Blood & Lymphoreticular

Non-Hodgkin lymphoma: subtypes and management overview

Clinical Overview and When to Suspect Non-Hodgkin Lymphoma

— Painless, persistent lymphadenopathy >2 cm lasting >4–6 weeks, especially supraclavicular, epitrochlear, or generalized

— B symptoms: unexplained fevers >38°C, drenching night sweats, weight loss >10% over 6 months

— Extranodal masses: GI (stomach—MALT; small bowel), Waldeyer ring, skin, CNS, testis, thyroid, orbit

— Cytopenias with marrow involvement; unexplained LDH elevation; hypercalcemia (HTLV-1 ATLL)

— Hyperviscosity symptoms (headache, blurred vision, epistaxis) → suspect Waldenström macroglobulinemia

Board pearl: Any adult with supraclavicular lymphadenopathy has malignancy until proven otherwise; combine with elevated LDH and B-symptoms and lymphoma jumps to the top of the differential ahead of metastatic carcinoma.

Non-Hodgkin lymphoma (NHL) = heterogeneous group of clonal lymphoid malignancies arising from B-cells (~85%), T-cells, or NK-cells; encompasses >60 WHO entities ranging from indolent (follicular, marginal zone, CLL/SLL, Waldenström) to aggressive (DLBCL, mantle cell) to highly aggressive (Burkitt, lymphoblastic).

Epidemiology: 7th most common US cancer; median age ~67; incidence rises with age, immunosuppression, and certain infections.

When to suspect NHL in clinic:

Risk factors: HIV (DLBCL, primary CNS, Burkitt, plasmablastic), EBV (Burkitt, post-transplant PTLD), HCV (splenic marginal zone), H. pylori (gastric MALT), HTLV-1 (adult T-cell), Sjögren and Hashimoto (MALT), celiac (EATL), chronic immunosuppression, prior chemo/radiation, agricultural pesticide exposure.

Step 3 management: A patient with rubbery cervical adenopathy persisting >4 weeks after empiric antibiotics needs excisional lymph node biopsy — not FNA, not core needle alone — because architecture is required for subtyping and grading.

Presentation Patterns and Key History

— Waxing/waning painless adenopathy over months to years

— Often asymptomatic, found on routine labs (lymphocytosis) or incidental imaging

— Splenomegaly common; cytopenias from marrow infiltration late

— Patients may live years untreated — "watch and wait" is legitimate first-line in asymptomatic, low-burden disease

— Rapidly enlarging mass over weeks

— Frequent B symptoms, bulky disease (>10 cm), high LDH

— Extranodal involvement: GI bleeding (gastric DLBCL), spinal cord compression (epidural mass), SVC syndrome (mediastinal mass)

— Doubling time in days; "starry sky" histology

— Endemic Burkitt: African child with jaw mass; sporadic: ileocecal/abdominal mass in US child/young adult; immunodeficiency-associated in HIV

— High risk of tumor lysis syndrome at presentation, even before treatment

— Duration and tempo of adenopathy growth

— Constitutional symptoms: fevers, night sweats requiring clothing change, unintentional weight loss, pruritus, fatigue

— Alcohol-induced nodal pain (classically Hodgkin but reported in NHL)

— Travel and infection history: HIV risk factors, HCV, HTLV-1 endemic regions (Japan, Caribbean), prior H. pylori treatment, celiac disease

— Autoimmune disease, transplant history, chronic immunosuppressants (methotrexate, TNF inhibitors)

— Occupational exposures: pesticides, benzene, prior radiotherapy/chemo

— Family history of hematologic malignancy

Key distinction: A rapidly enlarging neck mass over 2 weeks in a 60-year-old with LDH 800 = think aggressive NHL (DLBCL) and arrange urgent excisional biopsy; a fluctuating, painless 1.5 cm node present for 2 years with normal labs = think reactive or indolent process and reassess in 4–6 weeks before biopsy.

Indolent NHL pattern (follicular, marginal zone, CLL/SLL, Waldenström):

Aggressive NHL pattern (DLBCL, mantle cell, peripheral T-cell):

Highly aggressive (Burkitt, lymphoblastic):

Key history elements to elicit:

Physical Exam Findings and Disease Burden Assessment

— Cervical, supraclavicular, axillary, epitrochlear, inguinal, popliteal

— NHL nodes: rubbery, non-tender, mobile, matted with progression; size, number, and laterality drive staging

— Waldeyer ring (tonsils, base of tongue): inspect oropharynx — associated with GI involvement, mandates endoscopy

— Mycosis fungoides / Sézary syndrome: patches, plaques, erythroderma; Pautrier microabscesses on biopsy

— Cutaneous B-cell lymphomas: violaceous nodules on head/trunk

— Paraneoplastic pruritus, ichthyosis

— SVC syndrome: facial plethora, distended neck veins, arm edema — mediastinal mass

— Spinal cord compression: back pain, weakness, sensory level, urinary retention

— Tumor lysis suspicion: bulky abdominal mass + AKI signs

CCS pearl: On a CCS case suggesting lymphoma, document a complete lymph node exam, abdominal exam for organomegaly, skin survey, and neurologic exam in your initial orders — missing Waldeyer ring inspection or testicular exam in a male with DLBCL is a classic incomplete-exam ding because both sites alter staging and CNS prophylaxis decisions.

