Lymphoma overview: classification, staging, and prognosis

Overview

• Definition: lymphoma is a clonal disease of lymphocytes and lymph nodes. Lymphocytes originate in the bone marrow and travel peripherally through the blood and lymphatic system to the lymph nodes.
• This note is the parent overview: entity-specific notes (DLBCL, PMBL, Burkitt, MCL, indolent lymphomas, HL, T-cell lymphomas) build on the framework here.

WHO / ICC Classification Framework

• More than 85 subtypes and counting (Armitage JCO 1998; Swerdlow Blood 2016). Classification integrates morphology, immunophenotype, genetics, and clinical features.
• Harmonized framework: WHO 5th edition (2022) and ICC 2022 are largely concordant; minor differences exist in some entities (e.g., naming of HGBL).
• Major mature B-cell entities: DLBCL NOS, HGBL with MYC and BCL2 rearrangements (WHO-HAEM5); MYC/BCL6 without BCL2 is DLBCL NOS or HGBL NOS in WHO-HAEM5, a separate provisional HGBL with MYC and BCL6 in ICC 2022, HGBL with 11q aberration (renamed in WHO 2022 from the 2017 provisional Burkitt-like lymphoma with 11q aberration; ICC: LBCL with 11q aberration; MYC-negative), Burkitt lymphoma, FL, MZL (extranodal MALT, splenic, nodal), MCL, CLL/SLL, WM, HL.
• NLPHL renamed NLPBL (ICC 2022): the ICC 2022 reclassified nodular lymphocyte-predominant HL as nodular lymphocyte-predominant B-cell lymphoma; WHO 5th edition (2022) retained the name NLPHL while recognizing it as a B-cell neoplasm.
• Mature T/NK: PTCL-NOS, AITL = nodal TFH cell lymphoma, angioimmunoblastic-type (WHO-HAEM5; TFH family also includes follicular-type and NOS), ALCL (ALK+ / ALK−), CTCL (MF / Sezary), extranodal NK/T, ATLL.

Stages of B-cell Development and Cell of Origin

• Concept: mature B-cell neoplasms recapitulate a normal stage of B-cell differentiation; the arrested stage predicts the immunophenotype and drives classification (the "cell of origin").
• Early antigen-independent stages (bone marrow): pro-B and pre-B cells are TdT+ and give rise to precursor (lymphoblastic) neoplasms.
• Germinal center passage: mature B cells transit the germinal center (site of somatic hypermutation and class switching); GCB-derived tumors (e.g., FL, Burkitt, GCB-DLBCL) typically express CD10 and BCL6.
• Post-germinal center / plasma cell stages: ABC-type DLBCL, many MZLs, LPL/WM, and plasma cell neoplasms arise later; express MUM1/IRF4, CD138 as maturation advances.
• DLBCL cell of origin: Hans algorithm (CD10, then BCL6, then MUM1) classifies as GCB or non-GCB; gene-expression profiling (GEP) is more accurate. ABC (non-GCB) historically worse, but pola-R-CHP is narrowing the gap (see DLBCL note).

Clinical Presentation

• Tempo: aggressive lymphomas evolve over days to weeks; indolent lymphomas over months to years.
• Expansion of lymphocytes: enlargement of lymph nodes and spleen; invasion into extranodal sites; plethora and superior vena cava (SVC) syndrome from a mediastinal mass; neurologic deficits with CSF involvement.
• Cytopenias: infections (neutropenia), fatigue (anemia), bleeding and petechiae (thrombocytopenia), often from marrow involvement.
• Paraneoplastic syndromes: nephrotic syndrome; autoimmune hemolytic anemia and ITP.
• History: duration of symptoms; environmental and host factors (chronic infection with HIV, HCV, H. pylori; autoimmune disease; immunosuppression; chemicals and radiation); family history and number of siblings; ethnicity and place of birth.
• Exam: lymphadenopathy, hepatosplenomegaly, rash.
• Labs and procedures: LDH, SPEP, beta-2 microglobulin, sed rate; HIV, HBV, HCV, EBV, CMV, HTLV-1; lumbar puncture if confusion or CNS involvement suspected; echocardiogram before anthracycline.

B Symptoms

• Defined by cytokine secretion: (1) unexplained fever >38 degrees C, (2) drenching night sweats, (3) unexplained weight loss >10% of body weight over the 6 months before diagnosis.
• Presence (B) or absence (A) is appended to the stage and carries prognostic weight (worse with B).
• NOT B symptoms: pruritus and alcohol-induced pain (classic HL associations) and fatigue are prognostically relevant in HL but are not counted as formal B symptoms.

Diagnostic Principles

• Excisional or incisional biopsy preferred over FNA (architecture matters for classification); core biopsy acceptable when excision is not feasible.
• Morphology: chromatin structure and nodal architecture.
• Immunophenotype: flow cytometry and immunohistochemistry.
• Molecular and genetics: cytogenetics, FISH, PCR, NGS (BCR clonality, MYC FISH for HGBL, etc.).
• Bone marrow biopsy: for staging; optional in HL and DLBCL when PET adequately evaluates the marrow; often required in FL, MCL, MZL.

