Hematology & Oncology & Internal Medicine & Family Medicine
Hodgkin's lymphoma and non-Hodgkin's lymphoma
Lymphomas are cancers of the lymphatic system resulting from malignant clonal proliferation of lymphocytes (B, T or NK) at various stages of differentiation. They constitute a heterogeneous group of over 80 distinct histological entities, grouped into two major clinicopathological categories: Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). Hodgkin's lymphoma, described by Thomas Hodgkin in 1832, is characterized histologically by the presence of Reed-Sternberg cells (large binucleated or multinucleated cells of B origin) within a polymorphous inflammatory infiltrate - it accounts for around 10 % of all lymphomas, preferentially affects young adults (peak at 20-25 years) and adults over 55, and is treated with remarkable efficacy by chemotherapy (ABVD - Adriamycin + Bleomycin + Vinblastine + Dacarbazine) with cure rates exceeding 80-90 % for localized forms. Non-Hodgkin lymphomas account for the remaining 90 % - they include a wide variety of entities ranging from indolent (follicular + marginal zone lymphoma + small-cell lymphocytic lymphoma) to aggressive (diffuse large B-cell lymphoma - DLBCL - and Burkitt's lymphoma) and very aggressive. DLBCL (Diffuse Large B-Cell Lymphoma) is the most frequent NHL (30-35 % of NHL), treated with the R-CHOP protocol (Rituximab + Cyclophosphamide + Doxorubicin + Vincristine + Prednisolone) with complete remission rates of 60-80 % and cure rates of 50-60 %. Excisional lymph node biopsy remains the diagnostic gold standard - needle biopsy alone is insufficient to correctly classify lymphoma in the majority of cases.
Classification, clinical presentation and staging
- Lymphoma classification and main entities : Hodgkin's lymphoma (HL) - WHO 2022 classification: Classical LH (95 %): 4 histological subtypes → nodular sclerosis (NS - most common - 70 % - young adult + female + mediastinum) + mixed cellularity (MC - 20-25 % - HIV ++ + EBV +) + lymphocyte depletion (LD - rare - poor prognosis) + lymphocyte-rich (LR - rare - good prognosis) → Reed-Sternberg cells: CD15+ + CD30+ + CD20- (or weak) → nodular lymphocyte-predominant LH (LPLN - 5 %): distinct biology → «popcorn» cells (lymphocytic and histiocytic) → CD20+ + CD15- → indolent evolution → different treatment (rituximab); non-Hodgkin lymphomas (NHL) - main entities by frequency and aggressiveness: indolent B NHL (slow evolution → not curable but controllable): follicular lymphoma (FL - 20-25 % of NHL): grade 1-3A → CD20+ CD10+ BCL-2+ + translocation t(14;18) → IPI + FLIPI + rituximab ± chemotherapy depending on stage → marginal zone lymphoma (MZL): MALT + splenic + nodal → small-cell lymphocytic lymphoma (SLL) / CLL → lymphoplasmacytic lymphoma (Waldenström macroglobulinemia - MYD88 L265P mutation) → aggressive B NHL (curative if intensive treatment): DLBCL (30-35 % of NHL) → molecular subtypes: GCB (germinal center B-cell - better prognosis) + ABC/non-GCB (activated B-cell - poorer prognosis) + double-hit (MYC + BCL-2 or BCL-6 rearrangements - very aggressive) → R-CHOP + mantle cell lymphoma (MCL - 5-8 %): CD5+ + SOX11+ + t(11;14) cyclophosphamide D1 +CCND1 → intensive treatment (R-CHOP + ara-C + autograft) → Burkitt's lymphoma (BL - very aggressive): EBV ++ + t(8;14) MYC → hyper-intensive chemo → T and NK NHL (15 % NHL): peripheral T lymphoma + ALCL (ALK+ and ALK-) + extra-ganglionic NK/T lymphoma (EBV+) + mycosis fungoides (cutaneous T)
