Lymphoma

Background

Definition: malignant disorder of lymphoid cells that reside mostly in lymphoid tissues
Categorized as Hodgkin lymphoma (HL) / non-Hodgkin lymphoma (NHL)

Classically characterized by nontender lymphadenopathy & constitutional “B” symptoms (fevers, night sweats, weight loss).

HL (10%): superficial nodal disease with orderly, anatomic spread to adjacent nodes.
NHL (90%): diffuse nodal +/- extranodal disease with non-contiguous spread

Physical Exam: painless, firm, fixed, >1cm lymph nodes.
Lab tests: CBC, CMP, LDH, uric acid, phosphorus.
Consider HBV panel, HCV, HIV, EBV, Quant gold, treponemal Ab, ANA.
Imaging: CT chest, abdomen, pelvis; most will eventually need PET-CT to assess extent of disease and guide bx/therapy; MRI brain if neuro symptoms.
Pathology: diagnosis requires tissue (excisional preferred to see tissue architecture):
Excisional lymph node biopsy: Surgical Oncology, EGS, or ENT consult.
Core biopsy: CT guided procedure consult.
Of note, steroids may significantly impact the biopsy results (increased false negative rate).
LP: consider for NHL with high risk of CNS involvement or presence of neurological sx.
Risk factors: Burkitt, lymphoblastic, testicular involvement, double/triple hit.
Multiple LPs may be required to diagnose CNS lymphoma.
Staging: Lugano Classification.
Limited/Early Stage
- I. Single LN region or single extranodal site.
- II. ≥2 LN regions, same side of diaphragm.
Advanced Stage (III-IV)
- III. LN regions on both sides of diaphragm.
- V. Non-contiguous extranodal involvement.

ECG and TTE to establish baseline pre-chemo cardiac function—many regimens with anthracyclines.
Daily labs: CBC, TLS, LDH.
TLS prophylaxis: mIVF, allopurinol.
Treatment: see below.

Features	HL (10%)	NHL (90%)
Epidemiology	Bimodal distribution: 15-35 years and >50 years; M>F	Average 65 years, M>F, 85-90% B-cell
Histology	CD15+, CD30+ (Reed-Sternberg cells “owl eyes”)	Varies, but majority involve B cells (can also be T cell, NK cell)
Associations	EBV in immunocompromised	Immunodeficiency (HIV, post-transplant) Autoimmune disease Infection (EBV, HTLV-1, H pylori, HCV, Borrelia, C psittacosis, Coxiella)
Lymph Node Pattern	Contiguous spread	Non-contiguous spread
Subtypes	Classical Hodgkin (95%) (nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depleted) Nodular Lymphocyte-Predominant (5%)	B-Cell NHL (DLBCL, CLL/SLL, Follicular, Marginal zone, Mantle cell, Burkitt, Hairy cell) T-Cell/NK-Cell NHL (Peripheral T-cell, Anaplastic large cell, Mycosis fungoides/Sezary)
Prognosis	Generally better (more curable) IPS negative prognostic calculator: albumin <4, hemoglobin <10.5, male, stage IV disease, age >45, WBC count >15K, lymphocyte <8% of WBC count	Variable by subtype Good prognosis: Follicular, marginal zone, ALK+ ALCL, early-stage MF Poor prognosis: High-grade B-cell lymphoma (double/triple-hit with MYC + BCL2/BCL6), mantle cell, Burkitt, lymphoblastic, ALK− ALCL, advanced MF/Sezary Richter transformation: CLL/SLL → aggressive lymphoma (usually DLBCL)
Common Treatment Regimens	ABVD + radiation (early stage), Nivo-AVD (advanced stage)	R-CHOP, R-EPOCH, Hyper-CVAD, HD-MTX + R

Regimen	Components	Use
R-CHOP	rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone	NHL
R-EPOCH	etoposide plus the drugs above (inpatient administration with 4 days continuous infusion followed by pushes of chemotherapy on Day 5)	Aggressive B-cell NHL (including double/triple-hit)
Hyper-CVAD	cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (requires inpatient admission given BID dosing of cyclophosphamide and continuous mesna to prevent hemorrhagic cystitis)	NHL
HD-MTX + R	high dose methotrexate + rituximab (requires inpatient admission to follow MTX clearance and alkalize urine with continuous bicarb infusion)	Primary CNS Lymphoma
ABVD	doxorubicin, bleomycin, vinblastine, dacarbazine	HL
Nivo-AVD	Nivolumab, doxorubicin, vinblastine, dacarbazine	HL

CLL is a disease of monoclonal, functionally incompetent mature B lymphocytes
CLL and SLL are different manifestations of the same disease and are distinguished by the distribution of lymphocytes. CLL is mostly in peripheral blood whereas SLL is mostly in lymph nodes and patients often present with both. Treatment plans are identical.
CLL: >5000/uL malignant cells on peripheral smear
SLL: <5000/uL cells + LAN +/- splenomegaly

Most often asymptomatic, identified by lymphocytosis on CBC.
10-20% have B symptoms, LAN in 80%, HSM in 50%, AIHA in 10%, 1-2% have ITP.
Increased susceptibility to infections due to hypogammaglobulinemia from abnl B-cells
5% patients develop aggressive transformation into high-grade lymphoma (Richter’s)

CBC with diff (B-cell count), peripheral smear (lymphocytosis, smudge cells).
Flow cytometry: clonality with dim surface sIgdim, CD5+, CD19+, CD20dim, CD23+, cyclin D1-
Bone marrow biopsy is not required for diagnosis but may be normo or hypercellular.
Genetics: del 11q22-23 and del(17p) are unfavorable; trisomy 12 is neutral; del 13q14 and mutation IGHV is favorable.

Risk Status	Modified Rai System	Binet System
Low Risk	Rai Stage 0: Lymphocytosis	Binet Stage A: <3 involved nodal areas
Intermediate Risk	Rai Stage I: Lymphocytosis + LAN Rai Stage II: Lymphocytosis + Splenomegaly and/or hepatomegaly	Binet Stage B: >/=3 involved nodal areas
High Risk	Rai Stage III: Lymphocytosis + Hgb <11 g/dL Rai Stage IV: Lymphocytosis + Plt <10 x 104 g/uL	Binet Stage C: Hgb <10 g/dL and/or Plt <10 x 104 g/uL

Observation unless “active disease” (B symptoms, symptomatic adenopathy, cytopenias, lymphocyte doubling time < 6 months).
First line: If no del(17p)/TP53 use BTK inhibitor until disease progression (indefinite), venetoclax+obinutuzumab (fixed duration 12 months), or BTK inhibitor + venetoclax (fixed duration 14 months); if + del(17p)/TP53, use BTK inhibitor (longest duration of response) or venetoclax + obinutuzumab (shorter duration of response.
HSCT is the only curative treatment but rarely used given excellent prognosis with current treatments.