HOW LYMPHOMAS ARE DIAGNOSED AND TREATED

Lymphomas are a group of cancers that originate in the lymphatic system. They specifically develop from malignant transformation of lymphocytes (a type of white blood cell) or their precursors. These cells proliferate uncontrollably, accumulating in lymph nodes, the spleen, bone marrow, blood, and other organs. Unlike leukemia, which typically involves the bone marrow and circulating blood, lymphoma primarily starts in lymphatic tissues, forming solid tumors or infiltrations.

Classification of Lymphomas

Lymphomas are broadly categorized into two main types:

1. Hodgkin Lymphoma (HL):
   • Characterized by the presence of a specific type of abnormal cell called the Reed-Sternberg cell (large, often multi-nucleated B-cells).
   • Typically spreads in a predictable, contiguous manner from one lymph node group to the next.
   • More common in young adults (15-35 years) and older adults (>55 years).
2. Non-Hodgkin Lymphoma (NHL):
   • A much more diverse group comprising cancers of B cells, T cells, or Natural Killer (NK) cells.
   • Does not contain Reed-Sternberg cells.
   • Can arise in lymph nodes or extralymphatic sites (e.g., stomach, skin, brain).
   • Spreads in a less predictable pattern than HL.
   • Subclassified into numerous subtypes based on the specific type of lymphocyte involved, its maturity, and its growth pattern (e.g., indolent/low-grade, aggressive/high-grade). Common subtypes include Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), and Mantle Cell Lymphoma.

Clinical Manifestations of Lymphomas

The signs and symptoms of lymphoma can vary depending on the location and type of lymphoma, but common manifestations include:

1. Painless Lymphadenopathy: Enlarged, firm, non-tender lymph nodes, most commonly in the neck, armpit, or groin. This is the most frequent presentation.
2. B Symptoms: A constellation of systemic symptoms that can indicate more aggressive or widespread disease. These include:
   • Unexplained fever (often cyclical).
   • Drenching night sweats (requiring changing clothes/bedding).
   • Unexplained weight loss (typically >10% of body weight in the last 6 months).
3. Fatigue: Persistent and overwhelming tiredness.
4. Pruritus: Generalized itching, particularly associated with Hodgkin Lymphoma.
5. Splenomegaly/Hepatomegaly: Enlarged spleen and/or liver, which can cause abdominal discomfort or fullness.
6. Symptoms related to Extralymphatic Involvement: Depending on where the lymphoma is located outside the lymph nodes (e.g., gastrointestinal tract, skin, bone marrow, nervous system), patients may experience specific symptoms related to impaired organ function.

Appropriate Investigations to Diagnose Lymphoma

Diagnosing lymphoma requires a tissue sample for pathological examination. The primary diagnostic steps and supporting investigations include:

1. Biopsy: This is essential for definitive diagnosis and classification.
   • Excisional Biopsy: Removal of an entire affected lymph node is often preferred as it allows for comprehensive analysis of tissue architecture.
   • Core Needle Biopsy: Removal of a cylinder of tissue. Can be sufficient but may be less optimal than excisional biopsy for detailed subtyping.
   • Fine Needle Aspiration (FNA): Removal of cells using a thin needle. Usually not sufficient for initial diagnosis of lymphoma but may be used for follow-up or assessing recurrence.
   • Bone Marrow Biopsy and Aspiration: Often necessary for staging, especially in NHL, to determine if the bone marrow is involved.
2. Pathological Examination: The biopsy sample is analyzed by a hematopathologist using:
   • Histology: Microscopic examination of tissue structure.
   • Immunohistochemistry (IHC): Staining for specific protein markers on cell surfaces to identify cell type (B-cell, T-cell), maturity, and specific subtype markers.
   • Flow Cytometry: Analysis of cell populations based on surface markers, particularly useful for identifying malignant lymphocytes in blood, bone marrow, or fluid samples.
   • Cytogenetics and Molecular Genetics: Analysis of chromosomal abnormalities or genetic mutations to aid in subtyping and prognosis.
3. Blood Tests:
   • Complete Blood Count (CBC) to check blood cell counts.
   • Chemistry panel to assess kidney and liver function.
   • Lactate Dehydrogenase (LDH) levels, which can be elevated in aggressive lymphomas.
   • Erythrocyte Sedimentation Rate (ESR), often elevated in HL.
   • Viral studies (e.g., HIV, Hepatitis B/C, EBV) as these can be associated with certain lymphomas or impact treatment.
4. Imaging:
   • CT Scans (Computed Tomography): Used to visualize the size and extent of lymph node involvement and organ involvement in the chest, abdomen, and pelvis.
   • PET/CT Scans (Positron Emission Tomography/CT): A highly sensitive scan that helps identify areas of increased metabolic activity, distinguishing active lymphoma from residual tissue, and is crucial for accurate staging in most lymphomas, particularly HL and aggressive NHLs.
5. Lumbar Puncture: Performed if there is suspicion of Central Nervous System (CNS) involvement (more common in certain aggressive NHL subtypes).

