Hodgkin lymphoma is a B-cell lymphoma most common in young or HIV-positive adults, classically characterised by Reed-Sternberg cells and typically presenting as painless cervical lymphadenopathy, often associated with ‘B’ symptoms and EBV positivity.
Description
Hodgkin Lymphoma (HL) is a malignancy originating from B lymphocytes, characterised by the presence of a specific type of giant cell known as the Reed-Sternberg cell. HL typically demonstrates a predictable pattern of lymph node involvement, spreading contiguously and sparing extranodal sites in its early stages.
Pathogenesis
HL arises due to a clonal expansion of B lymphocytes. The pathogenesis involves chromosomal translocations, genetic and epigenetic changes, and interactions between tumour cells and the microenvironment. Reed-Sternberg cells, although rare, play a pivotal role in the disease progression by releasing cytokines that recruit an inflammatory infiltrate which contributes to the tumour bulk and supports the growth and survival of these malignant cells.
Subtypes
Hodgkin lymphoma can be classified into two broad categories, Classical Hodgkin lymphoma and Nodular Lymphocyte-Predominant Hodgkin Lymphoma.
- Classical Hodgkin Lymphoma (cHL): This category comprises about 95% of all Hodgkin lymphoma cases and is characterised by the presence of giant, abnormal cells called Reed-Sternberg cells. It can be further divided into four subtypes:
- Nodular Sclerosis Classical Hodgkin Lymphoma (NSCHL): This is the most common subtype, accounting for approximately 60-80% of cHL cases. It often affects young adults and is more common in females. It typically involves the mediastinal lymph nodes and is characterised by bands of fibrous tissue dividing the lymph nodes into nodules, with the presence of lacunar cells, a variant of Reed-Sternberg cells.
- Mixed Cellularity Classical Hodgkin Lymphoma (MCCHL): Accounting for about 15-30% of cHL cases, this subtype often affects older adults and individuals with HIV infection. It involves the peripheral lymph nodes and is characterised by a mix of different cell types, including numerous Reed-Sternberg cells.
- Lymphocyte-Rich Classical Hodgkin Lymphoma (LRCHL): This rare subtype makes up about 5% of cHL cases. Typically present with limited stage peripheral lymphadenopathy (Ann Arbor Stage I or II). It generally has a better prognosis compared to other subtypes. It is characterised by few Reed-Sternberg cells surrounded by many normal or small lymphocytes, with small germinal centres positioned eccentrically, without eosinophils or neutrophil.
- Lymphocyte-Depleted Classical Hodgkin Lymphoma (LDCHL): This is the rarest subtype, accounting for less than 5% of cHL cases. It is often seen in older adults, people with HIV infection, and those with advanced stage disease. It is associated with a poorer prognosis.
- Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL): Fundamentally different from other cHL. This category comprises about 5% of all Hodgkin lymphoma cases and often affects males. It typically presents as early-stage disease involving the peripheral lymph nodes, and it has a better prognosis compared to cHL. This subtype is characterised by the presence of large, abnormal cells called lymphocyte-predominant (LP) cells, which are variants of Reed-Sternberg cells.
Epidemiology, Risk Factors & Associations
- Peak incidence occurs in early adulthood (age 15-35 years) and again in those over 55.
- Epstein-Barr virus (EBV) infection is associated with approximately 40% of overall cases. Approximate associations:
- Nodular Sclerosis: 30-50%.
- Mixed Cellularity: 70-85%.
- Lymphocyte Rich: 20-50%.
- Lymphocyte Depleted: 80-90% (highest)
- Nodular Lymphocyte Predmoninant: 5% (lowest)
- Other risk factors include a family history of HL and a history of immunosuppression (HIV).
- HL is less common than Non-Hodgkin Lymphoma
Clinical Features
Nodal Disease
- HL is primarily a disease of the lymph nodes.
- It often presents with painless, swollen lymph nodes in the neck, armpit, or groin.
- Other symptoms, collectively known as “B symptoms”, include unexplained weight loss, fever, and night sweats.
Extranodal Disease
- Hepatic Involvement: Hepatomegaly and abnormal liver function tests.
- Splenic Involvement: Splenomegaly.
- Pulmonary Involvement: Shortness of breath and a dry cough.
