What it is:Lymphoma is cancer that starts in the immune cells that normally live in lymph nodes and other lymphoid tissue. There are two totally different diseases hiding under one name: Hodgkin lymphoma (HL), defined by the presence of Reed-Sternberg cells, and non-Hodgkin lymphoma (NHL), a huge and varied bucket of B-cell and T-cell cancers.
The core problem:A lymphocyte (usually B-cell) picks up mutations that block normal apoptosis and drive proliferation. In HL that transformed cell (Reed-Sternberg) is rare but surrounded by an inflammatory crowd; in NHL the malignant cells themselves are the tumor bulk.
What you do about it:HL is treated to cure almost everyone, with chemo, radiation, or both, chosen mostly by stage. NHL treatment forks hard depending on whether the subtype is indolent(slow, not curable, treat when symptomatic) or aggressive(fast, but curable with combination chemoimmunotherapy).
The single mental model that organizes this whole chapter: "Is it Hodgkin or non-Hodgkin, and if non-Hodgkin, is it indolent or aggressive?"Those three branches send you down completely different treatment logic. Indolent NHL is the paradox: it's the one you can't cure but the patient might outlive it anyway (median survival 8-10 years, sometimes spontaneous regression). Aggressive NHL is the one that looks scary but is often curable. Don't let "aggressive" in the name make you think "worse prognosis."
Before you can pick therapy you need three answers: HL or NHL, what stage, and (for NHL) what risk category.
| Question | Hodgkin Lymphoma | Non-Hodgkin Lymphoma |
|---|---|---|
| Cell of origin | Reed-Sternberg cells (malignant, but rare within the tumor mass) | Monoclonal B or T lymphocytes and their precursors (malignant cells arethe bulk) |
| Diagnosis requires | Reed-Sternberg cells on lymph node biopsy | Biopsy of an involved node, workup otherwise similar to HL |
| Spread pattern | Predictable, contiguous nodal spread | Unpredictable, often widespread/extranodal at diagnosis |
| Behavior split | Localized (~half of patients) vs advanced | Indolent (favorable, survival in years untreated) vs aggressive (unfavorable, survival in weeks to months untreated) |
"Indolent" does not mean "less dangerous" and "aggressive" does not mean "worse prognosis."Indolent lymphomas are not curable with standard therapy but progress slowly, so watchful waiting is a real option. Aggressive lymphomas grow fast but respond well to chemo, so they're often curable. Mixing these up is a classic exam trap.
Staging (Ann Arbor framework, both HL and NHL):Clinical staging uses history, exam, labs, and PET-CT. Pathologic staging adds biopsy findings from strategic sites like bone marrow, spleen, or abdominal nodes. Stage I/II is localized disease, stage III/IV is advanced. About half of HL patients present with localized disease; roughly 10-15% of all HL patients present at stage IV.
Limited-stage HL (I-II): 90-95% cure rate.Advanced-stage HL (III-IV): 60-80% cure rate.Age is the other big driver: patients over 65-70 have meaningfully lower cure rates than younger patients regardless of stage.
For aggressive NHL, five factors predict outcome: age >60, performance status ≥2, elevated LDH, extranodal involvement, and stage III/IV disease. More positive factors means worse prognosis and often more aggressive treatment. A modified version for indolent (follicular) lymphoma swaps out performance status for low hemoglobin (<12 g/dL), since these patients rarely have poor performance status at diagnosis.
During malignant transformation, the normal B-cell transcriptional program gets disrupted, so the cell stops making B-cell surface markers and immunoglobulin mRNA. At the same time, the apoptotic pathway gets rewired to favor survival over cell death. The signature move is overexpression of nuclear factor-κB (NF-κB)in the Reed-Sternberg cell, which drives both proliferation and antiapoptotic signaling. Viral and bacterial infections upregulate NF-κB too, which is part of why Epstein-Barr virusshows up in a meaningful chunk (not all) of HL tumors.
