Non‑Hodgkin Lymphoma

Chromosomal translocations

• t(14;18)(q32;q21) juxtaposes the BCL2 anti‑apoptotic gene to the immunoglobulin heavy‑chain locus, promoting follicular lymphoma and some higher‑grade subtypes.
• t(11;14)(q13;q32) leads to cyclin D1 overexpression in mantle cell lymphoma.
• 8q24 rearrangements dysregulate c‑MYC in Burkitt and related high‑grade lymphomas.
• t(2;5)(p23;q35) produces an NPM‑ALK fusion protein in most anaplastic large‑cell lymphomas.
• MALT lymphomas frequently harbour t(11;18)(q21;q21) or t(1;14)(p22;q32), creating aberrant MALT1 or BCL10 fusion proteins.

Oncogenic infections

Epstein‑Barr virus

• Drives endemic and some sporadic Burkitt lymphomas and contributes to lymphomas in immunocompromised settings.

Human T‑cell lymphotropic virus I

•  Induces adult T‑cell leukaemia/lymphoma via Tax‑mediated transcriptional dysregulation.

Hepatitis C virus 

• Fosters chronic B‑cell activation, implicated in splenic marginal zone and diffuse large B‑cell lymphomas.

Human herpesvirus 8 

• Underlies primary effusion lymphoma by encoding viral cyclin and interleukin‑6 homologues.

Helicobacter pylori 

• Infection drives gastric MALT lymphoma through persistent antigenic stimulation.

Other bacteria 

• Coxiella burnetii, Borrelia burgdorferi, Chlamydia psittaci, Campylobacter jejuni are linked to site‑specific MALT lymphomas.

Environmental and drug exposures

• Occupational contact with pesticides, phenoxyherbicides, solvents, wood preservatives, dust and hair dyes shows modest associations with NHL risk.
• Long‑term exposure to phenytoin, dioxin derivatives, certain chemotherapeutic agents, ionising radiation and anti‑TNF therapies carries a small elevated lymphoma risk.

Immunodeficiency states

• Congenital conditions (severe combined immunodeficiency, Wiskott‑Aldrich syndrome, ataxia‑telangiectasia, Chediak‑Higashi syndrome, Klinefelter syndrome), acquired immunodeficiency (HIV/AIDS, post‑transplant immunosuppression) and iatrogenic immunosuppression predispose to aggressive, often extranodal NHLs, including primary central nervous system lymphoma.

Autoimmune and chronic inflammatory conditions

• Autoimmune diseases (Sjögren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto thyroiditis) increase the risk of lymphomas, particularly MALT and thyroid types.
• Coeliac disease and other chronic enteropathies heighten risk for intestinal lymphoproliferative disorders, correlated with mucosal damage severity.

Clonal transformation of lymphoid cells

• Arises from B lymphocytes, T lymphocytes or natural killer cells after accumulated genetic hits—such as chromosomal translocations or viral integrations—confer unlimited proliferative capacity and survival

B‑cell lymphoma mechanisms

• Germinal‑centre processes: Class‐switch recombination and somatic hypermutation introduce DNA breaks; off‑target events can aberrantly mutate oncogenes (e.g. BCL6) or activate proto‑oncogenes, fostering malignant clones.
• Cell‑of‑origin subtypes:
  • Pre‑germinal‑centre (naïve B cells) → mantle cell lymphoma (via cyclin D1 overexpression).
  • Germinal‑centre → centroblasts (Burkitt lymphoma, GCB‑DLBCL) and centrocytes (follicular lymphoma).
  • Post‑germinal‑centre → plasmablasts (ABC‑DLBCL) and plasma cells (plasmablastic lymphoma).

Aberrant somatic hypermutation

• Physiologic hypermutation machinery can target non‑immunoglobulin genes (PIM1, MYC, PAX5), contributing to high‑grade lymphomas and immunodeficiency‑associated proliferations.

T‑cell and NK‑cell lymphoma mechanisms

•  T cell precursors undergo TCR gene rearrangement in the thymus; errors at any maturation stage can produce malignant T‑cell phenotypes. NK/T‑cell neoplasms share features, so ambiguous cases are grouped together.

Key genetic drivers

• Balanced translocations:
  • t(14;18) → BCL2 overexpression in follicular lymphoma
  • t(11;14) → cyclin D1 in mantle cell lymphoma
  • 8q24 → c‑MYC in Burkitt and related lymphomas
  • t(2;5) → NPM‑ALK in anaplastic large‑cell lymphoma
  • t(11;18), t(1;14) → MALT1/BCL10 fusions in MALT lymphoma
• Unbalanced alterations and somatic mutations accumulate during progression, notably affecting TP53 and chromatin‑modifying genes.