Staging: Lugano (modified Ann Arbor)

• Derived from Ann Arbor with Cotswolds modifications. Roughly 40% present stage I/II and 40% have extranodal disease (GI, BM, CNS).
• Limited, Stage I: one nodal region or one extranodal site (IE).
• Stage II: two or more nodal regions on the same side of the diaphragm; IIE if contiguous extranodal.
• Advanced, Stage III: nodal involvement on both sides of the diaphragm.
• Stage IV: additional noncontiguous, disseminated extranodal disease (BM, liver, lung, CNS).
• Modifiers: A/B (B symptoms, used mainly for HL), E (limited-stage localized extranodal disease or direct extension); Lugano records the largest mass size rather than an X (bulky) suffix.
• Bulky disease: in HL, a single nodal mass ≥10 cm or >1/3 of the transthoracic diameter at any level of the thoracic vertebrae by CT (record the longest measurement); NHL thresholds vary by histology.

Imaging and Response Assessment

• CT gives size; PET gives metabolic activity. SUV: 2 to 6 tends to be more indolent, and >15 tends to be more aggressive.
• PET-CT: standard for FDG-avid lymphomas (DLBCL, HL, FL, MCL, MZL, BL, PMBL) and for response assessment.
• Limited FDG avidity: CLL/SLL (low uptake, except in Richter transformation work-up), some MALT, some MF/Sezary.
• Deauville 5-point score compares lesion uptake to reference tissues: 1 = no uptake; 2 = ≤ mediastinal blood pool; 3 = > mediastinum but ≤ liver; 4 = moderately > liver; 5 = markedly > liver and/or new lesions.
• Complete metabolic response (CMR): Deauville 1 to 3 (a 3 may be read as residual in DLBCL/PMBL protocols).
• Surveillance imaging: per Lugano, not routinely indicated after CR in indolent NHL or even DLBCL; symptom-driven follow-up preferred (low yield, radiation exposure).

Prognostic Indices

• IPI (DLBCL), mnemonic APELS: Age >60, stages III/IV (Stage), LDH elevated, Performance ECOG ≥2, Extranodal sites >1; score 0 to 5.
• NCCN-IPI is a better discriminator: it uses more granular age and LDH ratio bands and specific extranodal sites (BM, CNS, liver/GI, lung).
• R-IPI: redistributes IPI factors into 3 risk groups in the rituximab era: very good (0), good (1 to 2), poor (3 to 5).
• FLIPI: age >60, stage III/IV, Hb <12, LDH elevated, >4 nodal areas. FLIPI-2: age >60, beta-2 microglobulin, BM involvement, largest node >6 cm, Hb <12.
• MIPI / MIPI-c (MCL): age, ECOG, LDH, WBC; MIPI-c adds Ki-67.
• IPS (advanced HL): 7 factors, age ≥45, male, stage IV, albumin <4, Hb <10.5, WBC ≥15K, lymphocytes <600 or <8%.
• CNS-IPI (DLBCL): 6 factors (the 5 IPI items plus kidney/adrenal involvement) stratify low/intermediate/high risk for CNS relapse; high risk prompts CNS prophylaxis (see DLBCL note).
• MYC biology: MYC alone or MYC plus BCL2 carries a poor prognosis; BCL2 rearrangement alone is not double-hit, though in GCB-DLBCL it may still confer somewhat inferior R-CHOP outcomes.

Pre-treatment Considerations

• HBV screening (HBsAg plus HBcAb): mandatory before rituximab or obinutuzumab (HBV reactivation risk; entecavir prophylaxis if HBcAb+ regardless of HBsAg).
• HIV and HCV: also screen.
• Echo: baseline if an anthracycline-containing regimen is planned (target LVEF >50%).
• PFTs: if bleomycin is planned (HL).
• Fertility counseling: alkylators, RT, and allo plans warrant sperm or oocyte preservation in young patients.
• Vaccinations: ideally before rituximab (rituximab blunts response for about 6 months).

Late Effects (especially mediastinal RT)

• Second cancers: breast (RT-related, start annual mammography plus breast MRI for survivors who received chest/mediastinal RT (≥10 Gy) at a young age (chest RT ages 10 to 30), beginning age 25 or 8 years post-RT, whichever is later), lung, thyroid, sarcoma; therapy-related MDS/AML from alkylators and etoposide.
• Cardiovascular: anthracycline cardiomyopathy; mediastinal RT causes CAD, valvular disease, and pericarditis. Echo plus CV risk modification.
• Endocrine: hypothyroidism (neck RT), gonadal failure, GH deficiency in pediatrics.
• Pulmonary: bleomycin pulmonary fibrosis; avoid hyperoxia.

High-Yield Pearls

• Excisional biopsy beats FNA; architecture is essential.
• HBcAb+ patients getting rituximab need entecavir prophylaxis.
• CNS-IPI ≥4 flags high CNS relapse risk; consider HD-MTX prophylaxis.
• Deauville 1 to 3 equals CMR; surveillance scans are not routinely indicated after CR.
• Bulky disease (HL): single mass ≥10 cm or >1/3 of the transthoracic diameter on CT (NHL thresholds are histology- and protocol-dependent).
• B symptoms are fever, drenching night sweats, and >10% weight loss; pruritus is not a B symptom.
• FDG-not-avid: CLL/SLL (use CT for staging unless concerned for Richter).