- Clinical presentation, B signs and Ann Arbor staging: clinical presentation of lymphomas: adenopathies: most frequent sign → lymph node(s) increased in volume + painless + firm + non-compressible → alarm characteristics: persistence >4 weeks + size >1-2 cm + hard + adherent + progressive growth + not attached to an infection + location: cervical (LH) + axillary + inguinal → mediastinal: mediastinal mass → dyspnea + cough + SVCS → LH nodular sclerosis ++ → B signs (pejorative prognostic factors in staging): unexplained fever >38°C + profuse night sweats (soak sheets) + unexplained weight loss >10 % of body weight in less than 6 months → all three must be unexplained by another cause → associated systemic signs: intense pruritus (LH - eosinophil release + cytokines) + lymph node pain on ingestion of alcohol (Hodgkin's pain - pathognomonic but rare) + splenomegaly + hepatomegaly → signs of compression or invasion depending on location + Ann Arbor staging modified (Cotswolds 1989) + IWG 2014 (Lugano): stage I: involvement of a single lymph node region + stage II: ≥2 lymph node regions on the same side of the diaphragm + stage III: lymph node regions on 2 sides of the diaphragm + stage IV: diffuse extralymphatic involvement (liver + marrow + lung + OS) → suffix A: absence of B signs → suffix B: presence of ≥1 B sign → localized NHL = stage I-II without adverse risk factors → advanced NHL = stage III-IV or stage I-II with risk factors (bulky mass + stage II + B signs + ≥3 sites) → IPI (International Prognostic Index) for aggressive NHL: age >60 + ECOG PS ≥2 + high LDH + stage III-IV + ≥2 extra-ganglionic sites → score 0-5 → low risk (0-1) + intermediate-low (2) + intermediate-high (3) + high (4-5) + FLIPI for follicular lymphoma
Diagnosis, treatment and follow-up
| Appearance / treatment | Data, protocols and results | Key studies and recommendations |
|---|---|---|
| Diagnosis - biopsy, workup and imaging excisional biopsy - insufficient needle biopsy - immunohistochemistry - PET-CT - staging - osteomedullary biopsy - LDH - beta-2-microglobulin - CBC - HIV EBV HBV infectious workup - FISH karyotype - genomics |
Diagnosis of lymphomas - rigorous approach: excisional lymph node biopsy: diagnostic gold standard → complete removal of an accessible lymph node → systematic referral to anatomopathology + immunohistochemistry (IHC) → CORE NEEDLE BIOPSY (FNA): insufficient alone for diagnosis and classification in the majority of cases → acceptable only if the lymph node is deep + inaccessible + and the biopsy yields sufficient material → always discussed in a multidisciplinary concertation meeting (RCP) + anatomopathology and IHC : antibody panel according to suspicion → LH: CD15 + CD30 + CD20 + PAX5 + EBV EBER ISH → DLBCL: CD20 + CD10 + BCL-2 + BCL-6 + MYC + Ki-67 (proliferation index) → MCL: cyclin D1 + CD5 + SOX11 → FISH if double-hit suspicion (MYC + BCL-2) → tumor genomics (NGS) for certain subtypes + complete initial biological workup: CBC + reticulocytes + blood smear → LDH (tumor mass marker + prognostic) → β2-microglobulin → albumin → hepatic + renal workup → uricemia → calcemia → serologies: HIV + HBV (HBsAg + anti-HBs + anti-HBc) → essential before any anti-CD20 immunotherapy (rituximab) → fatal HBV reactivation without antiviral prophylaxis if anti-HBc positive → EBV + HTLV-1 if T lymphoma → ANCA + autoimmune workup if MZL lymphoma; staging imaging - 18F-FDG PET-CT (gold standard): advantageously replaces CT alone + detects metabolically