Epigenetic and microenvironmental contributions

•  Mutations in histone modifiers (EZH2, CREBBP, MLL2) alter chromatin state; supportive stromal cells, macrophages and regulatory T cells in lymphoid tissues promote survival and expansion of malignant clones.

Viral oncogenesis

• Integration of viral genes (e.g. Epstein‑Barr virus, HTLV‑I, HHV‑8) sustains chronic antigenic stimulation and can directly dysregulate cellular proliferation pathways.

Geographical Variations

• The incidence of NHL subtypes varies geographically.
• Follicular lymphoma is more common in Western countries, while T-cell lymphomas are more frequently observed in Asia.
• Endemic Burkitt lymphoma, often linked to Epstein-Barr virus (EBV), is notably more common in equatorial Africa and New Guinea, with an incidence about 50 times higher than in the United States.

Age Distribution

• NHL is predominantly diagnosed in individuals aged 65 to 74, with the median age at diagnosis being 68 years.
• High-grade lymphomas like lymphoblastic lymphoma and small noncleaved lymphomas are more common in children and young adults.

Burkitt Lymphoma

Endemic Burkitt Lymphoma

• Most common in Africa, with peak incidence between ages 4 and 7. The male-to-female ratio is approximately 2:1. It comprises 30% of pediatric lymphomas in Africa, with a strikingly higher incidence compared to the U.S.

Sporadic Burkitt Lymphoma

• More common in the U.S. and Western Europe, affecting children, with a male-to-female ratio of about 3:1. It accounts for <1% of adult NHLs in the U.S.

Mantle Cell Lymphoma

• Constitutes around 7% of adult NHL cases in the U.S. and Europe.
• The incidence is about 4 to 8 cases per million individuals per year, with an increasing trend over time.
• The median age at diagnosis is 68 years, and approximately three-quarters of patients are male.

Peadiatric NHL

• NHL accounts for approximately 7% of childhood cancers in developed countries, with around 800 new cases diagnosed annually in the U.S.
• It is the fifth most common pediatric cancer.

Incidence Trends

• From the early 1970s to the early 21st century, NHL incidence rates nearly doubled, though the increase is not entirely explained by improved diagnostic techniques or HIV-associated cases.
• From 2012 to 2021, there was a slight decline in NHL incidence rates of 0.6% per year.

Demographic Factors

• Men are more likely to be diagnosed with NHL than women, with an incidence of 22.5 new cases per 100,000 for men versus 15.5 for women.
• In the U.S., non-Hispanic white individuals have a higher incidence compared to other racial and ethnic groups.

Subtypes and Incidence Rates in the U.S.

• Diffuse Large B-Cell Lymphoma (DLBCL): 6.9 cases per 100,000
• Follicular Lymphoma: 3.4 cases per 100,000
• Mantle Cell Lymphoma: 0.8 cases per 100,000
• Burkitt Lymphoma: 0.4 cases per 100,000
• Primary Central Nervous System Lymphoma: 0.3 cases per 100,000

Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL)

• A rare form of NHL, with increasing cases, particularly associated with textured breast implants.
• The U.S. FDA reported 1,264 cases and 63 related deaths as of June 2023.

General Clinical Presentation

• The clinical manifestations of NHL vary depending on factors such as the location of the lymphoma, the rate of tumor growth, and the function of affected organs.
• Low-grade lymphomas often present with painless, slowly progressive peripheral adenopathy.
• These lymphomas may also regress spontaneously, which can sometimes lead to confusion with infectious conditions.
• Advanced-stage disease may involve primary extranodal involvement and B symptoms, including unexplained fever, night sweats, and weight loss greater than 10% from baseline within six months.

Low-Grade Lymphomas

Peripheral Adenopathy

• Often painless and progressively enlarging.

Spontaneous Regression

• Can occur, mimicking an infectious condition.

B Symptoms

• Less common at presentation but frequent in advanced disease or malignant transformation (evolution from low-grade to higher-grade lymphoma).

Fatigue and Weakness

• Common due to bone marrow involvement, which may also lead to cytopenias.

Intermediate- and High-Grade Lymphomas

Adenopathy

• Almost all patients present with adenopathy, and over one-third of patients may have extranodal involvement.

Extranodal Sites

• The gastrointestinal tract, skin, bone marrow, sinuses, genitourinary tract, thyroid, and central nervous system (CNS) are common sites of extranodal involvement.

B Symptoms

• Seen in about 30–40% of patients, including unexplained fever, night sweats, and weight loss.

Lymphoblastic Lymphoma

• Often presents with anterior superior mediastinal mass, superior vena cava syndrome, and cranial nerve palsies from leptomeningeal disease.