NHL comes from monoclonal proliferation of malignant B or T lymphocytes (or their precursors) at some point arrested in normal development. The WHO classification sorts these by cell of origin, clinical features, and morphology, then layers on immunohistochemical markers, cytogenetics, and genotype to further subtype. WHO uses two separate axes that students often collapse into one: grade(histologic features like cell/nuclear size, chromatin density, proliferation fraction) and aggressiveness(how the tumor actually behaves clinically). A classic example of the biology driving therapy: follicular lymphomacarries the t(14;18) translocationin the majority of advanced cases, and that indolent, translocation-driven biology is exactly why it behaves so differently from diffuse large B-cell lymphoma.
Nearly every targeted NHL drug traces back to a piece of this biology. Rituximab and obinutuzumabtarget CD20, a B-cell surface marker retained on most malignant B cells. PI3K inhibitorsblock a signaling messenger that malignant B lymphocytes depend on for proliferation and survival. Tazemetostattargets EZH2, an epigenetic regulator mutated in 20-25% of follicular lymphoma. PD-1 inhibitorsexploit the same immune-evasion biology Reed-Sternberg cells use to survive. None of this is random; it's the pathophysiology turned into a drug target.
| Hodgkin Lymphoma | Non-Hodgkin Lymphoma | |
|---|---|---|
| Classic finding | Painless, rubbery, enlarged lymph node, usually supradiaphragmaticwith mediastinal involvement common | Painless, rubbery, discrete nodes, usually cervical/supraclavicular; can be localized or generalized |
| Other sites | Asymptomatic inguinal or axillary adenopathy | Extranodal disease is common (GI, bone marrow) and depends heavily on site |
| B symptoms | ~25% at diagnosis | ~40% at diagnosis |
| GI/mesenteric involvement | Less typical | Nausea, vomiting, obstruction, abdominal pain, palpable mass, GI bleeding |
| Marrow involvement | Less typical early | Anemia, neutropenia, or thrombocytopenia symptoms |
Fever, drenching night sweats, and weight lossare "B" symptoms, present in about a quarter of HL patients and closer to 40% of NHL patients at diagnosis. They matter beyond just being uncomfortable: they factor into staging (the "B" suffix, e.g. stage IIB) and carry prognostic weight.
NHL classification schemes keep evolving as molecular and genotypic markers get incorporated. Current research direction: prognostic significance of apoptosis markers, cell-cycle regulation, cell lineage, and proliferation markers, on top of the older morphology-based systems. You don't need to memorize the research frontier, just recognize that "indolent vs aggressive" and IPI are the practical framework you'll actually use.
The goal is to maximize cure while minimizing treatment-related toxicity, because most patients are cured and then live for decades carrying the long-term consequences of therapy. Options are radiation therapy (RT) alone, chemotherapy alone, or combined-modality therapy; surgery has essentially no therapeutic role regardless of stage.
Long-term complications of RT, chemo, and chemoradiotherapy include gonadal dysfunction, secondary malignancies(lung, breast, GI tract, connective tissue), and cardiac disease. This is exactly why so much of modern HL treatment design is about de-escalating therapy in patients who respond well early, using interim PET-CT to decide who can get less RT or fewer cycles.
Standard approach: treat all stages and risk groups with 8-12 weeks of chemotherapy, then get a restaging PET-CT. Most patients with unfavorable-risk disease will still need RT on top of chemo.
The goals are to relieve symptoms and cure when possible, while minimizing serious toxicity, but "possible" depends entirely on subtype.
Because immediate aggressive therapy doesn't extend survival in advanced indolent NHL, and because response rates and duration shrink with every retreatment anyway, watching and waiting until the patient actually needs treatment is standard of care, not a cop-out. Students often assume "cancer = treat now." Here that instinct is wrong.
