Limfoma Non-Hodgkin

01Pathophysiology

Non-Hodgkin lymphoma represents a heterogeneous group of lymphoid malignancies arising from the clonal expansion of lymphocytes that have acquired genetic mutations at different stages of their maturation. Unlike Hodgkin lymphoma, which originates from a single abnormal cell type (the Reed-Sternberg cell) within a reactive inflammatory background, NHL arises directly from the neoplastic lymphocyte population itself. This distinction is fundamental because it explains why NHL behaves so differently: it spreads in a non-contiguous pattern (skipping lymph node stations and seeding distant extranodal sites early) rather than the orderly, contiguous nodal spread seen in Hodgkin disease.

The majority of cases (~85%) derive from B lymphocytes. During normal B-cell development, the processes of V(D)J recombination, somatic hypermutation, and class-switch recombination involve intentional DNA breaks. These breaks create vulnerability windows where chromosomal translocations can occur. The translocation typically juxtaposes a proto-oncogene next to the immunoglobulin heavy chain promoter on chromosome 14, resulting in constitutive overexpression of the oncogene product. For example, t(14;18) places the BCL-2 gene under the control of the IgH promoter, leading to overexpression of an anti-apoptotic protein. Cells that should undergo programmed cell death instead survive indefinitely, accumulating in lymph nodes as an indolent (slow-growing) follicular lymphoma. By contrast, t(8;14) relocates the c-MYC oncogene, a transcription factor that drives aggressive cell proliferation, producing the extremely high-grade Burkitt lymphoma with doubling times as short as 24 to 48 hours.

T-cell lymphomas arise from post-thymic T lymphocytes and tend to be more aggressive and less responsive to standard chemotherapy. Mycosis fungoides, the most common cutaneous T-cell lymphoma, follows an indolent course through patches, plaques, and tumor stages of skin involvement. Its leukemic variant, Sezary syndrome, is defined by erythroderma and circulating malignant T-cells with characteristic cerebriform (convoluted) nuclei.

The pathophysiology also explains several clinical features that appear in vignettes. Elevated LDH reflects high tumor cell turnover and correlates with tumor burden. Beta-2 microglobulin rises because it is shed from the surface of proliferating lymphocytes, and its level independently predicts prognosis. Extranodal involvement is common because the neoplastic lymphocytes retain their normal homing receptors and can traffic to mucosal sites (GI tract is the most common extranodal site), skin, CNS, and testes. This contrasts sharply with Hodgkin lymphoma, where extranodal disease is late and unusual.

02Classification and Clinical Manifestation

The working framework divides NHL into categories based on clinical behavior (indolent vs. aggressive vs. highly aggressive), cell of origin, and the characteristic translocation or marker. This table is essential for exam purposes because the vignette will usually describe a clinical scenario that maps to one of these subtypes.

Major B-Cell Subtypes

Major T-Cell and NK-Cell Subtypes

03Diagnostic Workup

The diagnostic approach begins with the recognition that fine-needle aspiration alone is never sufficient to diagnose lymphoma. FNA cannot preserve tissue architecture, and architecture is what differentiates follicular from diffuse patterns and allows the pathologist to classify the subtype. An excisional biopsy of the most accessible, abnormal lymph node is the required first step. If excisional biopsy is not feasible (e.g., deep retroperitoneal node), a core needle biopsy with multiple passes is an acceptable alternative, but the question stem will almost always test excisional biopsy as the correct answer.

Once tissue is obtained, immunohistochemistry and flow cytometry are performed to determine the immunophenotype. CD20 positivity identifies the tumor as B-cell origin and predicts response to rituximab. Cyclin D1 positivity points to mantle cell lymphoma. CD10 and BCL-6 positivity in a follicular pattern confirms follicular lymphoma. This step is what allows the pathologist to assign the correct WHO subtype, which directly determines treatment.

Staging follows the Ann Arbor staging system (modified Lugano classification), the same system used for Hodgkin lymphoma. PET-CT is the preferred imaging modality for FDG-avid subtypes (DLBCL, Burkitt, follicular grade 3), while CT alone may suffice for indolent, non-FDG-avid subtypes. Bone marrow biopsy is performed to complete staging, though PET-CT may replace it in DLBCL when PET clearly shows marrow uptake.

For prognostic stratification, the International Prognostic Index (IPI) is the most commonly tested scoring system for aggressive NHL (DLBCL). It uses five clinical variables, each contributing one point: age >60, elevated LDH, ECOG performance status 2 or greater, Ann Arbor stage III or IV, and involvement of more than one extranodal site. Higher scores predict worse outcomes and may influence therapy intensity.