Lymph node exam — characterize every accessible station:

Hepatosplenomegaly: palpate carefully; massive splenomegaly suggests splenic marginal zone, CLL/SLL, or hairy cell variants; hepatomegaly may indicate hepatic infiltration or portal adenopathy

Skin findings:

Neurologic exam: cranial nerve deficits (leptomeningeal disease, especially Burkitt, lymphoblastic, testicular DLBCL); focal deficits (primary CNS lymphoma in HIV); cord compression signs

Oncologic emergencies on exam:

Performance status (ECOG 0–4) — drives treatment intensity and trial eligibility

Hemodynamic concerns: sepsis from neutropenia in treated patients; pericardial effusion from mediastinal disease causing tamponade

Diagnostic Workup — Initial Labs, Imaging, Biopsy Strategy

— CBC with differential — cytopenias, lymphocytosis, circulating lymphoma cells

— Comprehensive metabolic panel — renal/hepatic function, calcium

— LDH — prognostic in IPI; elevated in high-turnover disease

— Uric acid — baseline tumor lysis risk

— β2-microglobulin — prognostic (FLIPI for follicular)

— HIV, HBV (HBsAg, anti-HBc, anti-HBs), HCV — mandatory before rituximab (HBV reactivation risk)

— Pregnancy test in women of childbearing age

— SPEP/UPEP, quantitative immunoglobulins if Waldenström or marginal zone suspected

— Peripheral smear — circulating malignant cells, "smudge cells" (CLL), villous lymphocytes

— CT chest/abdomen/pelvis with contrast — initial staging of nodal stations and organ involvement

— PET-CT (FDG) is the preferred staging modality for FDG-avid lymphomas (DLBCL, follicular, mantle cell, Hodgkin); not standard for CLL/SLL or marginal zone unless transformation suspected

— Echocardiogram (LVEF) prior to anthracycline-containing regimens (R-CHOP)

— Excisional (or generous incisional) lymph node biopsy is preferred — preserves architecture

— FNA alone is inadequate for initial diagnosis of lymphoma

— Core needle biopsy acceptable only when excisional is not feasible (deep node, frail patient) and must include flow cytometry, IHC, and molecular studies

Board pearl: Always order HBV serology before rituximab; reactivation can cause fulminant hepatitis. HBsAg+ or anti-HBc+ patients need entecavir or tenofovir prophylaxis through therapy and ≥12 months after.

Initial laboratory panel:

Imaging:

Tissue diagnosis — the cornerstone:

Bone marrow biopsy — for staging, prognosis, and exclusion of marrow involvement; may be omitted in DLBCL if PET shows clear marrow disease

Diagnostic Workup — Advanced and Confirmatory Studies

— B-cell markers: CD19, CD20, CD22, CD79a, PAX5

— T-cell markers: CD2, CD3, CD4, CD5, CD7, CD8

— Germinal center: CD10, BCL6

— Activated B-cell (ABC) DLBCL: MUM1/IRF4

— Mantle cell: CD5+, CD23–, cyclin D1+, SOX11+

— CLL/SLL: CD5+, CD23+, dim CD20, dim sIg

— Follicular: CD10+, BCL2+, BCL6+

— Burkitt: CD10+, BCL6+, BCL2–, Ki-67 ~100%

— Hodgkin Reed-Sternberg: CD15+, CD30+, CD20– (distinguishes from NHL)

— t(14;18) BCL2 — follicular lymphoma

— t(11;14) CCND1/cyclin D1 — mantle cell

— t(8;14) MYC — Burkitt

— t(11;18) API2-MALT1 — gastric MALT resistant to H. pylori eradication

— "Double-hit" / "triple-hit" lymphoma (MYC + BCL2 ± BCL6 rearrangements) — high-grade B-cell lymphoma, aggressive, poor prognosis

— MYD88 L265P — Waldenström macroglobulinemia

— del(17p) / TP53 — adverse in CLL, mantle cell

Key distinction: CLL vs mantle cell — both CD5+ B-cell neoplasms, but CLL is CD23+/cyclin D1–, mantle cell is CD23–/cyclin D1+/SOX11+. Mantle cell is far more aggressive and demands prompt treatment.