You won't be expected to hand-calculate these from memory in practice (BSA-based dosing is built into order sets), but knowing the drug lineup of each regimen and its cycle length is high-yield for recognizing regimens on an exam or a chart.
| Regimen | Drugs | Cycle | Used for |
|---|---|---|---|
| Hodgkin lymphoma | |||
| ABVD | Adriamycin (doxorubicin), Bleomycin, Vinblastine, Dacarbazine | Every 28 days, days 1 & 15 | Most common frontline HL regimen |
| MOPP | Mechlorethamine, Oncovin (vincristine), Procarbazine, Prednisone | Every 21 days | Older regimen, higher long-term toxicity (infertility, secondary leukemia) |
| MOPP/ABVD or MOPP/ABV hybrid | Alternating or combined MOPP + ABVD components | Varies | Historical hybrid strategies |
| Stanford V | Doxorubicin, Vinblastine, Mechlorethamine, Etoposide, Vincristine, Bleomycin, Prednisone | 12-week single course | Shorter-course multi-agent option |
| BEACOPP (standard/escalated) | Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin, Procarbazine, Prednisone (+G-CSF if escalated) | Every 21 days | Higher-risk/advanced disease; escalated dose is more intense with growth factor support |
| A-AVD | Brentuximab vedotin (anti-CD30) + Doxorubicin, Vinblastine, Dacarbazine | Every 28 days, days 1 & 15 | Swaps bleomycin out for brentuximab vedotin |
| Non-Hodgkin lymphoma | |||
| CHOP | Cyclophosphamide 750 mg/m² · Doxorubicin 50 mg/m² · Vincristine 1.4 mg/m² (cap 2 mg) · Prednisone 100 mg | 21 days; C/D/V day 1, prednisone days 1-5 | Backbone for aggressive NHL |
| R-CHOP | Rituximab + CHOP | 21 days | Standard of care for DLBCL |
| DHAP / ESHAP / ICE / MINE | Platinum- or ifosfamide-based combinations (see salvage section) | Varies | Salvage therapy for relapsed/refractory aggressive NHL |
Bleomycin causes pulmonary fibrosis, so it's the drug most likely to get dropped from a regimen when a patient has (or develops) lung issues. That's part of why brentuximab vedotin replacing bleomycin in A-AVD was a meaningful upgrade, not just a swap.
Initial therapyis 8-12 weeks of chemo followed by restaging PET-CT; most unfavorable-risk patients still need RT on top.
Salvage therapyis needed when initial treatment fails or the disease relapses. The choice depends on extent and site of recurrence, prior therapy, and how long the first remission lasted.
Brentuximab vedotin(anti-CD30 antibody-drug conjugate) is approved after autologous HSCT failure, or after failure of at least two prior multi-agent regimens in patients who aren't HSCT candidates, and also as consolidation after autologous HSCT in patients at high relapse risk. PD-1 inhibitors(nivolumab, pembrolizumab) are approved for relapsed HL, exploiting the same immune-evasion signaling Reed-Sternberg cells use to survive.
Occurs mostly in older adults; most present with advanced disease carrying t(14;18). Clinical course is generally slow, median survival 8-10 years, and 20-30% of patients even show spontaneous regression of objective disease. Time to relapse after treatment is typically only 18-36 months, and each retreatment yields a lower response rate than the last.
Localized (stage I-II):Locoregional RT is standard and usually curative. Chemo generally isn't added unless the patient has high-risk stage II disease. Immunotherapy (rituximab) with or without chemo/RT is also an option.
Advanced (stage II bulky, III, IV):Not curable with standard approaches, so management is deliberately conservative until treatment is actually needed: watchful waiting, RT, single-agent chemo, combination chemo, biologic therapy, radioimmunotherapy, or combined-modality therapy. Immediate aggressive therapy does not beat watchful-waiting-then-treat on survival.
Rituximabis a chimeric monoclonal antibody against CD20 on B cells, and it's the most widely used agent in follicular lymphoma: approved first-line alone or with chemo, and as maintenance therapy (up to 2 years) after a stable, partial, or complete response to induction. The most common chemo partner is CHOP (i.e. R-CHOP).
Fever, chills, respiratory symptoms, fatigue, headache, pruritus, and angioedema, especially with the first infusion. Premedicate with oral acetaminophen 650 mg and diphenhydramine 50 mg, 30 minutes before infusion.