04Management and Treatment

R-CHOP, the workhorse regimen for DLBCL, is administered in 21-day cycles for 6 cycles. Each cycle consists of rituximab 375 mg/m^2 IV on day 1, cyclophosphamide 750 mg/m^2 IV on day 1, doxorubicin 50 mg/m^2 IV on day 1, vincristine 1.4 mg/m^2 IV (capped at 2 mg) on day 1, and prednisone 100 mg orally on days 1 through 5. The addition of rituximab (the "R") to CHOP improved overall survival by approximately 10 to 15 percentage points and is considered one of the landmark advances in oncology. Rituximab is a monoclonal antibody targeting CD20 on the surface of B lymphocytes.

Before initiating rituximab, hepatitis B serologies must be checked. Rituximab-induced B-cell depletion can trigger fatal HBV reactivation in patients with chronic or resolved hepatitis B. Patients who are HBsAg-positive or anti-HBc-positive require antiviral prophylaxis (entecavir or tenofovir) throughout treatment and for at least 12 months after the last dose.

For Burkitt lymphoma, the single most testable management pearl is tumor lysis syndrome (TLS) prophylaxis. Because of the tumor's extraordinary proliferation rate and exquisite chemosensitivity, massive cell lysis occurs within hours of treatment initiation. This releases intracellular potassium, phosphate, and uric acid into the bloodstream, causing hyperkalemia, hyperphosphatemia, hypocalcemia (from calcium-phosphate precipitation), hyperuricemia, and acute kidney injury. Prophylaxis includes aggressive IV hydration, rasburicase (a recombinant urate oxidase that rapidly degrades uric acid), and close electrolyte monitoring. Allopurinol is an alternative but is less effective and slower acting than rasburicase. A classic exam trap is to present a Burkitt patient who develops acute renal failure and electrolyte derangements shortly after starting chemotherapy and ask for the underlying mechanism or the preventive agent.

For gastric MALT lymphoma, the concept being tested is that an infectious etiology (H. pylori) can drive a malignancy, and eradicating the infection can cure the cancer. This is essentially the only lymphoma where antibiotic therapy is the first-line treatment. If the tumor harbors the t(11;18) translocation, it is unlikely to respond to eradication alone and will require radiation or systemic therapy.

In follicular lymphoma, the key management concept is that asymptomatic patients with low tumor burden do not benefit from immediate treatment. The "watch and wait" approach does not compromise overall survival. Treatment is initiated when the patient develops B symptoms, symptomatic or bulky adenopathy, cytopenias from marrow infiltration, or organ compromise. This concept is frequently tested because it contradicts the intuition that cancer should always be treated immediately.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on NHL questions is by failing to distinguish between subtypes, particularly confusing an indolent lymphoma with an aggressive one. A vignette describing a 65-year-old with slowly waxing and waning lymphadenopathy over several years, with a biopsy showing a follicular pattern and t(14;18), is testing whether you know that the answer is "observation" rather than jumping to chemotherapy. Conversely, a rapidly enlarging abdominal mass in a child with elevated LDH and uric acid is testing whether you recognize Burkitt lymphoma and immediately think about tumor lysis syndrome prophylaxis before initiating chemotherapy.

Another frequently tested trap involves the diagnostic approach. When presented with a patient who has lymphadenopathy and you are asked for the best next step, the answer is almost always excisional lymph node biopsy. Students who select FNA will get the question wrong every time, because FNA cannot evaluate nodal architecture, which is essential for subtyping. This is one of the most reliable "rules" on the exam.

The gastric MALT lymphoma question is a perennial favorite. The vignette will describe a patient with dyspepsia, an endoscopy showing a gastric mass, and a biopsy revealing MALT lymphoma. The correct next step is H. pylori testing, and if positive, the treatment is eradication therapy, not chemotherapy or surgery. Students who jump to oncologic treatment miss the point entirely.

For Burkitt lymphoma, always anticipate two linked questions: (1) the biopsy will describe a "starry sky" pattern with t(8;14), and (2) the follow-up question will involve a patient who develops hyperkalemia, hyperphosphatemia, elevated uric acid, and rising creatinine after starting chemotherapy. The tested concept is tumor lysis syndrome, and the expected prophylactic agent is rasburicase.

Finally, remember that rituximab requires HBV screening before administration. A question may present a patient with DLBCL about to start R-CHOP and ask what must be checked first. The answer is hepatitis B serologies (HBsAg and anti-HBc), because rituximab-induced immunosuppression can reactivate dormant HBV with potentially fatal consequences. This pearl tests whether you understand the real-world safety considerations behind prescribing biologic therapies.