Histopathology + immunohistochemistry (IHC):

Cytogenetics / FISH / molecular:

Flow cytometry on blood, marrow, or fluid — establishes clonality (kappa/lambda restriction in B-cell neoplasms)

CSF analysis with flow cytometry — for CNS lymphoma, high-risk DLBCL (testicular, breast, paranasal sinus, epidural, ≥2 extranodal sites + elevated LDH, double-hit), Burkitt, lymphoblastic

Staging: Lugano classification (modified Ann Arbor) — stages I–IV with E (extranodal) and B (B-symptoms) designators

Risk Stratification and First-Line Management Logic

— IPI (International Prognostic Index) for aggressive NHL/DLBCL: Age >60, Stage III/IV, ECOG ≥2, LDH elevated, ≥2 extranodal sites — each 1 point; 0–1 low, 4–5 high

— R-IPI (revised, rituximab era) and NCCN-IPI refine DLBCL prognosis

— FLIPI (follicular): Age ≥60, Stage III/IV, Hb <12, LDH elevated, ≥4 nodal areas

— MIPI (mantle cell): age, ECOG, LDH, WBC ± Ki-67

— CLL-IPI: TP53, IGHV mutation, β2-microglobulin, stage, age

— Indolent, asymptomatic, low burden (follicular, marginal zone, CLL): watch and wait until GELF/iwCLL criteria met (bulky disease, cytopenias, B symptoms, organ dysfunction)

— Indolent, symptomatic or high burden: treat with immunochemotherapy (BR, R-CHOP, obinutuzumab-based) or targeted agents

— Aggressive (DLBCL): treat with curative intent immediately

— Highly aggressive (Burkitt, lymphoblastic): urgent admission, tumor lysis prophylaxis, intensive multi-agent chemo + CNS prophylaxis

Step 3 management: A 68-year-old with stage III follicular lymphoma, no B symptoms, normal LDH, two 2-cm nodes — watchful waiting with exam and labs every 3–6 months is appropriate; treating asymptomatic low-burden indolent disease does not improve overall survival.

Prognostic indices — must know:

Treatment philosophy by subtype:

Limited-stage DLBCL (stage I/II, non-bulky): 3–4 cycles R-CHOP ± involved-site radiation, or 6 cycles R-CHOP alone

Advanced DLBCL: 6 cycles R-CHOP; consider Pola-R-CHP (POLARIX) for IPI 2–5

Gastric MALT, H. pylori positive: triple therapy eradication first — regression in 60–80%; persistent disease → radiation

Mycosis fungoides early stage: skin-directed therapy (topical steroids, PUVA, NBUVB, local radiation)

Pharmacotherapy — First-Line Regimens by Subtype

— Rituximab (anti-CD20) 375 mg/m² day 1

— Cyclophosphamide 750 mg/m² day 1

— Hydroxydaunorubicin (doxorubicin) 50 mg/m² day 1 — anthracycline, cardiotoxic

— Oncovin (vincristine) 1.4 mg/m² day 1 — neurotoxic

— Prednisone 100 mg PO days 1–5

— Cycle every 21 days × 6; cure rates ~60–70% overall

— Pola-R-CHP (polatuzumab vedotin replacing vincristine) for IPI 2–5: improved PFS (POLARIX trial)

— Allopurinol or rasburicase + IV hydration for tumor lysis prophylaxis

— PJP prophylaxis (TMP-SMX) with bendamustine, high-dose steroids, fludarabine

— HBV antiviral prophylaxis with rituximab if HBsAg+ or anti-HBc+

— G-CSF for febrile neutropenia risk >20%

Board pearl: Rituximab + anthracycline + HBV reactivation + anthracycline cardiotoxicity are the four pharmacology landmines — order baseline echo, HBV serologies, and counsel on infusion reactions before R-CHOP cycle 1.

DLBCL — R-CHOP (gold standard):

Follicular lymphoma: BR (bendamustine + rituximab) or R-CHOP; obinutuzumab-based regimens in high-tumor-burden; rituximab maintenance every 2 months × 2 years

Mantle cell: Young/fit — intensive regimens (R-DHAP/R-CHOP alternating, hyperCVAD) followed by autologous stem cell transplant; older/unfit — BR or R-CHOP; ibrutinib/acalabrutinib (BTK inhibitors) increasingly used

Burkitt: DA-EPOCH-R or CODOX-M/IVAC ± rituximab + intrathecal CNS prophylaxis; aggressive tumor lysis prophylaxis

Marginal zone (MALT): H. pylori eradication for gastric; rituximab ± bendamustine for nodal/splenic

CLL: BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) or venetoclax + obinutuzumab; chemoimmunotherapy now rarely first-line

Waldenström: ibrutinib, BR, or bortezomib-based

Mandatory supportive care:

Advanced Therapeutics — Targeted Agents, Cellular Therapy, Radiation

— Second-line: CAR-T cell therapy (axicabtagene ciloleucel, lisocabtagene maraleucel) is now preferred for primary refractory or early-relapse (<12 months) DLBCL — superior to autologous transplant (ZUMA-7, TRANSFORM)

— Late relapse (>12 months) chemo-sensitive: salvage chemo (R-ICE, R-DHAP, R-GDP) → autologous stem cell transplant

— Third-line options: loncastuximab tesirine, tafasitamab + lenalidomide, selinexor, bispecific T-cell engagers (epcoritamab, glofitamab)

— Cytokine release syndrome (CRS): fever, hypotension, hypoxia → tocilizumab (IL-6R blocker) ± steroids

— ICANS (immune effector cell-associated neurotoxicity): confusion, aphasia, seizures → steroids; tocilizumab does NOT cross BBB

— Prolonged cytopenias, hypogammaglobulinemia, B-cell aplasia

— BTK inhibitors (ibrutinib, acalabrutinib): CLL, mantle cell, Waldenström — watch for AF, bleeding, HTN

— BCL2 inhibitor venetoclax: CLL — risk of fatal tumor lysis on ramp-up

— PI3K inhibitors idelalisib, copanlisib: relapsed indolent — colitis, pneumonitis, hepatitis

— Lenalidomide: follicular, mantle cell; teratogenic (REMS program)

— Brentuximab vedotin (anti-CD30): peripheral T-cell, ALCL, cutaneous T-cell

CCS pearl: A DLBCL patient relapsing 4 months after R-CHOP — order PET-CT, repeat biopsy to confirm relapse, then refer to a CAR-T center; do not waste time with multiple salvage chemo lines.