Burkitt Lymphoma

• Typically presents with a large abdominal mass and symptoms related to bowel obstruction or gastrointestinal bleeding.

Primary CNS Lymphoma

• A high-grade lymphoma of B-cell origin, more common in immunocompromised individuals.
• Symptoms include headache, focal neurological deficits, seizures, and altered mental status.

Specific Lymphoma Types and Presentation

Mantle Cell Lymphoma

• Most patients present with advanced-stage disease.
• Symptoms include lymphadenopathy, spleen involvement, and systemic B symptoms like fever, night sweats, and weight loss.

Gastrointestinal Lymphoma

• Symptoms include epigastric pain, anorexia, weight loss, nausea, vomiting, and early satiety.

Testicular NHL

• Common in men over age 60, often presenting as a testicular mass.

Primary CNS Lymphoma (repeated for clarity)

• Symptoms can include headache, lethargy, focal neurological deficits, seizures, and spinal cord compression.

Risk Factors

Age

• Increased risk with age, particularly over 50 years.

Sex

• Males are more likely to be diagnosed with NHL than females.

Infections

• Epstein-Barr virus (EBV) is associated with several types of lymphoma, including Burkitt lymphoma and primary CNS lymphoma.

Immunodeficiency

• Conditions like HIV/AIDS and post-transplant states increase the risk of lymphoma, particularly in CNS involvement.

Autoimmune Conditions

• Sjögren’s syndrome, rheumatoid arthritis, and coeliac disease are linked to increased risk of lymphoma.

Environmental Factors

• Exposure to pesticides, phenoxyherbicides, and breast implants have been associated with an increased risk of NHL.

Other Clinical Features

Liver and Spleen Involvement

• Infiltration by lymphoma cells can cause hepatomegaly and splenomegaly.

Pulmonary Involvement

• Shortness of breath may result from pleural effusions or pulmonary involvement.

Abdominal Discomfort

• Often seen with gastrointestinal, liver, spleen, or lymph node involvement.

Neurological Symptoms

• Headache, confusion, focal weakness, and cognitive changes may suggest CNS involvement.

Skin Lesions

• Common in cutaneous NHL or other types that involve the skin, presenting as raised plaques, ulcers, or itching.

General Findings

 Low-Grade Lymphomas

• These may present with peripheral adenopathy, splenomegaly, and hepatomegaly.
• Splenomegaly is observed in approximately 40% of patients, though the spleen is rarely the only site involved at presentation.

Intermediate- and High-Grade Lymphomas

• These types often present with rapidly growing and bulky lymphadenopathy, as well as splenomegaly and hepatomegaly.

Large Abdominal Mass

• Typically seen in Burkitt lymphoma.
• May also present with a testicular mass or skin lesions, such as those associated with cutaneous T-cell lymphoma (mycosis fungoides), anaplastic large-cell lymphoma, or angioimmunoblastic lymphoma.

Lymphadenopathy

 Peripheral Lymphadenopathy

• Common across various lymphoma subtypes, especially in advanced-stage disease.

Extranodal Involvement

• Common sites include the gastrointestinal tract, skin, bone marrow, sinuses, genitourinary tract, thyroid, and central nervous system (CNS).

Abdominal and Pelvic Findings

 Splenomegaly

• Seen frequently, particularly in splenic marginal zone lymphoma.
• May cause splenic infarction.

Hepatomegaly

• May be present due to infiltration by lymphoma cells.

Ascites

• Can be a sign of lymphatic obstruction.
• Often chylous in nature due to compression of the thoracic duct or abdominal lymphatic vessels.

Abdominal Mass

• A large mass, typically in Burkitt lymphoma, may be palpated.

Gastrointestinal Involvement

• Symptoms may include abdominal discomfort or bloating.
• Often linked to lymphatic or liver involvement.

Chest and Lung Findings

 Superior Vena Cava Syndrome

• May indicate thoracic lymphoma.
• Symptoms include swelling of the face and neck, shortness of breath, and upper body oedema.

Pleural Effusions

• May cause shortness of breath.
• Can be related to lymphoma infiltration in the lungs or pleura.

Mediastinal Involvement

• Common in primary mediastinal large B-cell lymphoma.
• Often presents as a persistent cough or chest discomfort.

Neurological Findings

 Headache

• Can suggest increased intracranial pressure due to meningeal involvement or brain metastasis.

Focal Neurological Deficits

• Includes symptoms like ataxia, focal weakness, and cognitive changes.
• Indicates CNS involvement or secondary spread.

Spinal Cord Compression

• A medical emergency often caused by NHL involvement of the epidural space.
• Leads to irreversible loss of motor, sensory, or autonomic function.

