Abstract
Background: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) with variant histopathology or aberrant immunophenotype is exceedingly rare and there is paucity of data with regards to its clinical characteristics and course. Case Report: Herein, we present three cases of NLPHL with aberrant immunophenotype or variant histopathological picture, which displayed distinct clinical and imaging findings. These case reports involved a patient with CD30 and CD20 positivity without Reed-Sternberg cells present, a NLPHL patient with aggressive, persistent disease activity with progressive transformation to germinal centres, and a patient with combined morphology of NLPHL and classical Hodgkin’s lymphoma. Conclusion: Aberrant immunophenotype/variant NLPHL might represent a distinct form of NLPHL, sharing characteristics with classical Hodgkin, non-Hodgkin lymphomas or benign, progressive transformation of germinal centre lymphadenopathy.
NLPHL is a rare presentation of Hodgkin’s lymphoma (HL), representing approximately 5% of the HL patient cohort and an incidence of approximately 1,500,000 patients globally per year (1). In contrast to classical Hodgkin’s lymphoma (cHL), NLPHL has separate and distinct pathological and clinical characteristics. The median age at presentation is 20-40 years and most commonly presents in men with early-stage disease (1, 2). Pathologically, cells are arranged in a nodular formation, surrounded by multi-nucleated atypical ‘popcorn’ cells (LP cells) within B-cell rich lymphoid follicles. Variants with LP cells outside nodules (Pattern C), T-cell-rich nodular (Pattern D), T-cell and B-cell rich (Patterns E and F) are also recognised (3). In contrast to Reed-Sternberg cells of cHL, LP cells typically express CD20, however, they show CD30 and Epstein-Barr virus negativity (2). Immunophenotyping of the cells is important for the prognosis, as variance in histology is associated with greater relapse rate and advanced disease (4). In general, NLPHL is associated with a favourable prognosis (4, 5). The aim of amalgamating the following three cases was to highlight and increase awareness of this rare, but novel, aberrant phenotype of NLPHL.
Case Report
Case 1. A 74-year-old female presented with a left axillary mass, denying any pyrexia, night sweats or weight loss. She demonstrated a haemoglobin of 143 g/l, lactate dehydrogenase (LDH) 256 (U/l), Beta 2-microglobulin 2 (mg/l), and white cell count 9.38×109/l. Core needle biopsy was performed, which demonstrated macro-follicular structures supported by meshworks of CD21+ dendritic cells and large ‘popcorn’ morphological cells (Figure 1). The immunophenotype of these cells exhibited CD30 (uniformly positive), CD20, PAX5, and OCT2 strong positivity. Fascin was negative. Classical Reed-Sternberg cells were not identified. These cells were not rosetted by T-follicular helper (T-FH) background lymphocytes. Therefore, a diagnosis of aberrant immunophenotype nodular lymphocyte predominant HL was concluded.
Immunohistochemical images illustrating characteristic ‘popcorn cells’ rosetted by small lymphocytes (left panel) and neoplastic cells strongly and uniformly positive for CD30 (right panel) in the same patient sample.
Staging positron emission tomography-computed tomography (PET-CT) demonstrated multiple ‘plaque-like’ subcutaneous soft tissue lesions (Figure 2). Also, a lymph node with a nodular architecture and lymphoid material of ‘popcorn’ morphology with well-formed CD21+ follicular dendritic cell network were observed. Immunophenotype matched the previous biopsy confirming the diagnosis.
Positron emission tomography-computed tomography images demonstrating scattered markedly avid plaque-like soft tissue lesions. The left panel illustrates this in the left lateral chest wall, and left anterior chest wall lateral to the sternum, whereas the right panel exhibits a lesion in the lower back across the midline, posterior to the paraspinal muscles.
In spite of Haematology advice, the patient decided to be monitored under surveillance. Eighteen months since diagnosis, she developed a new right scapular lump (PET-CT avid). An excision biopsy was performed, which demonstrated a higher density of neoplastic cells, solid cluster formation with appearances of transformation to diffuse large B-cell lymphoma (DLBCL). The patient was treated with 50% dose reduction of Rituximab-cyclophosphamide, doxorubicin, vincristine and prednisolone (mini R-CHOP).
Case 2. A 44-year-old male presented to the emergency department with lethargy, drenching sweats, unintentional weight loss. On clinical examination, a 2 cm left axillary lymph node was palpated. His blood panel demonstrated Hb 119 (g/l), WCC 14 (×109/l), LDH 401 (U/l), Beta-2 microgloublin 5.8 (mg/l), and C-reactive protein 51 (mg/l). Biopsy of the node was reported to indicate CD20, CD79a, PAX5, OCT2 positivity, and CD30, CD15, and Fascin negativity. T-cells expressed PD1 and Epstein-Barr virus (EBV) mRNA was not detected. A diagnosis of NLPHL (nodular with T-cell rich background) was concluded. Staging PET-CT illustrated avid nodes in the left axilla (largest 33×20 mm), marked avidity in right anterior diaphragmatic nodes, three foci in the liver, splenic lesions, left external iliac nodes, and extensive multifocal marrow disease. The patient consented to R-CHOP and post-treatment PET-CT revealed persistent foci of avidity within the spleen.