active sites of involvement → evaluation of extent of disease → guides biopsies → evaluation of response during treatment + at the end (Lugano 2014 response criteria - Cheson): complete remission (CR) = negative PET-CT (Deauville score 1-2) → partial remission (PR) = reduction ≥50 % in tumor mass + Deauville score 4 → bone marrow biopsy (BOM): if suspicion of bone marrow involvement → less and less practiced with PET-CT → but remains useful for indolent lymphomas + NHL to reveal PET/BOM discordance + TAP scan + neck as adjunct if PET-CT unavailable or non-contributory | Cheson 2014 - Journal of Clinical Oncology (Lugano criteria): lymphoma response → PET-CT + Lugano criteria → international reference + Barrington 2014 - JCO: PET-CT + lymphoma staging + Swerdlow 2022 - Blood (WHO 2022 classification): lymphoma classification → reference + Connors 2022 - Annals of Oncology: LH → diagnosis + staging + treatment → ESMO guidelines + Tilly 2022 - Annals of Oncology (ESMO): DLBCL → guidelines → reference + Zelenetz 2023 - NCCN guidelines: lymphomas → workup + staging → Association des hémato-oncologues du Québec (AHOQ) + INESSS Québec: excisional biopsy + PET-CT + serologies → protocols + RAMQ: PET-CT reimbursed in documented lymphomas + staging workup. |
| Treatment of Hodgkin's lymphoma ABVD - bleomycin - pulmonary - BEACOPP escalated - brentuximab vedotin - nivolumab - pembrolizumab - intermediate evaluation PET - advanced unfavorable stage - radiotherapy ISRT - cure 85-90 % |
Treatment of classical Hodgkin's lymphoma - protocols according to stage: LH favorable stage (I-II without unfavorable factors): ABVD × 2 cycles + involved-site radiotherapy (ISRT 20 Gy) → complete remission rate >95 % → cure rate 90-95 % → or ABVD × 4 cycles without radiotherapy (to reduce late toxicity) → LH unfavorable stage (I-II with risk factors): ABVD × 4 cycles + ISRT 30 Gy → or escalated BEACOPP (Bleomycin + Etoposide + Adriamycin + Cyclophosphamide + Vincristine + Procarbazine + Prednisone × 2 escalated cycles then 2 ABVD cycles) → Advanced stage LH (III-IV): ABVD × 6 cycles → intermediate PET-CT evaluation after 2 cycles (iPET2) → if iPET2 positive (Deauville score 4-5) → escalation to escalated BEACOPP → if iPET2 negative → continue ABVD → 5-year results (RATHL trial - Johnson 2016 - NEJM) : PET-guided de-escalation → withdrawal of bleomycin (lung toxicity) if iPET2 negative → no inferiority on survival → reduced lung toxicity → Engert 2010 - NEJM (HD15 trial): 6 escalated BEACOPP cycles → non-inferiority vs. 8 cycles → reduced toxicity → brentuximab vedotin (BV - Adcetris): anti-CD30 + auristatin E → post-ASCT consolidation in refractory or relapsed forms → AETHERA trial (Moskowitz 2015 - Lancet): BV post-ASCT → PFS improvement → frontline in advanced stages → ECHELON-1 (Connors 2018 - NEJM n=1,334): A-AVD (BV + doxorubicin + vinblastine + dacarbazine) vs ABVD → PFS improvement → BV + AVD possible in 1st-line stage III-IV → checkpoint inhibitors (PD-1): nivolumab (CheckMate 205) + pembrolizumab (KEYNOTE-087) → refractory-relapsed LH → response rate 60-70 % → standard of care in 2nd or 3rd line → bleomycin pulmonary toxicity: 5-15 % of patients on ABVD → risk increased by: smoking + oxygen + pulmonary RT + advanced age → monitoring by spirometry (DLCO) before each cycle | Johnson 2016 - NEJM (RATHL trial): PET-guided de-escalation in advanced HL → bleomycin withdrawal if iPET2 negative → reference + Engert 2010 - NEJM (HD15): BEACOPP 6 vs 8 cycles → non-inferiority + Connors 2018 - NEJM (ECHELON-1 n=1,334): A-AVD vs ABVD stage III-IV LH → PFS improvement → Moskowitz 2015 - Lancet (AETHERA): BV post-ASCT relapsed LH → PFS improvement + Armand 2016 - JCO (CheckMate 205): nivolumab + relapsed LH → response rate 66 % + ESMO 2022 + NCCN 2024: LH → treatment + AHOQ + INESSS Québec: ABVD + BEACOPP + brentuximab + nivolumab + pembrolizumab → reimbursed according to indication + RAMQ: nivolumab pembrolizumab brentuximab reimbursed in refractory LH |