Skin Findings

 Skin Lesions

• Cutaneous involvement is common in T-cell lymphoma, mycosis fungoides, or other lymphoma types.
• Lesions may range from patches to raised plaques.
• Some lesions may ulcerate or cause itching.

Breast Involvement

• Swelling or masses in patients with breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
• Often presents with seroma occurring more than a year post-implantation.

Extranodal Involvement

 Gastrointestinal Lymphoma

• Most common site for primary extranodal disease.
• Symptoms include abdominal pain, nausea, and early satiety.

Testicular Lymphoma

• Often presents as a mass.
• Constitutes 1% of all NHLs and 2% of extranodal cases, particularly in men over 60.

Bone Lymphoma

• Can present as pain, mass, swelling, or pathologic fractures.
• Especially common in disseminated disease.

Renal Involvement

 Renal Failure

• Occurs in 2–14% of NHL patients.
• Often presents with ureteral obstruction or acute uric acid nephropathy at diagnosis.

Ureteral Obstruction

• Caused by retroperitoneal disease or direct lymphoma invasion.
• Leads to renal insufficiency.

Examination of Lymphoid Sites

 Head and Neck

• Enlargement of preauricular nodes or tonsillar asymmetry may suggest involvement of Waldeyer's ring or extranodal spread in the head and neck region.

Lymphoid Survey

• All potentially involved lymphoid sites should be examined.
• Includes cervical, supraclavicular, axillary, inguinal, and femoral nodes, as well as abdominal nodal sites like mesenteric and retroperitoneal areas.

Other Common Findings

 Pallor

• Common in anaemia, which may result from bone marrow involvement or systemic effects of lymphoma.

Purpura

• Often due to thrombocytopenia, coagulation abnormalities, or disseminated intravascular coagulation (DIC), especially with liver involvement.

Initial Investigations

Lactate Dehydrogenase (LDH)

• Elevated LDH levels often correlate with tumour activity.
• High LDH levels serve as an important diagnostic and prognostic marker.
• The degree of elevation can influence the urgency of treatment and the management of tumour lysis syndrome.

Uric Acid

• High uric acid levels are common in aggressive (high-grade) lymphomas due to rapid tumour cell turnover.
• This elevation may necessitate careful attention to tumour lysis syndrome prophylaxis.

Complete Blood Count (CBC) with Differential

• May indicate anaemia, thrombocytopenia, leukopenia, or pancytopenia due to bone marrow involvement.
• Thrombocytopenia may also be linked to liver dysfunction.
• Some NHL subtypes, such as adult T-cell leukaemia/lymphoma (ATLL) or T-cell prolymphocytic leukaemia (T-PLL), may show lymphocytosis.

Peripheral Blood Smear

• Nucleated red blood cells and a left shift, indicating early stages of white blood cell production, are common with bone marrow involvement.
• Additionally, abnormal lymphocytes and, in rare cases, circulating blasts (e.g., in mantle cell lymphoma’s blastic phase) may be observed.

Serum Metabolic Panel (Including Liver Function Tests)

• Assesses kidney and liver function, electrolytes, and glucose.
• Vital for detecting organ dysfunction and evaluating potential organ involvement.
• Abnormal results may suggest liver infiltration or dysfunction due to lymphoma.

Lymph Node Biopsy

• The best method for diagnosing lymphoma is through an excisional or incisional biopsy of the largest and most accessible lymph node.
• Allows for the assessment of lymph node architecture and provides a conclusive diagnosis.

Bone Marrow Biopsy and Aspirate

• Crucial for confirming involvement, especially in cases where lymph node biopsy results are inconclusive.
• Bone marrow infiltration typically signifies advanced (stage IV) disease.

Immunohistochemistry

• Performed on biopsy samples to help confirm the lymphoma subtype.
• Complements findings from other diagnostic methods such as flow cytometry.

Flow Cytometry

• Performed on blood, bone marrow aspirates, or other fluids.
• Detects lymphoma-specific markers, assisting in the identification of the lymphoma subtype.

Fluorodeoxyglucose (FDG)-PET/CT Scan

• Used for diagnosis, staging, and follow-up care.
• More sensitive than CT alone in detecting both nodal and extranodal lesions, especially in aggressive lymphomas like DLBCL and follicular lymphoma.
• Useful for identifying biopsy sites and monitoring disease progression or transformation.

Additional Investigations to Consider

Core Needle Biopsy

• Can be considered when excisional biopsy is not possible or when lymph nodes are difficult to access.
• Not as optimal as excisional biopsies.

Fine-Needle Aspiration (FNA) Biopsy

• Typically insufficient for a definitive diagnosis of lymphoma.
• May be used initially, with follow-up excisional biopsy if lymphoma is suspected.