Approximately 6 months later, he continued to complain of fatigue and night sweats (non-drenching). PET-CT showed several new intensely avid lymph nodes above and below the diaphragm. Biopsy of a lymph node demonstrated follicular enlargement with expanded germinal centres. These were surrounded by thin IgD+ mantle zones with a reactive immunophenotype. No lymphoid cells noted and this was determined to be progressive transformation of germinal centres with no evidence of lymphoma. The patient remains well without evidence of relapsing NLPHL.
Case 3. A 55-year-old female presented with lower lumbar pain and subsequent MRI of the lumbar spine detected an incidental finding of left external iliac lymphadenopathy (3 nodes measuring 26×22 mm, 21×15 mm, 19×17 mm). Blood tests and screening CT were all within normal limits, aside from an LDH of 271 U/l. A biopsy demonstrated large cells, arranged in a vague nodular pattern with follicular dendritic cell aggregates, which were rosetted by small PD1 positive T lymphocytes. Immunohistochemistry (IHC) showed positivity for Pax 5, Fascin, CD15, CD30, and CD79a and negativity for CD20. A diagnosis of cHL was established. However, further specalised opinion was sought as low volume adenopathy in an asymptomatic patient casted doubt on the diagnosis. The biopsy was reported as effacement of normal archiecture by a nodular infiltrate and large cells with prominent nucleoli repsenting lymphocyte predominant (LP) cells. The overall picture suggested NLPHL, however, the phenotype of the LP cells was aberrant in that they lacked OCT2 expression and showed significant down-regulation of some of the B lineage markers (CD20 and CD19). An active monitoring approach was adopted.
Four years later, the patient developed lumbar pain and PET-CT illustrated progression of the disease (Stage III) with new nodes above and below the diaphragm. Biopsy of a para-aortic lymph node illustrated a few atypical ‘hodgkinoid’ lymphoid cells strongly positive for CD30 IHC and negative CD79a, CD10, and CD3, lacking restting of PD1+ lymphocytes and therefore surprisingly representing (composite) cHL. The patient was commenced on ABVD therapy and interim PET illustrated a reduction in nodal activity. End of treatment PET showed a new active node in the left para aortic space and thus, following radiotherapy, follow-up PET-CT demonstrated complete metabolic response.
Discussion
Case 1 depicted a 74-year-old female with a uniformly positive CD30 and CD20 immunophentyping. Fascin staining was negative, however, resulting in a diagnosis of NLPHL with aberrant phenotype. This phenomenon is not commonly observed and concomitant JunB positivity could be used in differentiating cHL with NLPHL (6). The patient also presented with disease in subcutaneous tissues, an entity in NLPHL only previously described in one clinical trial (7), and is associated with a poorer prognosis in cHL (8).
This patient’s condition was further complicated with transformation to DLBCL, a phenomenon observed in 3-6% of cases in a review by Yang et al. (9) and the observed risk was 0.74 per 100 patient-years of follow-up in a large observational study (10). Consenus on the management of this complication is varied with strategies akin to de novo DLBCL.
Case 2 demonstrated an aggressive form of NLPHL, which exhibited an excellent, but partial response to treatment. The patient then developed progressive transformation of germinal centres (PTGC) on repeat biopsy. PGTC shares morphological similarities with NLPHL and, therefore, it can be difficult to differentiate the two entities. It does not normally warrant treatment but a study (11) did demonstrate increased relapse of lymphoma patients without prior Rituximab exposure. Therefore, the treating clinician and patient must be aware that PTGC may develop post treatment, in disease remission. Therefore, subsequent detailed pathological examination must be performed to distinguish the two entities and shorter follow-up periods might be considered for surveillance.
The final case initially posed a diagnostic challenge between NLPHL and cHL; CD15-expressing NLPHL diagnosis was favoured on biopsy review as the lymph node was characterised by cell rosetting around LP cells. Venkataraman et al. have described an extensive case series of NLPHL with 6% (8/105) CD15 positivity rate (12). CD15-expressing NLPHL had an aggressive clinical course and all cases exhibited strong CD20 positivity in contrast to the CD20 negativity in our case. Eventually, the second biopsy few years later, demonstrated CD79a negativity and a pathological picture clearly corresponding to cHL. Composite lymphoma cases consisting of simultaneous or metachronous diagnosis of cHL and NLPHL have been rarely described (13-15).
It is apparent that NLPHL presentation, pathology, and management differs from cHL and the clinician may be confronted with cases where the two entities overlap significantly. NLPHL with aberrant immunophenotype may also represent a grey-zone intermediate lymphoma, presenting a further diagnostic challenge. Further studies are warranted into the association and prognosis of NLPHL and PGTC to influence survelliance and management. We highlight these cases to propose that aberrant phenotype NLPHL warrants multicentre clinical and molecular studies so as to optimise diagnosis and management of this unique entity.
Acknowledgements
The Authors would like to express their gratitude to Dr. Zbigniew Rudzki for diagnostic support and provision of histopathology pictures.
Footnotes
Authors’ Contributions
Conception and Design: Alexandros Kanellopoulos, Manuscript Writing: Gurvin Chander, Hansini Dassanayake, Alexandros Kanellopoulos. The rest of the Authors provided critical intellectual input through patient management decisions and MDT discussions. Overall manuscript responsibility: Alexandros Kanellopoulos.
Conflicts of Interest
The Authors declare no conflicts of interest with regards to this study.
- Received June 6, 2021.
- Revision received June 27, 2021.
- Accepted June 28, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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