Staging System for Lymphomas

The most widely used system for staging lymphomas is the Ann Arbor Staging system, often modified (e.g., Lugano Classification for PET/CT findings). Staging describes the extent of disease spread and is critical for determining prognosis and guiding treatment.

• Stage I: Involvement of a single lymph node region or a single extralymphatic site (Ie).
• Stage II: Involvement of two or more lymph node regions on the same side of the diaphragm, or localized involvement of an extralymphatic site plus one or more lymph node regions on the same side of the diaphragm (IIe).
• Stage III: Involvement of lymph node regions on both sides of the diaphragm, or involvement of the spleen (IIIs), or localized extralymphatic involvement (IIIe), or a combination (IIIes).
• Stage IV: Widespread, disseminated involvement of one or more extralymphatic organs (e.g., bone marrow, liver, lung, brain) with or without associated lymph node involvement.

Suffixes are added to the stage:

• A: Absence of B symptoms.
• B: Presence of B symptoms (fever, night sweats, significant weight loss).
• E: Extralymphatic involvement (involvement of a site other than lymph nodes, thymus, spleen, Waldeyer’s ring).
• X: Bulky disease (large tumor mass, size criteria vary slightly).

Management of Lymphomas

The management of lymphoma is highly individualized and depends on the specific type and subtype of lymphoma, the stage, the patient’s overall health status, age, and symptoms. General treatment modalities include:

1. Chemotherapy: Using anti-cancer drugs to kill lymphoma cells. Treatment often involves combination chemotherapy regimens (e.g., ABVD for HL, R-CHOP for DLBCL).
2. Radiotherapy (Radiation Therapy): Using high-energy rays to kill cancer cells, often used for localized disease, to consolidate treatment after chemotherapy for bulky sites, or for palliative purposes.
3. Immunotherapy: Using the body’s own immune system to fight cancer. This includes:
   • Monoclonal Antibodies: Targets specific proteins on lymphoma cells (e.g., rituximab targets CD20 on B-cells). Often used in combination with chemotherapy.
   • Immune Checkpoint Inhibitors: Helps the immune system recognize and kill cancer cells (more commonly used in relapsed/refractory HL).
   • CAR T-cell Therapy: A type of adoptive immunotherapy where a patient’s T-cells are genetically modified to target lymphoma cells and infused back. Used for certain aggressive, relapsed/refractory NHLs.
4. Targeted Therapy: Drugs that target specific molecular pathways or abnormalities within lymphoma cells.
5. Stem Cell Transplant (Bone Marrow Transplant):
   • Autologous Stem Cell Transplant: Using the patient’s own stem cells after high-dose chemotherapy. Often used for relapsed/refractory HL and some aggressive NHLs.
   • Allogeneic Stem Cell Transplant: Using stem cells from a donor. Used for certain lymphomas, particularly more aggressive or relapsed subtypes.
6. Watchful Waiting (Observation): For some very indolent (slow-growing) lymphomas, especially if asymptomatic and limited in extent, the initial approach may be observation without immediate treatment until symptoms develop or the disease progresses.

Treatment goals range from achieving a cure (common for many HL and aggressive NHLs) to controlling the disease, managing symptoms, and improving quality of life for more indolent or advanced cases. Treatment decisions are made by a multidisciplinary team of specialists.