Definition
• B-cell lymphoma comprising two distinct disease entities: nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classic Hodgkin lymphoma (cHL)
Pathogenesis
• The neoplastic cell of origin in both cHL and NLPHL is a B cell. Gene expression studies indicate that in cHL, the B-cell/germinal center program is more deranged with significant crippling of the immunoglobulin production machinery compared with NLPHL
• A certain proportion of cHL is associated with Epstein-Barr virus (EBV) within the neoplastic B cells, termed Hodgkin/Reed-Sternberg (HRS) cells. The association is almost universal in cHL in the eastern population with a high EBV seroprevalence.
Clinical features
Epidemiology
• Nearly 95% of all Hodgkin lymphomas are represented by cHLs; typically show a bimodal age prevalence peaking at 15 to 35 years and later in life. Pattern is more apparent in the western population.
• Only 5% of all Hodgkin lymphomas are constituted by NLPHLs, which typically occur in the 30- to 50-year age group.
Presentation
• cHL typically is found in nodal locations (specifically, cervical in >75% of cases). Primary mediastinal location is noted in approximately 60% of patients (majority with nodular sclerosis subtype of cHL [NSCHL]); extranodal and primary pulmonary presentation is rare. Also, bone marrow involvement is rare outside the context of immunosuppression/HIV infection.
• B-symptoms (drenching night sweats, fever, weight loss>10% of body weight) occur in up to 40% of cHL patients
• NLPHL typically is seen at superficial nodal locations with stage I/II disease in most patients. Mediastinal, splenic, and marrow involvement are extremely rare, and only 5% to 25% of patients present with stage III/IV disease
Prognosis and treatment
• In NLPHL, stage I/II disease has an excellent outcome with more than 80% 10-year overall survival rate. However, frequent relapses occur that respond well to therapy
• Advanced stage disease has an unfavorable prognosis: progression to diffuse large B-cell lymphoma (DLBCL)is noted in a small but significant proportion of cases
• Consensus is that chemotherapy is necessary in advanced stage disease, but it is unclear as yet if early-stage disease clearly benefits from any radiation therapy or chemotherapy
• NSCHL has a better prognosis than the other subtypes of cHL (except the lymphocyte-rich subtype of cHL [LRCHL]) and is characterized by >85% cure rate using modern chemotherapy regimens
• LRCHL demonstrates excellent survival rates similar to NLPHL, although relapses are less common than in NLPHL
Pathology
Histology
• cHL: current World Health Organization (WHO) 2008 recognizes four distinct subtypes of cHL—nodular sclerosis (NS), mixed cellularity (MC), lymphocyte rich (LR), and lymphocyte depleted (LD)
• NSCHL is the most prevalent subtype in the western population and is histologically characterized by multiple nodules surrounded by fibrous bands. The nodules contain variable numbers of HRS cells admixed with histiocytes, neutrophils, or eosinophils. The HRS cells often lie within a clear space in formalin-fixed tissues, imparting a lacunar appearance. Hence, the HRS cells are termed lacunar cells in this subtype. When numerous HRS cells are seen as aggregates, the term syncytial variant is used
• In MCCHL, the nodal architecture may be obliterated or the involvement may be interfollicular with HRS cells scattered amidst a polymorphous cellular background comprising neutrophils, eosinophils, plasma cells, and histiocytes. The histiocytes may become numerous with formation of epithelioid cell granulomas in some cases
• LRCHL subtype has a distinct architectural pattern leading to the distinction of nodular and diffuse variants. The nodular variant bears striking similarity to NLPHL in some cases. The nodular growth pattern has regressed germinal centers cuffed by expanded and prominent mantle cuffs that contain singly scattered mononuclear variants of HRS cells
• LDCHL is most often associated with HIV infection and shows a histiocyte-rich proliferation with variable degrees of fibrosis and scattered HRS cells that range in size from small to large-monstrous variants. Cases that clearly demonstrate presence of NS are classified as NSCHL
• NLPHL: predominant growth pattern is nodular, resembling LRCHL with a scattered collection of histiocytes and singly scattered large atypical cells with convoluted, “popcornlike” nuclei containing vesicular chromatin, often termed lymphocytic and histiocytic (L&H) cells or “popcorn” cells. These cells constitute the neoplastic cells of NLPHL. The background milieu is varied in NLPHLs and consists predominantly of lymphocytes with admixed histiocytes.