| Treatment of NHL - DLBCL, follicular and special situations R-CHOP - DLBCL - GCB ABC - double-hit - polatuzumab vedotin - CAR-T - axicabtagen - tisagenlecleucel - follicular lymphoma - watch and wait - bendamustine-rituximab - obinutuzumab - autograft - allograft - HBV prophylaxis |
Treatment of DLBCL (Diffuse Large B-Cell Lymphoma) - the most common NHL: R-CHOP × 6 cycles: standard of care for 2 decades → Coiffier 2002 - NEJM (n=399): R-CHOP vs CHOP → OS + EFS improvement → historical reference → complete remission (CR) rate: 60-80 % → 5-year overall survival: 60-70 % → R-CHOP-14 (every 14 days with G-CSF) vs R-CHOP-21 (every 21 days) → non-superior (Cunningham 2013 - Blood) → polatuzumab vedotin + rituximab + cyclophosphamide + doxorubicin + prednisone (Pola-R-CHP): POLARIX trial (Tilly 2022 - NEJM n=879): Pola-R-CHP vs R-CHOP in 1st line → reduced risk of progression by 27 % → reference for high-risk DLBCL → Health Canada 2022 + CAR-T cells (Chimeric Antigen Receptor T-cell therapy): axicabtagen ciloleucel (Yescarta) + tisagenlecleucel (Kymriah) → targeting CD19 → for relapsed-refractory DLBCL (2nd line after 2 lines of chemotherapy or 1st early relapse <12 months) → ZUMA-7 (Locke 2022 - NEJM): axicabtagen ciloleucel vs autograft + catch-up chemo in early 2nd line → superior → TRANSFORM (Bishop 2021 - Blood) → Health Canada 2019 (axicabtagen) → RAMQ Quebec: coverage + double-hit (MYC + BCL-2) lymphoma: aggressive form → more intensive treatment (R-DA-EPOCH) → high-dose chemotherapy + autograft + anti-HBV prophylaxis : any HBsAg-positive or anti-HBc-positive patient before rituximab → entecavir or tenofovir during and 12-18 months after → HBV reactivation without prophylaxis → fulminant hepatitis + death → MANDATORY; treatment of follicular lymphoma (FL): stage I-II: radiotherapy → curability possible + stage III-IV: watch and wait if asymptomatic (objectification of a treatment-free period → in case of indolent non-progressive disease) → or rituximab monotherapy → or bendamustine-rituximab (B-R) or R-CHOP depending on volume + obinutuzumab-bendamustine : GALLIUM trial (Marcus 2017 - NEJM): obinutuzumab + chemo vs rituximab + chemo → improved PFS → lenalidomide + rituximab (R²): RELEVANCE trial (Morschhauser 2018 - NEJM): R² vs R-chimio → non-inferior PFS + better tolerance → RAMQ: rituximab + obinutuzumab + bendamustine + lenalidomide → reimbursed according to INESSS criteria. | Coiffier 2002 - NEJM (n=399): R-CHOP vs CHOP → DLBCL → OS + EFS → founding historical reference + Tilly 2022 - NEJM (POLARIX n=879): Pola-R-CHP vs R-CHOP → reduced risk of progression 27 % → possible new standard + Locke 2022 - NEJM (ZUMA-7): CAR-T axicabtagen vs autograft + chemo 2nd line → superior + Marcus 2017 - NEJM (GALLIUM): obinutuzumab + chemo vs rituximab + chemo → FL → PFS improvement + Morschhauser 2018 - NEJM (RELEVANCE): R² vs R-chimio → FL → non-inferior + Tilly 2022 - Annals of Oncology (ESMO guidelines DLBCL) + ESMO 2023 FL guidelines + NCCN 2024 → AHOQ + INESSS Quebec: R-CHOP + Pola-R-CHP + CAR-T + rituximab + obinutuzumab → reimbursements + RAMQ: CAR-T (Yescarta + Kymriah) + rituximab + bendamustine + lenalidomide → reimbursed Quebec |
