Hodgkin lymphoma (HL) is of two types. Classical (cHL) and nodular lymphocyte predominant (NLPHL). NLPHL is rarer and runs a more indolent clinical course.
NLPHL accounts for about 5% of all HL.
Age: The disease is characterised by two peaks. The first one in childhood and the second between the ages of 30-40.
Gender: NLPHL shows a male predominance. About three-fourth of the patients are males. Male preponderance is less marked in blacks.
Racial Differences: Black patients are younger, more often female and more often present with axillary involvement. Little is known of NLPHL in other races (Cancer 2015; 121:3472-80).
Familial Susceptibility: Family members of patients with NLPHL at increased risk NLPHL. The standardised incidence ratio in one study was reported to be 19 (J Clin Oncol 2013; 31;938-43).
The normal architecture of the node is effaced and replaced by large nodules. Occasionally there may be large nodules with diffuse areas. Sometimes uninvolved nodal tissue may be seen. This is usually located peripheral in a sub-capsular area.
Microscopically NLPHL shows the malignant cell, LP cell, in a background mainly made up of small lymphocytes and with a prominent follicular dendritic cell (FDC) network. The follicular dendritic cell meshwork is absent from the diffuse areas. Unlike most other malignancies (and like cHL and T cell/Histolytic rich large B cell lymphoma) the normal reactive cells form the bulk of the enlarged node.
The LP cell has a nucleus that shows complex lobulation. It resembles a exploded kernel of corn and hence the cell is also referred to as the popcorn cell. The nucleolus is smaller than that of the RS cell and lies peripherally and is basophilic. There is a thin rim of cytoplasm.
The infiltrate in a nodule mainly consists of small lymphocytes. Unlike cHL, Eosinophils and plasma cells are occasional or may be absent. Most of the small lymphocytes making up the nodule are CD20+, CD79+ small B lymphocytes. The LP cells is however immediately surrounded by CD20–, CD3+ T helper cells that express PD-1 and CD57. Diffuse area have CD4+ T cells and areas between nodes have CD3+ parafollicular T cells.
Varient histological patterns are known, associated with adverse prognosis and should be reported (Am J Surg Pathol 2003;27:1346-56).
Immunophenotype helps in diagnosis and has given clues to the origin of LP cells. The LP cells show a B cell phenotype and express CD20, CD79, CD22, PAX-5 and CD45. They express BCL-6 indicating the germinal centre origin. They do not express BCL-2. They strongly express the B cell transcription factor OCT-2 and its cofactor BOB.1. This distinguishes then from the Reed-Sternberg (RS) cells of cHL. RS cells show a weak expression or do not express these factors. RS cells express CD15, CD30 and fascin that are not expressed by the LP cells. About a fifth of the patients express IgD. These patients tend to be male, present with cervical adenopathy and have a greater risk of having a variant histology.
The normal counterpart of the LP cell appears to be the germinal centre B cell at the cenrtoblastic stage of differentiation.
NLPHL as well as cHL are diseases characterised by malignant cells surrounded by an infiltrate of normal cells. Unlike other cancers, the normal cells form the bulk of the tumour mass in both the cases. The malignant cells affect and are affected by the normal cells surrounding them. LP cells, like normal germinal centre cells, appear to depend on normal immunoglobulin receptor signalling. RS cells depends on other signalling receptors e.g. CD30 and CD40. The growth of normal germinal centre cells depends on The FDC and follicular T cells. These cells also support the growth of LP cells. The LP cell do not produce cytokines at levels seen in the RS cell. B symptoms are less common NLPHL less common than cHL.
The most common presentation of NLPHL is isolated lymphadenopathy, most often in the cervical, axillary or the inguinal region. The swelling is usually present for a long time and has been growing slowly. About 80% of the patients present with localised disease and less than 20% with stage III/IV (Ann Hematol. 2016; 95: 417–423). B symptoms are uncommon (about 5%). Extranodal disease is very uncommon.
NLPHL runs a more indolent course that cHL. It is characterised by a relapses and transformation to high grade lymphoma diffuse large B cell lymphoma (including T cell/ histiocyte rich large B cell lymphoma). Relapses usually respond to treatment.
NLPHL, like cHL is classified by the Ann Arbor staging system with Cotswolds modifications. The stages are summarised below. A more detailed staging can be found here.
- Stage I: Involvement of one nodal region, lymphoid structure or one extra-nodal site
- Stage II: More than one region involved but disease limited to one side of the diaphragm.
- Stage III: Disease on both sides of the diaphragm but limited to the lymphoid system.
- Stage IV: Disease disseminated to one or more extra nodal organs.
Patients with fever with hight sweats and significant (>10% in the preceding 6 months) are said to have B symptoms.
The staging workup should include clinical examination, haemogram, ESR and biochemistry. NLPHL is PET avid. PET-CT is better than CT for staging. It is of value in to exclude diseases dissemination in patients where observation or local treatments are being considered. The value is interim PET-CT is NLPHL is uncertain. The bone marrow is very uncommonly involved (about 1-2%). Only patients with advanced disease should be subjected to bone marrow examination.
- Lymphocyte Rich Classical Hodgkin lymphoma
- T cell/ Histiocyte Rich Large B Cell Lymphoma
- Progressively Trasnformed germinal centres
- Follicular Lymphoma
- Mantle cell Lymphoma
Early disease (Stage I/IIA)
Patients who have undergone excision biopsy that has resulted in a complete removal of all disease may be observed. Despite a lower progression free survival the patients who are observed do not show an inferior overall survival. This indicates that delaying treatment (radiation, chemotherapy or both as may be appropriate) does not hamper it’s efficacy.
Advanced Disease (Stage IIB, III, IV)
These patients need chemotherapy with the anti-CD20 antibody, rituximab. Three approaches are possible
- Classical Hodgkin lymphoma like therapy with Rituximab with ABVD: R-ABVD (Rituximab, doxorubicin, bleomycin, vinblastine and dacarbazine) should be administered to patients needing chemotherapy.
- B cell non-Hodgkin Lymphoma like therapy: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is the standard treatment for high grade B cell non-hodgkin lymphoma. R-CHOP has been shown to effective in disease control and reducing the risk of transformation. It may be preferred in patients at a high risk of transformation, though there is not comparative trial with R-ABVD. Males and those with variant histology are at a higher risk of transformation. Models for predicting transformation are available.
- Single agent Rituximab: Single agent rituximab is indicated in patients with co-morbidities. The risk of relapse remains high.
Treatment of Relapse
Relapses must be rebiopsied to confirm NLPHL and to exclude transformation to a high grade lymphoma. Localized relapses may be treated with radiation. Chemotherapy should be used for other patients. Patients who have a chemosensitive relapse may be considered for allogenic stem cell transplant (Am J Haematol 2017 Oct 3. doi: 10.1002/ajh.24927).
Treatment of Transformation
Patients who undergo transformation are treated with regimen for regimens for high grade B cell lymphoma. The limited data suggests that the outcome is no different from that of de novo large B cell lymphoma.
The prognosis of NLHPL is better than conventional HL partially because of a more favourable disease profile – early stage, no B symptoms, no Bulky disease. One study showed a 94% overall survival at 10years (Ann Hematol. 2016; 95: 417–423). The progression free survival was 75% indicating relapses are common but are curable. Progression to diffuse large B cell lymphoma is seen in 5-10% of the patients. Atypical histology increases the risk of relapse (Blood. 2013 Dec 19;122(26):4246-52).
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