Relapsed/refractory DLBCL pathway:

CAR-T toxicities — must recognize:

Targeted agents by pathway:

Radiation therapy roles: involved-site RT for limited-stage DLBCL, early-stage follicular (can be curative), MALT not responsive to H. pylori, palliation of bulky symptomatic disease, CNS prophylaxis (rare)

Allogeneic transplant: reserved for relapsed mantle cell, T-cell lymphomas, and select aggressive relapses

Special Populations — Elderly and Organ Dysfunction

— DLBCL is curable even in octogenarians; do not undertreat based on age alone

— Use geriatric assessment (G8, CGA) to identify fit vs frail patients

— Fit elderly: full-dose R-CHOP; consider Pola-R-CHP

— Frail elderly: R-mini-CHOP (attenuated doses) — proven OS benefit over palliative care

— Pre-phase with prednisone ± vincristine before cycle 1 to reduce early toxicity

— Mandatory echocardiogram before anthracycline; if LVEF <50%, substitute non-anthracycline regimen (R-CEOP with etoposide)

— Doxorubicin lifetime cumulative dose limit ~400–450 mg/m² (lower with prior chest RT)

— Alternatives: liposomal doxorubicin, etoposide-based regimens

— Methotrexate (CNS prophylaxis) requires CrCl >60; use leucovorin rescue and urinary alkalinization

— Cyclophosphamide: dose-reduce if CrCl <30

— Bendamustine: avoid if CrCl <30

— Rituximab: no renal adjustment

— Tumor lysis risk amplified — early rasburicase for high-risk disease (Burkitt, bulky DLBCL, elevated baseline uric acid/LDH)

— Doxorubicin and vincristine: reduce dose with bilirubin >1.2–3 mg/dL; avoid if bilirubin >5

— Monitor for HBV reactivation in HBcAb+ patients regardless of HBsAg status

— Early palliative care integration improves QOL and may extend survival

— Discuss realistic curative vs palliative intent before initiating therapy

Step 3 management: An 82-year-old with newly diagnosed DLBCL, ECOG 2, EF 55%, mild CKD — R-mini-CHOP every 21 days × 6 cycles with PJP prophylaxis, growth factor support, and pre-phase steroids is the evidence-based regimen, not best supportive care.

Elderly patients (>70–80):

Cardiac comorbidity:

Renal impairment:

Hepatic impairment:

Frailty and goals of care:

Special Populations — Pregnancy, Pediatrics, and Immunocompromised

— NHL during pregnancy is rare but aggressive subtypes predominate

— First trimester: chemotherapy is teratogenic; options include termination, delayed therapy if disease permits, or single-agent steroids as bridge

— Second/third trimester: R-CHOP is generally safe — rituximab, anthracyclines, cyclophosphamide, vincristine have acceptable fetal safety profiles after organogenesis

— Avoid methotrexate (teratogenic, abortifacient) and radiation to abdomen/pelvis

— Plan delivery ≥3 weeks after last cycle to allow maternal and fetal count recovery

— Avoid breastfeeding during chemotherapy

— Dominated by Burkitt, lymphoblastic lymphoma, DLBCL, and anaplastic large cell lymphoma

— Treated on intensive cooperative-group protocols with high cure rates (>85% for Burkitt)

— Mandatory CNS-directed therapy

— Long-term survivor issues: secondary malignancy, cardiotoxicity, infertility, growth/endocrine effects

— Increased incidence of DLBCL, Burkitt, primary CNS lymphoma, plasmablastic, primary effusion lymphoma

— Continue or initiate ART concurrently with chemotherapy — improves survival

— Standard R-CHOP or DA-EPOCH-R; PCNSL often treated with high-dose methotrexate

— PJP, MAC, antifungal prophylaxis based on CD4

— EBV-driven in most cases after solid organ or HSCT

— First step: reduce immunosuppression

— Add rituximab if no response; chemotherapy for monomorphic PTLD

Board pearl: Pregnant patient with rapidly enlarging DLBCL in the second trimester — start R-CHOP now; delaying curative-intent therapy to "protect" the fetus increases maternal mortality without improving fetal outcomes.