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An adenopathy persisting for more than 4 weeks, larger than 1 cm, firm, painless and with no obvious infectious cause should raise the suspicion of lymphoma - excisional biopsy is the reference diagnostic examination and should not be replaced by a simple needle biopsy in the majority of cases: prior to any treatment with rituximab (anti-CD20), it is mandatory to screen for HBV infection (HBsAg + anti-HBc) - reactivation without antiviral prophylaxis can be fatal. PET-CT is the gold standard for staging and response assessment. Superior vena cava syndrome (SVCS) associated with a mediastinal mass is an oncological emergency.
Situations requiring urgent oncology care
Bulky mediastinal mass + progressive dyspnea + orange peel edema of neck + face + upper limbs + visible thoracic collateral venous circulation → superior vena cava syndrome (SVCS) → oncological emergency → call 911 → hospitalization → emergency chest CT scan → biopsy as soon as possible (accessible cervical lymph node?) → treatment according to etiology → corticoids if LH + SVCS compromising airway → urgent radiation oncology if compressive mass.
Patient with known lymphoma on rituximab + fever + jaundice + very high transaminases + HBV risk factors (untreated anti-HBc positive) → HBV reactivation under rituximab → hepatological emergency → urgent entecavir or tenofovir + hepatological follow-up → can be fatal if unrecognized → reminder: MANDATORY antiviral prophylaxis in any anti-HBc-positive patient on anti-CD20.
Cervical or axillary adenopathy ≥2 cm + firm + painless + persistent >4 weeks + B signs (fever + night sweats + weight loss >10 %) ± intense pruritus ± elevated LDH → suspicion of lymphoma → urgent excisional biopsy + biological workup + HIV HBV serologies + PET-CT → hemato-oncological referral → DO NOT prescribe corticoids prior to biopsy (mask histological findings).
Patient undergoing chemotherapy for lymphoma + fever >38.3°C + profound neutropenia (PNN <0.5 × 10⁹/L) → febrile neutropenia → call 911 → oncological emergencies → blood cultures × 2 + cultures + broad-spectrum IV antibiotic therapy within 60 minutes (piperacillin-tazobactam + or meropenem if shock) → G-CSF discussed → MASCC or CISNE score to assess risk.
Consult at Clinique Omicron
Clinique Omicron's physicians recognize signs of lymphoma (persistent adenopathy + B signs + mediastinal mass), prescribe the initial biological work-up (CBC + LDH + β2M + LDH + HIV VHB EBV serologies), make urgent referrals to the hematology-oncology department for biopsy and staging, monitor patients between chemotherapy cycles, recognize and manage urgent complications (febrile neutropenia + SVCS + HBV reactivation), and coordinate long-term follow-up of patients in remission. Consultations are available at several points of service in Quebec, and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The contents of this page are provided for information purposes only and do not replace the advice of a hematologist or oncologist. The diagnosis and treatment of lymphomas require a specialized multidisciplinary team and a confirmatory histological biopsy. Never prescribe corticosteroids prior to biopsy in a patient with suspected lymphoma.
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