W=Weak, D=Diffuse, F=Focal, NA= Not Available

We also came across two interesting cases in our series. One case showed the presence of NLPHL in one axillary lymph node and DLBCL in another (ipsilateral) axillary lymph node (composite lymphoma). Another case showed coexistent NLPHL and Rosai-Dorfman disease (RDD) in the same (submandibular) lymph node. These two unique cases need special mention.

Follow-up information was available for 8 patients. Two of the patients had died. The remaining 6 patients were alive with no relapse at the time of follow-up (the range of follow up period was 9 months-7yrs with a mean follow up period of 21 months).

NLPHL is a distinct subtype of HL with unique clinical features, a different treatment paradigm, and better patient outcomes. NLPHL involves men more than women. In our study also, we found that there were marginally more male patients than female patients. However the small number of total cases available in the series precludes the assessment of real gender prevalence. NLPHL commonly involves a peripheral group of lymph nodes, which was also observed in our study with the majority of the cases (9/10) involving a cervical, submandibular, axillary, and supraclavicular group of lymph nodes.

On histomorphology, NLPHL is chiefly characterized by nodules that are well appreciated in low magnification. In a large study of 137 biopsy samples by Fan et al., pattern A was documented to be the most common pattern, both as a pure pattern (54/137) as well as a predominant pattern (31/137); and mixed patterns were found to be more common than pure patterns.^[4] All the cases with pure patterns showed nodular morphology in our study as well. In addition, it was the predominant component in the lymph nodes showing mixed patterns.  However, pure morphological patterns were more commonly observed than mixed ones in this study (7 cases vs 3 cases), contrary to the findings of Fan et al.

A multivariate analysis by Hartmann S et al. showed that histopathological variants of NLPHL were significantly associated with advanced diseases and higher relapse rates.^[8] The same study also concluded that variant histology is an independent prognostic factor for progression/relapse. We also came across a case (case no. 8), (Table 1), which showed pattern C (variant histology) with the higher frequency of LP cells within the background population. These LP cells showed marked lobulation with prominent nucleoli as compared to the rest of the cases (Figures 2a-2c). The patient succumbed to death within 9 months due to septic shock.

The main differential diagnosis of NLPHL is Tcell/ histiocyte-rich large B cell lymphoma (THRLBCL). In general, NLPHL has a favorable prognosis despite the tendency for disease recurrence. Studies showed that histopathological variants of NLPHL (pattern C, D, E &F) are associated with increased relapse and advanced stages.^[8] Bone marrow involvement is very uncommon in NLPHL.^[4] However, if stage 4 disease is present, the prognosis is poor.^[11]

NLPHL tends of transformation to DLBCL at the time of relapse and the rate of transformation ranges from 3-10%. ^[9-12] Eyre TA et al. showed the median time for transformation to be 5 years and 33 days, and this time was greatly variable from case to case.^[11] The transformation was associated (although not significantly) with the presence of extranodal disease most notably liver, spleen and bone marrow involvement. Compared to the de novo DLBCL cohort, there was a higher rate of bone marrow involvement (P = 0.013) in the patients where this transformation had occurred.^[11] Most studies have shown that transformation is associated with significantly poorer outcomes.^[7]

There is no clear treatment regimen that fits all cases of NLPHL. However, the consensus is, towards conservative management rather than aggressive curative intent. The NCCN recommends site-specific radiation therapy (ISRT) for early-stage favorable disease. An ABVD/CHOP regime with ISRT is recommended for early-stage unfavorable disease and advanced-stage disease. Rituximab may also be considered in combination with ABVD/CHOP. For refractory disease, maintenance rituximab may be considered.^[12] It is recommended that a biopsy should be done on relapse to detect transformation to aggressive B cell lymphoma, if present.

We came across two interesting cases, which require separate mention. One was (case no. 6), (Table 1) a unique case, where NLPHL was associated with RDD in the same lymph node. We observed both diseases (Figures 3a-3c) in adjacent areas. They were not overtly intermixed with each other and could be appreciated easily. In RDD areas, abnormal histiocytes were strongly positive for S-100 and negative for CD1a. The NLPHL component showed a classic nodular pattern (pattern A) and the typical IHC features of L&H cells. In literature, many case reports are available in which RDD is present along with lymphoma, but mostly involving different anatomic sites. Only a few case reports are available where RDD and lymphoma are simultaneously present in the same lymph node. Moreover, most of these cases showed non-Hodgkin lymphoma (NHL) component with RDD. An extensive literature search revealed only a few case reports describing the coexistence of RDD and HL.^[13] In our case, the patient underwent lymph node excision and we received an intact lymph node for diagnosis. The patient didn’t receive any other therapy and is doing well to date (follow-up period of 3 years). Pathologists should be aware of this coexistence, as it may cause a problem in diagnosis by an inexperienced pathologist, especially in a small/ needle biopsy sample. Otherwise, it carries no prognostic or therapeutic implications and is to be managed in accordance with the type of lymphoma component being present.

There was another interesting case (case no. 7), (Table 1) of composite lymphoma, where we received two different axillary lymph nodes at the same time and both showed different morphology. The larger lymph node was replaced by diffuse sheets of large- sized, atypical lymphoid cells, compatible with DLBCL. In the smaller lymph node, the characteristic histological features of NLPHL were present. The final diagnosis of composite lymphoma, comprising DLBCL and NLPHL, was given.

Composite lymphoma is defined as two distinct lymphomas which occur concurrently in a patient, and is a rare condition with the incidence varying from 1% to 4.7%.^[14] Most of the case reports in the literature are of CHL with NHL, usually of B-cell type. The combination of NLPHL with DLBCL is a rare occurrence. Although NLPHL tends to progress to DLBCL, in our case the two conditions were present simultaneously in two different lymph nodes and the patient didn’t have any history of any type of lymphoma in the past. These cases are diagnostically challenging as sometimes one lymphoma component may mask the other component and also one of the components can be missed in a small biopsy sample. No definite treatment protocol is currently available for the treatment of composite lymphoma. Generally these are treated according to the high-grade component. Our patient received chemo and radiotherapy and is well to date (2 years follow-up).

NLPHL has a better prognosis than CHL. Follow-up was available in 8/10 cases in our study, where 75% (6/8) of cases were alive and didn’t have any relapse. However 2 deaths were recorded; one was due to septic shock, while the cause of death in the second patient was not known.

Conclusion

NLPHL, due to its rarity and variable morphological patterns, can often be misdiagnosed (both over-diagnosed and underdiagnosed), especially in small biopsies. It has a better prognosis in comparison to CHL but with frequent relapses. Because of an indolent course and a conservative therapeutic approach, accurate diagnosis is crucial. Its morphological classification needs special mention by the pathologist as it carries some prognostic implications. It was recommended that a biopsy should be repeated if there is a relapse, to detect transformation to high-grade lymphoma, which needs to be treated aggressively with chemotherapy. NLPHL showing variant histology is a risk factor in itself for poor outcomes. In our study, two cases of deaths also showed variant histology (i.e. pattern A+B+D and pattern C), however exact prognosis and survival cannot be commented on in such a small study. Studies including larger numbers of variant histology cases are needed to define a definite impact on outcome and prognosis.

Acknowledgments

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Conflict of interest

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Financial support

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Ethics statement

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