Immunopathology/special stains
• CHL: HRS cells express CD30, CD15, and PAX-5 (weak) with variable CD20 expression. CD79a is positive in a minority, BCL-6 is variably positive, and CD10 is negative, reflective of a deranged germinal center program. Additionally, they express Mum-1 and fascin in most cases. They are negative for CD45 and CD3 and often show loss of the nuclear transcription factors, Oct-2 and/or Bob.1. Phenotype of the HRS cells is the same in all subtypes of cHL.
• The background milieu consists of CD3+ T cells with CD4 predominance. In LRCHL, the neoplastic cells are located within the mantle zones, comprising lymphocytes with an IgM+/IgD+ positive phenotype, and express CD20 and BCL-2. The HRS cells have a similar phenotype as in NSCHL. Epstein-Barr virus encoded small RNA (EBER) is present on the HRS cells in 20% to 40% of NSCHL and up to 65% of MCCHL cases.
• NLPHL: L&H cells express CD20, CD79a, PAX-5, BCL-6, Oct-2, Bob.1, and PU.1; a minority of cases may express focal and weak CD30; however, CD15, fascin, and EBER are universally negative on L&H cells.
• Multiple immunoarchitectural patterns have been described in NLPHL based on the relationship and proportions of the L&H cells to the background lymphocytes. Typically, L&H cells are located within a background of small B cells. The atypical cells are rosetted immediately by CD4+ T cells that are additionally positive for CD57, MUM-1, BCL-6, PD-1, and CXCL13, consistent with a follicular helper T-cell phenotype.
• Other variant patterns include T-cell rich nodular, diffuse T-cell rich, and T-cell/histiocyte-rich large B-cell lymphoma (T/HRBCL)-like patterns
Main differential diagnoses
• cHL:
• Senile EBV-positive B-cell lymphoproliferative disorders often contain variable numbers of CD30+, EBV+ B cells in a polymorphous background rich in T cells and need to be distinguished from cHL. Senile EBV lymphoproliferative disorders typically show a spectrum in the size of the atypical cells: EBV in small as well as large lymphoid cells, while cHL typically has neoplastic cells of relatively uniform size with EBV expression restricted to only the large cells
• B-cell lymphoma; unclassifiable; features intermediate between DLBCL and cHL (WHO 2008). Cases of morphologically typical cHL may show immunophenotypic features at variance with the diagnosis of cHL (lack of CD30 and/or CD15 with strong expression of B-cell markers like CD20, PAX-5, Oct-2, Bob.1) warranting a diagnosis of “gray-zone lymphoma”. Both morphological and immunophenotypic features should be considered to arrive at a correct diagnosis
• Peripheral T-cell lymphoma (PTCL) with EBV+ Hodgkin-like cells: although rare, some PTCLs with a nodular, LRCHL-like morphology at low power on H&E sections have been shown to harbor EBV-positive HRS cells. T-cell gene rearrangement studies often help in resolving this diagnosis
• Anaplastic large-cell lymphoma (ALCL): case of ALCL including the lymphohistiocytic variants with scattered CD30+ atypical cells may be confused with cHL; however, the expression of PAX-5 and lack of ALK-1 on the neoplastic cells supports classification as cHL
• NLPHL:
• LRCHL often resembles NLPHL because both have a common nodular growth pattern. However, the morphological and immunophenotypic features of the atypical cells, in conjunction with the background cellular population (T cells vs. B cells) help in making the distinction in most cases
• Diffuse cases of NLPHL rich in T cells and histiocytes are often seen as bordering on T/HRBCL. The loss of PU.1 on the neoplastic cells in T/HRBCL with a preponderance of CD8+ /TIA-1–positive cells in the background lymphoid population supports the diagnosis of T/HRBCL
Fig 1 Hodgkin lymphoma of the mediastinum. Low power H&E-stained section, showing replacement of nodal architecture with broad bands of fibrosis. Even at this magnification, large cells with cytoplasmic clearing are noted.
Fig 2 Hodgkin lymphoma of the mediastinum. Higher magnification shows pathognomic lacunar cells, which are large cells with hyperchromatic nuclei and perinuclear cytoplasmic clearing.
Fig 3 Hodgkin lymphoma of the mediastinum. High-power view with strong immunoreactivity for CD15 in HRS cells.
Fig 4 Hodgkin lymphoma of the mediastinum. HRS cells show strong membrane and Golgi immunostaining for CD30.
Fig 5 Hodgkin lymphoma of the mediastinum. HRS cells also show strong reactivity for fascin, an actin cross-linking protein.
Fig 6 Hodgkin lymphoma of the mediastinum. EBER by in situ hybridization is positive in rare HRS cells.