Pregnancy:

Pediatric NHL:

HIV-associated lymphoma:

Post-transplant lymphoproliferative disorder (PTLD):

Autoimmune-disease patients on methotrexate/TNF inhibitors: withdrawal of immunosuppression alone can induce regression

Complications and Adverse Outcomes

— Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia → AKI, arrhythmias, seizures

— Highest risk: Burkitt, lymphoblastic, bulky DLBCL, high LDH, CLL with venetoclax ramp-up

— Prevention: IV hydration (3 L/m²/day), allopurinol (low/intermediate risk) or rasburicase (high risk, but contraindicated in G6PD deficiency)

— Avoid potassium and calcium in IV fluids during high risk

— ANC <500 + fever ≥38.3°C (or ≥38.0°C sustained 1 hr)

— Broad-spectrum antibiotics within 1 hour (cefepime, pip-tazo, or meropenem); add vancomycin if line infection, MRSA risk, or hemodynamically unstable

— G-CSF for high-risk regimens

— Anthracycline cardiomyopathy — monitor with serial echo; can present years later

— Vincristine neuropathy — sensory > motor; dose-cap at 2 mg

— Cyclophosphamide: hemorrhagic cystitis (use mesna with high doses), secondary AML/MDS, infertility

— Bleomycin pulmonary toxicity — monitor DLCO

— Rituximab infusion reactions, late-onset neutropenia, HBV reactivation, PML

Key distinction: Sudden clinical deterioration in a stable CLL patient with new B-symptoms, rapidly enlarging single nodal area, and LDH spike → suspect Richter transformation; PET-guided biopsy of the most FDG-avid site is the next step.

Tumor lysis syndrome (TLS):

Febrile neutropenia:

Treatment-specific toxicities:

CNS relapse: higher risk with testicular, breast, paranasal, epidural, renal/adrenal involvement, double-hit, IPI 4–5 → intrathecal or high-dose methotrexate prophylaxis

Secondary malignancies: AML/MDS, solid tumors after alkylators and radiation

Histologic transformation: indolent → aggressive (Richter transformation in CLL → DLBCL); abrupt clinical worsening, rising LDH — re-biopsy

When to Escalate Care — Inpatient Triage and Consults

— Suspected or confirmed highly aggressive lymphoma (Burkitt, lymphoblastic) — start therapy and TLS prophylaxis inpatient

— Bulky disease with high LDH — TLS risk

— Oncologic emergencies:

— SVC syndrome with airway/cerebral symptoms → emergent CT, biopsy, steroids, possible RT

— Spinal cord compression → emergent MRI, dexamethasone 10 mg IV, neurosurgery and radiation oncology consult

— Hyperviscosity syndrome (Waldenström, IgM >4 g/dL) → plasmapheresis

— Cardiac tamponade from pericardial effusion → pericardiocentesis

— Acute airway obstruction from mediastinal/Waldeyer mass → ENT, anesthesia

— Febrile neutropenia (MASCC score <21 = high risk)

— Symptomatic hypercalcemia, AKI, severe cytopenias

— Septic shock, respiratory failure, severe CRS post-CAR-T, severe TLS with AKI requiring dialysis

— Status epilepticus from ICANS or CNS lymphoma

— Hematology/oncology — at diagnosis for all NHL

— Radiation oncology — limited-stage disease, MALT, palliation, cord compression

— Surgery / interventional radiology — biopsy access

— Cardiology — pre-anthracycline LVEF, cardio-oncology surveillance

— Infectious disease — HIV, HBV/HCV management, opportunistic infection

— Fertility specialist — sperm banking, oocyte cryopreservation before therapy in reproductive-age patients

— Palliative care — symptom control and goals of care

CCS pearl: On a CCS case of suspected Burkitt with bulky abdominal mass — admit, IV fluids, allopurinol or rasburicase, q6h chemistries, telemetry, heme/onc consult, urgent biopsy, and CNS staging (LP with flow) before initiating DA-EPOCH-R.

Immediate inpatient admission criteria:

ICU triage:

Consultations:

Outpatient vs inpatient first cycle: consider inpatient cycle 1 for elderly, bulky disease, or significant comorbidity

Key Differentials — Other Lymphoid/Hematologic Causes

— Reed-Sternberg cells, CD15+/CD30+/CD20–; contiguous nodal spread; bimodal age (15–35 and >55); mediastinal mass common

— Treated with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine); highly curable

— Key distinction from NHL: spread pattern (Hodgkin contiguous; NHL skip lesions), extranodal involvement (rare in Hodgkin, common in NHL), CD20 (negative in classical Hodgkin)

— ALL vs lymphoblastic lymphoma — same disease biology, distinguished by marrow blast percentage (>25% = ALL)

— CLL vs SLL — same disease; CLL has lymphocytosis >5,000/µL, SLL is tissue-based without lymphocytosis

— AML with extramedullary myeloid sarcoma can mimic lymphoma — IHC distinguishes (myeloperoxidase+)

— Plasmablastic lymphoma overlaps with myeloma — clinical context (HIV, oral cavity) and IHC differentiate

— Waldenström macroglobulinemia (lymphoplasmacytic lymphoma) sits between NHL and plasma cell disorders

— Unicentric (surgical cure) vs multicentric (HHV-8 associated, often HIV+); polyclonal lymphadenopathy, lymph node "onion-skin" follicles, can mimic NHL clinically

Board pearl: A CD5+ B-cell lymphoma — narrow to CLL/SLL (CD23+, cyclin D1–) vs mantle cell (CD23–, cyclin D1+, SOX11+); this single distinction changes prognosis from indolent to aggressive and treatment urgency dramatically.