- Bone Marrow Involvement: Anemia, thrombocytopenia, or leukopenia.
- Gastrointestinal Tract: Involvement of the stomach or intestines can lead to abdominal pain, nausea, and vomiting.
- Superior Vena Cava Syndrome: Compression of the superior vena cava due to mediastinal lymphadenopathy can lead to facial swelling, shortness of breath, and cyanosis.
- Paraneoplastic Syndromes: Hodgkin lymphoma can present with several paraneoplastic syndromes such as pruritus, nephrotic syndrome, or hypercalcemia.
Complications
Late complications of HL and its treatment include cardiovascular disease, second malignancies, and pulmonary disease.
Pathological Features
Histopathology
- Macroscopic: Enlarged lymph nodes with a rubbery consistency.
- Microscopic:
- Nodular Sclerosis: Bands of fibrous tissue divide the node into nodules with Reed-Sternberg cells displaying an ‘owl-eye‘ appearance.
- Mixed Cellularity: Numerous classic Reed-Sternberg cells amid a mixed inflammatory background with both diffuse or nodular growth patterns but no band-forming sclerosis.
- Lymphocyte Rich: Sparse Reed-Sternberg cells within a reactive lymphoid background.
- Lymphocyte Depleted: Few reactive lymphocytes with many Reed-Sternberg cells.
- Nodular Lymphocyte Predominant: Nodules composed of LP cells with a surrounding rosette of lymphocytes.
Serology
- Elevated ESR, anaemia, leukocytosis.
Biochemistry
- Abnormalities are non-specific but may include elevated LDH and alkaline phosphatase.
Immunohistochemistry
- CHL: Lacks mature B cell antigens and is CD15+ and/or CD30+.
- NLPHL: Almost always CD20+ and strongly BSAP+ and negative for CD15 and CD30 expression. In addition, it can be positive for EMA (not always present, but strongly supports the diagnosis
Radiological Features
General Features
- HL characteristically demonstrates enlarged, homogeneous lymph nodes, often with a mediastinal predominance.
- Calcifications are rare in HL.
- Hepatosplenomegaly and extranodal involvement are more common in advanced disease.
CT
- Non-contrast: Shows enlarged lymph nodes, potentially hepatosplenomegaly in advanced disease.
- Contrast-enhanced: Lymph nodes appear homogeneously enhancing.
NM
- PET FDG: HL characteristically shows intense uptake, aiding in staging, assessing treatment response, and predicting prognosis.
Grading and Staging
The Ann Arbor staging system is commonly used for HL, incorporating the presence of B symptoms and splenic, hilar, mediastinal, or retroperitoneal nodal involvement.
- Stage I: Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer’s ring)
- Stage II: Involvement of two or more lymph node regions on the same side of the diaphragm
- Stage III: Involvement of lymph node regions on both sides of the diaphragm; this may also include the spleen and/or limited contiguous extra-lymphatic organ or site
- Stage IV: Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement
Each stage can be further classified with an “A” or “B”.
- “A” signifies absence of B symptoms (i.e., weight loss >10% of body weight over the past six months, unexplained fever above 38°C, and night sweats).
- “B” denotes the presence of B symptoms.
Additionally, the letter “E” is used to denote involvement of an extralymphatic organ or site that is not a direct invasion or extension from the primary site or its regional lymph nodes. If the spleen is involved, the letter “S” is added. Lastly, “X” denotes bulky disease, which refers to a mass in the chest that is at least one-third the width of the chest, or an outside lymph node mass that is 10 cm or more in diameter.
Diagnosis
Diagnosis is confirmed by lymph node biopsy revealing Reed-Sternberg cells.
Differential Diagnosis
- Non-Hodgkin lymphoma: Can also present with lymphadenopathy but lacks Reed-Sternberg cells.
- Metastatic carcinoma: May also cause lymphadenopathy. Differentiated by histology and immunohistochemistry.
- Infectious mononucleosis: May mimic HL clinically and is associated with EBV infection, but lacks Reed-Sternberg cells and the typical histologic features of HL.
Management
Management typically involves chemotherapy, with or without radiotherapy. The specific regimen is determined by the stage and subtype of the disease. Stem cell transplantation may be considered for relapsed or refractory HL.