Bendamustine, an IV alkylator, is approved for relapsed/refractory indolent NHL and has shown noninferiority to R-CHOP when paired with rituximab. Obinutuzumabis a second anti-CD20 antibody approved with chemo across first-line, second-line, and later settings. Lenalidomideis an immunomodulator approved with rituximab for first- and second-line therapy. 90Y-ibritumomab tiuxetanis an anti-CD20 radioimmunoconjugate that delivers radiation directly to CD20-expressing tumor cells (and some adjacent non-expressing cells); it's generally well tolerated but carries risk of infusion reactions, myelosuppression, and possible MDS/AML.
PI3K inhibitors(idelalisib, copanlisib, duvelisib for second-line; umbralisib third-line) block a signaling messenger driving malignant B-lymphocyte survival, but all carry risk of severe neutropenia, diarrhea, infection, and pneumonia on top of drug-specific toxicities. Tazemetostat, a first-generation EZH2 inhibitor, targets the activating EZH2 mutation found in 20-25% of follicular lymphoma cases, and is approved for EZH2-mutant relapsed/refractory disease after two prior lines, or for EZH2-wild-type/unknown relapsed disease with no satisfactory alternative.
High-dose chemo plus autologous or allogeneic HSCT is an option for relapse. Allogeneic HSCT has a lower recurrence rate than autologous, but that benefit is offset by higher treatment-related mortality. Classic risk-benefit tradeoff worth remembering as a pair.
Diffuse large B-cell lymphoma (DLBCL)is the most common lymphoma across all ages, though it peaks in the seventh decade. Extranodal disease is present in 30-40% at diagnosis, and IPI score tracks with prognosis. Despite being biologically aggressive, it's chemosensitive, and a real subset of patients are cured.
| Disease extent | Approach |
|---|---|
| Stage I / nonbulky II | 3-4 cycles R-CHOP + locoregional RT, or6-8 cycles R-CHOP with no RT |
| Disease at RT-morbid sites | Consider 6 cycles R-CHOP without radiation |
| Bulky stage II, III, IV | R-CHOP or rituximab + CHOP-like regimen until complete response, usually 4-6 cycles. Maintenance after CR does not improve survival. |
| High-risk responders | Consider high-dose chemo + autologous HSCT if they meet transplant criteria |
Historically elderly adults have had lower complete response and survival rates than younger patients, but full-dose R-CHOP is still the recommended initial treatmentin elderly patients with aggressive lymphoma rather than an automatically dose-reduced regimen. Lenalidomide is an option for maintenance in older adults who responded to initial treatment.
About one-third of aggressive lymphoma patientswill eventually need salvage therapy. Response to salvage tracks with response to the original chemo: patients who were chemosensitive (had a complete response initially) respond better to salvage than those who were primarily or partially resistant.
Tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucelare approved for relapsed/refractory disease after failure of two or more lines of systemic therapy. The defining toxicity is cytokine release syndrome: fever, hypoxia, hypotension, sometimes severe enough to need vasopressors. Also watch for severe neurologic toxicity, including encephalopathy and seizures. These are inpatient-monitored therapies for a reason.
| Parameter | When | Watching for |
|---|---|---|
| PET-CT | Diagnosis (staging), after 8-12 weeks of HL therapy (restaging), and at treatment completion | Residual disease, response depth, guides whether more RT/chemo is needed |
| CBC with differential | Before each chemo cycle | Myelosuppression from cytotoxic regimens; dose delay/reduction triggers |
| Pulmonary function | Baseline and periodically on bleomycin-containing regimens | Pulmonary fibrosis, the dose-limiting bleomycin toxicity |
| Cardiac function (echo/MUGA) | Baseline and with cumulative doxorubicin exposure | Anthracycline-induced cardiomyopathy |
| Infusion vitals | During and after rituximab/obinutuzumab, especially first dose | Infusion reactions: fever, chills, respiratory symptoms, angioedema |
| Symptom review (B symptoms) | Every visit | Fever, night sweats, weight loss as markers of disease activity |
| CRS/neurotoxicity monitoring | Continuous, inpatient, after CAR T-cell infusion | Fever, hypoxia, hypotension, encephalopathy, seizures |
| Secondary malignancy / fertility counseling | Survivorship, years after treatment | Long-term consequence of RT and alkylator/topoisomerase-inhibitor exposure |