Hodgkin lymphoma:

Acute and chronic leukemias:

Multiple myeloma and plasma cell neoplasms:

Castleman disease:

Reactive lymphoid hyperplasia, infectious mononucleosis (EBV), CMV, toxoplasmosis, cat-scratch, HIV seroconversion — flow cytometry shows polyclonal pattern, no clonal rearrangement

Lymphomatoid granulomatosis — EBV-driven angiocentric B-cell process with pulmonary nodules

Key Differentials — Non-Lymphoid Causes of Adenopathy and Masses

— Bacterial: strep/staph cervical adenitis (tender, warm, fluctuant), cat-scratch (Bartonella), tularemia, brucellosis, mycobacterial (TB, atypical — chronic, matted, fistulizing)

— Viral: EBV mononucleosis, CMV, HIV acute retroviral syndrome, measles, rubella

— Parasitic/fungal: toxoplasmosis (posterior cervical), histoplasmosis, coccidioidomycosis

— Treponemal: secondary syphilis with generalized adenopathy

— Supraclavicular node (Virchow's, left): GI/GU primary

— Sister Mary Joseph nodule: umbilical metastasis from intra-abdominal malignancy

— Hard, fixed, irregular nodes — biopsy with carcinoma-specific IHC (cytokeratins, organ-specific markers)

— SLE, RA, Sjögren, adult-onset Still disease — reactive adenopathy, often generalized

— Sarcoidosis — bilateral hilar adenopathy, non-caseating granulomas, elevated ACE; can mimic lymphoma on imaging

— Kikuchi-Fujimoto disease — young women with cervical adenopathy and fever; self-limited

— IgG4-related disease — multi-organ fibroinflammatory; can mimic lymphoma

Key distinction: Bilateral hilar adenopathy in a young Black woman with erythema nodosum and uveitis = sarcoidosis, not lymphoma; serum ACE elevated, biopsy shows non-caseating granulomas. PET-avidity does not distinguish — tissue is required.

Infectious lymphadenopathy:

Metastatic carcinoma:

Autoimmune and inflammatory:

Drug-induced lymphadenopathy: phenytoin, allopurinol, carbamazepine (DRESS syndrome)

Endocrine masses: thyroid carcinoma with cervical adenopathy; pheochromocytoma; adrenal masses

Survivorship — Maintenance, Surveillance, and Late Effects

— End-of-treatment PET-CT (Deauville 5-point scale) for FDG-avid lymphomas; scores 1–3 = complete metabolic response

— Avoid routine surveillance imaging in asymptomatic patients in complete remission — guided by symptoms and exam

— Follicular lymphoma: rituximab maintenance every 2 months × 2 years after first-line induction (PRIMA trial — improves PFS, not OS)

— Mantle cell: rituximab maintenance after R-CHOP or post-ASCT

— DLBCL: no role for maintenance after curative R-CHOP

— H&P + labs every 3 months × 2 years, every 6 months × 3 years, then annually

— Imaging only if clinically indicated

— Most relapses occur within 2 years

— Inactivated vaccines (influenza annually, pneumococcal PCV20 or PCV15+PPSV23, COVID-19, RSV when indicated, recombinant zoster) — give ≥3–6 months after rituximab when possible

— Avoid live vaccines during and for 6 months after chemo/anti-CD20 (MMR, varicella, yellow fever, live zoster, BCG, oral typhoid)

— Hepatitis B vaccination if non-immune

— Cardiotoxicity: echo at baseline and periodically post-anthracycline (every 1–5 years depending on risk)

— Secondary malignancies: age-appropriate cancer screening, plus skin and oral exams; AML/MDS surveillance with CBC

— Infertility: referral pre-treatment; reproductive counseling post-treatment

— Thyroid dysfunction after neck radiation — annual TSH

— Psychosocial: depression, anxiety, cognitive effects ("chemo brain")

Step 3 management: A DLBCL survivor 18 months post-R-CHOP returns with new cervical adenopathy — order PET-CT and biopsy of the most FDG-avid site; do not assume relapse without tissue, and do not delay with prolonged observation.

Post-treatment response assessment:

Maintenance therapy by subtype:

Surveillance schedule (DLBCL in remission):

Vaccinations:

Late effects monitoring:

Lifestyle: tobacco cessation, weight management, exercise, sun protection (post-RT skin)

Follow-Up, Monitoring Parameters, and Counseling

— CBC with differential before each cycle — hold or dose-reduce for ANC <1,000 or platelets <75–100K

— CMP for renal/hepatic function, electrolytes

— TLS labs (uric acid, phosphorus, calcium, potassium, LDH) — every 6–12 hours during initial cycles for high-risk disease

— Pre-cycle LVEF is not routine but obtain if symptoms of HF

— Glucose monitoring during prednisone pulses, especially in diabetics

— PET-CT after 2–4 cycles (interim PET, Deauville) in DLBCL — Deauville 4–5 suggests inadequate response, consider regimen change or trial enrollment