Genetic Testing

• Includes karyotyping, FISH, and PCR.
• Helps detect genetic abnormalities associated with NHL subtypes (e.g., BCL2, MYC).

Hepatitis B and C Serology

• Essential to avoid reactivation of these viruses during chemotherapy.
• Particularly relevant with treatments like rituximab.

HIV Testing

• Crucial for certain NHL subtypes such as Burkitt lymphoma and primary CNS lymphoma.
• Guides treatment decisions, including antiretroviral therapy.

Epstein-Barr Virus (EBV) Testing

• Plays a critical role in diagnosing EBV-associated lymphomas.
• Especially relevant in HIV-related B-cell lymphomas or certain T-cell lymphomas.

Human T-cell Lymphotropic Virus (HTLV) Testing

• Helps diagnose specific T-cell lymphomas such as ATLL.

MRI (Brain and Spine)

• Performed when neurological symptoms suggest CNS involvement.
• Especially relevant for primary CNS lymphoma or spinal cord compression.

Ultrasound (Breast, Axilla)

• Recommended if breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is suspected.
• If abnormalities like masses or effusions are detected, further biopsy is necessary.

Lumbar Puncture

• Indicated when CNS involvement is suspected.
• Especially important in high-risk subtypes like Burkitt lymphoma or primary CNS lymphoma.
• CSF analysis typically shows elevated protein, lymphocytic pleocytosis, and possibly malignant lymphoid cells.

Endoscopy and Colonoscopy

• Useful in diagnosing extranodal lymphomas in the gastrointestinal tract.
• Particularly relevant in MALT lymphoma and mantle cell lymphoma.

Serum Protein Electrophoresis with Immunofixation

• Detects monoclonal proteins.
• Particularly useful in splenic marginal zone lymphoma or Waldenström’s macroglobulinaemia.

Quantitative Immunoglobulins

• Elevated levels are typically seen in lymphoplasmacytic lymphoma or splenic marginal zone lymphoma.

Serum Beta-2 Microglobulin

• Elevated levels are associated with poorer prognosis in certain lymphoma subtypes.

Helicobacter Pylori Testing

• Positive results may indicate gastric MALT lymphoma.

Cardiac Evaluation (MUGA Scan or Echocardiography)

• Important before initiating chemotherapy with anthracyclines.
• Used to monitor for potential cardiotoxicity.

Hodgkin Lymphoma

• Symptoms: Pruritus, alcohol-induced pain, and a bimodal age distribution (peaks at 20-34 years and over 55 years).
• Investigation: Lymph node biopsy revealing Reed-Sternberg cells is diagnostic.

Epstein-Barr Virus (EBV) Infection

• Symptoms: Pharyngitis, rash, myalgias, and acute onset, often affecting young adults (high school and university students).
• Investigation: Monospot test (positive), EBV serology (positive), polyclonal B-cell population on flow cytometry.

Systemic Lupus Erythematosus (SLE)

• Symptoms: Malar rash (butterfly-shaped), photosensitivity, skin lesions, and oral ulcers.
• Investigation: Positive antinuclear antibody (ANA), anti-double-strand DNA, anti-Smith antibodies, and abnormal full blood count (FBC).

Acute Lymphoblastic Leukaemia (ALL)

• Symptoms: Acute onset with ecchymoses, petechiae, easy bruising, and frequent infections.
• Investigation: Peripheral blood smear showing leukaemic lymphoblasts, bone marrow biopsy confirming leukaemic lymphoblasts, flow cytometry with ALL markers, and cytogenetic analysis revealing Philadelphia chromosome or BCR::ABL1 fusion gene.

Infectious Mononucleosis

• Symptoms: Tender lymphadenopathy, acute onset with fever, pharyngitis, and myalgias.
• Investigation: Monospot test (positive), EBV serology (positive), polyclonal B-lymphocyte population on flow cytometry.

Hepatitis C Infection (HCV)

• Symptoms: Abdominal pain, malaise, nausea, and symptoms of liver disease. Often associated with intravenous drug use or HIV.
• Investigation: HCV-antibody enzyme immunoassay test (positive), reverse transcription polymerase chain reaction (PCR) for HCV RNA (positive).

Cytomegalovirus (CMV) Infection

• Symptoms: Common in immunocompromised individuals (e.g., post-transplant), presenting with fever, bone pain, visual symptoms, and diarrhoea.
• Investigation: CMV serology (positive), PCR for CMV DNA, biopsy confirming CMV.

Tuberculosis

• Symptoms: Risk factors include HIV, homelessness, or residence in a tuberculosis-endemic area. Symptoms include cough, malaise, and weight loss.
• Investigation: Chest X-ray, CT scan, tuberculin skin test (TST), acid-fast bacillus test, and tuberculosis culture.

HIV Infection

• Symptoms: Often associated with multiple sexual partners or history of intravenous drug use. May present with fever and rash.
• Investigation: ELISA (screening), Western blot (confirmatory), HIV RNA PCR for viral load.

Syphilis

• Symptoms: Risk factors include prior genital chancre and rash. Often associated with sexual history.
• Investigation: Treponema-non-specific tests (e.g., RPR, VDRL), and specific Treponema tests (e.g., FTA-ABS, TPHA).

Sarcoidosis

• Symptoms: Cough, dyspnoea, skin lesions, Bell's palsy, and general malaise. Often asymptomatic.
• Investigation: Chest X-ray or CT scan showing hilar adenopathy, bronchoscopy with biopsy of lymph nodes showing non-caseating granulomas.

Rheumatoid Arthritis

• Symptoms: Characterised by joint pain, swelling, stiffness, and heat, more common in females.
• Investigation: Positive rheumatoid factor, elevated erythrocyte sedimentation rate (ESR), and imaging of synovitis.

Mycobacterial and Other Bacterial Infections

• Symptoms: Can present with benign lymph node infiltration and reactive follicular hyperplasia.
• Investigation: Microbiological cultures, biopsy, and imaging.

Metastasis from Primary Tumors (e.g., Nasopharyngeal Carcinoma, Soft Tissue Sarcoma)

• Symptoms: May mimic lymphoma with similar presentations of lymphadenopathy.
• Investigation: Biopsy of suspected primary site for histology.

Granulocytic Sarcoma

• Symptoms: Lymphadenopathy, splenomegaly, and possible skin lesions.
• Investigation: Biopsy showing myeloid markers, histopathology confirming granulocytic infiltration.

Multicentric Castleman Disease

• Symptoms: Fever, weight loss, and lymphadenopathy, often with systemic features.
• Investigation: Lymph node biopsy, histology showing characteristic vascular proliferation and increased interfollicular cellularity.

General Considerations

• Prognostic tools such as the International Prognostic Index (IPI) or Stage-Modified IPI (smIPI) are integral for risk stratification, which informs treatment decisions, especially in aggressive subtypes.
• Clinical trials should be considered for all patients, particularly for those with aggressive lymphomas, relapsed, or refractory disease.
• Symptom severity is a key factor in determining the timing for initiating therapy.

Aggressive B-cell Lymphoma: Diffuse Large B-cell Lymphoma (DLBCL)

Stage I-II (Non-bulky or Bulky Disease, Low-Risk)

• First-line treatment: R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) for 3 cycles, followed by interim PET/CT for restaging.
• Further cycles (up to 6) with or without involved-site radiotherapy (ISRT) based on response.
• For patients with bulky disease or those who require radiation, a 3-4 cycle regimen of R-CHOP-21 followed by PET/CT is recommended.

Stage II (Extensive Mesenteric Disease) or Stage III-IV

• First-line treatment: R-CHOP-21 or Pola-R-CHP (polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone) for 2-4 cycles, followed by PET/CT or CT for restaging.

CNS Prophylaxis in DLBCL

• Consideration: CNS relapse occurs in about 5% of patients post-treatment.
• CNS prophylaxis, including high-dose methotrexate and intrathecal cytarabine, may be considered for high-risk patients with CNS-IPI scores of 4–6, testicular lymphoma, or primary cutaneous DLBCL.

Refractory or Relapsed DLBCL

• Treatment options: CAR T-cell therapy (e.g., axicabtagene ciloleucel or lisocabtagene maraleucel) for primary refractory disease or early relapse.
• Salvage chemotherapy options include DHA, ICE, and Gemcitabine-based regimens.
• For late relapse, salvage chemotherapy followed by autologous stem cell transplant (ASCT) is recommended if suitable.

Aggressive B-cell Lymphoma: Burkitt's Lymphoma

• First-line treatment for patients <60 years with low-risk disease: R-CODOX-M or R-hyper-CVAD.
• For high-risk patients, regimens include R-CODOX-M alternating with R-IVAC or R-EPOCH.
• CNS prophylaxis is necessary due to Burkitt's lymphoma's high risk for CNS involvement.

Aggressive B-cell Lymphoma: Mantle Cell Lymphoma (MCL)

Treatment Strategy

• Indolent Stage I–II (non-bulky): Bendamustine plus rituximab or VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisolone).
• Advanced Stage (II-bulky, III–IV): R-CHOP, LyMA regimen (R-DHA), or NORDIC regimen for aggressive induction.
• Maintenance therapy with BTK inhibitors (ibrutinib, acalabrutinib) and rituximab.