— End-of-treatment PET 6–8 weeks after final cycle

— Infection prevention: hand hygiene, avoid sick contacts, report fever >38°C immediately to oncology — do not "wait it out"

— Nutrition: neutropenic diet of limited utility, but emphasize food safety

— Sexual health and contraception: effective contraception during and 6–12 months after chemo for both sexes; teratogenicity counseling

— Fertility preservation: sperm banking, oocyte/embryo cryopreservation before cycle 1

— Fatigue: common, persists months post-treatment; encourage graded exercise

— PICC/port care to prevent line infections

— Screen for depression and anxiety at each visit (PHQ-9, GAD-7)

— Financial toxicity screening — connect with social work, patient assistance programs

— Support groups, Leukemia & Lymphoma Society resources

CCS pearl: Discharge orders for a DLBCL patient after cycle 1 R-CHOP must include: pegfilgrastim (if high FN risk), PJP prophylaxis (TMP-SMX), HBV antiviral if indicated, antiemetics PRN, allopurinol, return precautions for fever ≥38°C, and clinic follow-up in 7–10 days for CBC.

On-treatment monitoring:

Interim response assessment:

Patient counseling:

Psychosocial and adherence:

Ethical, Legal, and Patient Safety Considerations

— Must include curative vs palliative intent, alternatives (including no treatment), specific toxicities (cardiotoxicity, infertility, secondary malignancy, infection, death), expected response rates

— Fertility counseling is a documented standard of care — failure to offer sperm banking or oocyte cryopreservation before gonadotoxic therapy is a recognized medicolegal vulnerability

— Capacity assessment in elderly or cognitively impaired patients; engage healthcare proxy when appropriate

— Cancer diagnoses are reportable to state cancer registries

— HIV is reportable; coordinate with public health

— HBV/HCV diagnoses may be reportable depending on state

— Discharge after cycle 1 chemotherapy is a major safety transition — ensure patient knows fever precautions, has antiemetics, GCSF if prescribed, and a 24/7 contact number

— Medication reconciliation — chemotherapy interactions with warfarin (vincristine), allopurinol (azathioprine, 6-MP), CYP3A4 modulators (ibrutinib, venetoclax)

— Communicate plan to PCP for shared follow-up

— Document goals of care early, especially in elderly or relapsed patients

— Discuss code status before complications

— Hospice referral when curative options exhausted — patients should receive ≥30 days of hospice for full benefit but referrals are often too late

— Offer to all eligible patients — equity in access is an ethical obligation

— Therapeutic misconception — clarify that trials test unproven therapies

— Two-provider verification of chemo orders, body surface area, cumulative anthracycline dose

— Vincristine must never be given intrathecally — fatal; use minibag, not syringe

— Extravasation protocols for vesicants (doxorubicin, vincristine)

Board pearl: A young man newly diagnosed with DLBCL needing urgent R-CHOP — document offering sperm cryopreservation before cycle 1; even a 24–48 hour delay for banking is acceptable and medicolegally protective.

Informed consent for chemotherapy:

Mandatory reporting and registry:

Transitions of care — high-risk handoffs:

Goals of care and advance directives:

Clinical trial enrollment:

Patient safety in chemotherapy administration:

Equity: racial and socioeconomic disparities in lymphoma outcomes — address access to CAR-T centers, transportation, and financial assistance

High-Yield Associations and Rapid-Fire Clinical Facts

— t(14;18) BCL2 → follicular

— t(11;14) cyclin D1 → mantle cell

— t(8;14) MYC → Burkitt

— t(11;18) → gastric MALT resistant to H. pylori eradication

— t(2;5) ALK → anaplastic large cell lymphoma

— EBV → Burkitt (endemic), Hodgkin, PTLD, NK/T-cell nasal, plasmablastic, primary CNS lymphoma in HIV

— HHV-8 → primary effusion lymphoma, multicentric Castleman

— HTLV-1 → adult T-cell leukemia/lymphoma (hypercalcemia, lytic lesions, "flower cells")

— HIV → DLBCL, Burkitt, PCNSL, plasmablastic

— HCV → splenic marginal zone, lymphoplasmacytic

— H. pylori → gastric MALT

— Borrelia burgdorferi → cutaneous marginal zone (Europe)

— Chlamydia psittaci → ocular adnexal MALT

— Campylobacter jejuni → IPSID (small intestinal MALT)

— Sjögren → parotid MALT

— Hashimoto → thyroid MALT

— Celiac → enteropathy-associated T-cell lymphoma (EATL)

— RA, SLE → general lymphoma risk increased

— Bilateral testicular DLBCL → always give CNS prophylaxis + contralateral testicular RT

— Primary CNS lymphoma → high-dose methotrexate, not whole-brain RT first-line

— Mycosis fungoides → Pautrier microabscesses, Sézary cells in blood

— Burkitt → starry sky, Ki-67 ~100%, doubling in days

— Waldenström → MYD88 L265P, hyperviscosity, IgM monoclonal

Key distinction: Primary CNS lymphoma in an HIV+ patient with single ring-enhancing brain lesion vs toxoplasmosis — PCNSL is usually solitary, periventricular, with high thallium SPECT/PET uptake and EBV+ CSF PCR; toxoplasmosis is typically multiple lesions and responds to empiric pyrimethamine-sulfadiazine.