Aggressive T-cell Lymphoma

• First-line treatment for peripheral T-cell lymphoma: Brentuximab vedotin (for CD30+ cases) with CHP or CHOEP (cyclophosphamide, doxorubicin, etoposide, and prednisolone).
• Dose-adjusted EPOCH is considered for more aggressive cases.

Consolidation

• Patients in complete remission after initial treatment may be considered for consolidation with autologous stem cell transplant (ASCT).

Refractory or Relapsed Disease

• Treatment options include: Brentuximab vedotin, romidepsin, pralatrexate, or duvelisib.
• For patients failing two or more lines of therapy, CAR T-cell therapy or bispecific antibody therapy (e.g., epcoritamab) is considered.

Indolent B-cell Lymphoma: Follicular Lymphoma (cFL)

Stage I–II

• ISRT and/or rituximab (with or without chemotherapy).

Stage III–IV (Symptomatic Disease)

• R-CHOP or bendamustine plus rituximab for high tumour burden.
• Lenalidomide plus rituximab for low tumour burden or in elderly patients with significant comorbidities.

Relapsed or Refractory cFL

• Second-line treatment includes rituximab, obinutuzumab, or lenalidomide plus rituximab.
• CAR T-cell therapy (e.g., axicabtagene ciloleucel) or bispecific antibody therapy for relapsed disease.

Management of Localised and Extranodal Lymphomas (e.g., MALT)

Gastric MALT lymphoma associated with H. pylori infection

• Antibiotics for H. pylori eradication.
• ISRT for resistant or H. pylori-negative MALT.

Primary Cutaneous Lymphomas

• ISRT for localized PCFCL and PCMZL.
• R-CHOP or rituximab with CHOP for generalized lesions.

Supportive Therapy

• Tumour Lysis Syndrome (TLS): Prevention with hydration, allopurinol, and rasburicase for hyperuricaemia.
• Neutropenia: G-CSF for chemotherapy-induced neutropenia.
• Infection: Antibiotic prophylaxis for severe neutropenia.
• Chemotherapy-related toxicities: Monitoring for nausea, fatigue, and cardiac toxicity (e.g., from doxorubicin).

Management in Special Populations

Children

• Managed by paediatric oncologists with appropriate dosing.

Pregnant Women

• Treatment depends on trimester.
• Chemotherapy may be avoided until after delivery if possible, especially for high-risk disease in early pregnancy.

Long-Term Monitoring

• Regular follow-up care is needed to assess for adverse effects, disease progression, and response to treatment.
• This includes blood counts, liver function tests, and imaging (CT scans every 4–12 months).
• Symptomatic management for pain, mucositis, and fatigue.

Tools in NHL

• Age >60 years
• Elevated serum LDH levels
• ECOG performance status ≥2
• Clinical stage III or IV disease
• Extranodal involvement (more than one site)

• Low risk (0-1 adverse factors)
• Intermediate risk (2 adverse factors)
• Poor risk (3 or more adverse factors)

Key Prognostic Factors in NHL

• Tumour histology (cell type and differentiation)
• Tumour stage (extent of spread)
• Patient age (younger patients generally have better outcomes)
  Tumour bulk (size of the tumour or extent of disease)
• Performance status (overall physical condition)
• Serum LDH levels (reflects tumour burden)
• Beta2-microglobulin levels (indicates tumour activity)
• Extranodal disease (presence of disease outside the lymph nodes)

Survival and Response to Treatment

Five-Year Survival Rates

• The overall five-year relative survival rate for NHL patients is approximately 74.3%, which has improved over the last two decades due to advancements in therapy.
• Younger patients typically experience better outcomes, particularly those who achieve complete remission after initial therapy.
• Indolent lymphomas tend to have a prolonged survival of 6-10 years, but they are not curable and can transform into aggressive forms.

Prognosis by Biomarkers and Genetic Factors

• Tumor cell biomarkers, such as the expression of BCL-2 or BCL-6 proteins, can provide valuable prognostic information.
• Cytogenetic abnormalities and oncogene expression (such as MYC, BCL2, and BCL6 translocations) significantly affect prognosis, with poorer outcomes associated with certain genetic alterations.

Impact of Vitamin D and Environmental Factors

• Emerging evidence suggests that low vitamin D levels may be associated with poorer clinical outcomes in aggressive B-cell lymphoma subtypes such as DLBCL and T-cell lymphoma. 
• Further research is needed to clarify the role of vitamin D in lymphomagenesis and disease progression.

Risk of Secondary Malignancies

• NHL survivors are at increased risk for developing a second primary malignancy, with hazard ratios of 2.70 for men and 2.88 for women. 
• Long-term monitoring for secondary cancers is essential.

Prognostic Models and Risk Stratification

• Prognostic models such as the IPI, FLIPI, and MIPI continue to guide clinical decisions and the selection of treatment regimens for various NHL subtypes.
• These tools help in stratifying patients into risk categories and predicting their response to therapy.

Life-threatening Complications

Febrile Neutropenia

• A condition often seen in patients undergoing chemotherapy, particularly those receiving myelosuppressive therapy.
• It requires urgent management with broad-spectrum antibiotics and supportive care.

Hyperuricemia and Tumour Lysis Syndrome (TLS)

• TLS is caused by the rapid destruction of tumour cells, releasing intracellular contents into the bloodstream, including potassium, uric acid, phosphate, and nucleic acids.
• It manifests as fatigue, nausea, vomiting, reduced urine output, and metabolic imbalances such as hyperkalemia, hyperphosphatemia, and hypocalcemia.
• TLS can be managed with vigorous hydration, allopurinol, and, in severe cases, dialysis.
• It is particularly common in rapidly growing tumours, such as Burkitt's lymphoma, and in patients with high tumour burden.

Spinal Cord or Brain Compression

• NHL can cause focal compression in various parts of the body, including the central nervous system (CNS).
• Compression can lead to neurological symptoms depending on the location of the tumor, such as airway obstruction (mediastinal lymphoma), intestinal obstruction, or even ureteral obstruction.

Superior or Inferior Vena Cava Obstruction

• Vena cava syndrome occurs when large tumours compress the superior or inferior vena cava.
• This leads to venous congestion, swelling, and possibly respiratory distress.

Hyperleukocytosis

• An elevated white blood cell count, often seen in aggressive forms of NHL.
• This can increase the risk of tumour lysis syndrome or other complications due to excessive cell turnover.

• This occurs when tumour cells infiltrate the pericardial sac, leading to fluid accumulation and compression of the heart.
• It causes acute cardiac tamponade, which requires urgent intervention.

Autoimmune Hemolytic Anaemia and Thrombocytopenia

• Certain NHL subtypes, such as small lymphocytic lymphoma, can lead to autoimmune complications including hemolytic anaemia and thrombocytopenia.
• These conditions complicate both diagnosis and treatment.

Complications of Immunotherapy and Chemotherapy

Cytokine Release Syndrome (CRS)

• CRS is a major adverse effect of chimeric antigen receptor T-cell (CAR T-cell) therapy, characterised by a systemic inflammatory response.
• It is often seen in younger patients (under 25) and presents with symptoms such as fever, nausea, headache, rash, and multi-organ dysfunction.

Cardiovascular Complications

• Cardiac toxicities such as myocardial ischemia, hypertension, and arrhythmias can arise during CAR-T cell therapy and with Bruton's tyrosine kinase inhibitors (e.g., ibrutinib).
• These complications are often more severe in patients with pre-existing cardiac conditions.

Chemotherapy-Related Complications

R-CHOP Toxicities

• R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is commonly used for NHL.
• It is associated with various toxicities such as myelosuppression, immunosuppression (leading to infections), mucositis (particularly with high-dose methotrexate), and renal failure due to tumour lysis syndrome.
• Anthracycline-induced cardiotoxicity and peripheral neuropathy from vincristine are also common adverse effects.

Secondary Leukaemias and Myelodysplastic Syndromes

• Alkylating agents (e.g., cyclophosphamide) and topoisomerase II inhibitors (e.g., etoposide) have been associated with an increased risk of secondary acute myeloid leukaemia (AML) and myelodysplastic syndrome.

Radiation-Related Complications

Secondary Cancers

• Radiation therapy for NHL, especially when used at higher doses, can result in the development of secondary cancers.
• These include solid tumours and secondary leukaemias such as acute lymphocytic leukaemia (ALL) and acute myeloid leukaemia (AML).

Pneumonitis

• Lung inflammation (pneumonitis) can occur, particularly with mediastinal radiation therapy.
• This leads to difficulty breathing and requires prompt medical management.

Bone Marrow Transplant-Related Complications

Graft-Versus-Host Disease (GVHD)

• GVHD remains a significant complication in patients undergoing allogeneic stem cell transplantation.
• Donor cells attack the recipient’s tissues, causing systemic inflammatory reactions.

Hepatic Veno-Occlusive Disease

• This condition occurs when the small veins in the liver become blocked, leading to liver failure.
• It can be a result of both chemotherapy and bone marrow transplant therapies.

Tumour Lysis Syndrome (TLS)

• A life-threatening complication, particularly in high-grade NHLs such as Burkitt's lymphoma.
• TLS is marked by rapid tumour cell death leading to the release of large amounts of intracellular contents into the bloodstream.
• The clinical manifestations include hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.
• These can lead to renal failure and, without prompt treatment, potentially fatal outcomes.

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