Translocations:

Infections and lymphoma associations:

Autoimmune associations:

Classic syndromes:

Lugano staging: I (1 nodal region), II (≥2 same side of diaphragm), III (both sides), IV (extranodal/disseminated); E = extranodal extension, B = B-symptoms

Board Question Stem Patterns

— 65-year-old with 3 months of fatigue, 8 kg weight loss, night sweats, and a 5-cm cervical mass; LDH 600; biopsy shows CD20+ large B-cells. Answer: R-CHOP × 6 cycles; check HBV serologies and echo first; PET-CT for staging.

— 55-year-old with epigastric pain; EGD shows gastric ulcer; biopsy shows lymphoid infiltrate, CD20+ B-cells, H. pylori positive. Answer: Triple therapy for H. pylori eradication; repeat endoscopy in 3 months. If t(11;18) present or no regression → radiation.

— 22-year-old HIV+ man with rapidly enlarging abdominal mass, LDH 3,000, K 5.8, phos 6.0, Ca 7.5, creatinine 2.0. Answer: Admit, aggressive IV hydration, rasburicase (check G6PD), continuous telemetry, urgent biopsy, DA-EPOCH-R with intrathecal CNS prophylaxis, continue ART.

— 70-year-old with painless 2-cm inguinal node × 1 year; biopsy follicular lymphoma grade 1; CT shows 3 nodes <3 cm; LDH normal, no B-symptoms. Answer: Watchful waiting with surveillance every 3–6 months.

— 62-year-old with generalized adenopathy, splenomegaly, GI polyps on colonoscopy; biopsy CD5+, CD23–, cyclin D1+. Answer: Mantle cell lymphoma; if fit, intensive induction → autologous SCT; if older, BR or BTK-based.

— 70-year-old with headache, blurred vision, epistaxis, IgM 6 g/dL, retinal venous engorgement. Answer: Plasmapheresis first for symptom relief, then ibrutinib or BR.

— Known lymphoma patient with new back pain and bilateral leg weakness. Answer: Dexamethasone 10 mg IV immediately, urgent MRI spine, radiation oncology and neurosurgery consults.

— DLBCL patient with HBsAg negative but anti-HBc positive starting R-CHOP. Answer: Start entecavir or tenofovir prophylaxis and continue ≥12 months after last rituximab.

Step 3 management: Recognize the trigger phrase to act immediately — "supraclavicular node + LDH high" → excisional biopsy; "Burkitt + bulk" → admit for TLS prophylaxis; "rituximab + anti-HBc" → antiviral prophylaxis.

Stem 1 — Classic DLBCL presentation:

Stem 2 — Gastric MALT:

Stem 3 — Burkitt with TLS:

Stem 4 — Follicular, asymptomatic:

Stem 5 — Mantle cell:

Stem 6 — Waldenström hyperviscosity:

Stem 7 — Cord compression:

Stem 8 — Rituximab + HBV:

One-Line Recap

Non-Hodgkin lymphoma is a biologically diverse family of B-, T-, and NK-cell malignancies whose management is driven by precise histologic subtyping and stage, ranging from watchful waiting in asymptomatic indolent disease to curative R-CHOP–based immunochemotherapy in DLBCL to urgent intensive multi-agent therapy with CNS prophylaxis and tumor lysis prevention in Burkitt and lymphoblastic lymphoma.

Board pearl: When in doubt on any Step 3 NHL vignette, the highest-yield reflex actions are (1) excisional biopsy, (2) check HBV/HIV/HCV before rituximab, (3) start TLS prophylaxis in bulky/high-LDH disease, and (4) document fertility counseling — each is both an exam trigger and a real-world standard of care.

Diagnosis: Always excisional biopsy with IHC, flow, and cytogenetics; never rely on FNA alone; PET-CT for FDG-avid subtypes; baseline HIV, HBV, HCV, LDH, echo before anthracycline.

Risk-stratify and treat by subtype: Use IPI/R-IPI/FLIPI/MIPI to gauge prognosis; indolent + asymptomatic = observation; DLBCL = R-CHOP (or Pola-R-CHP for IPI 2–5); Burkitt = DA-EPOCH-R + intrathecal MTX; gastric MALT = H. pylori eradication; mantle cell = intensive induction + ASCT or BTK inhibitor.

Anticipate complications: Tumor lysis (rasburicase if G6PD-normal), febrile neutropenia (antibiotics within 1 hour), anthracycline cardiotoxicity, rituximab-induced HBV reactivation (prophylactic entecavir/tenofovir), CNS relapse in high-risk sites (testicular, breast, paranasal).

Survivorship and ethics: Offer fertility preservation before cycle 1, give non-live vaccines, screen for cardiotoxicity and secondary malignancies, integrate palliative care early when appropriate, and ensure safe transitions with fever return precautions and PCP communication.