Non-Hodgkin Lymphoma

Overview

NHLs = large heterogeneous group, more common than HD (62% vs 8%). Multiple WHO subtypes (unlike HD’s single scheme). CLL/SLL covered separately.

Follicular lymphoma (~22% of NHLs)

Older patients, waxing-waning painless lymphadenopathy, extranodal spread rare. Follicular pattern; small cleaved (low grade, slow) to large cleaved (high grade, fast) nuclei. CD19+, CD20+, BCL-2+ (distinguishes from normal germinal centre). t(14;18). Marrow infiltration paratrabecular. ~half of low-grade cases → DLBCL. Median survival 7-9yr.

DLBCL (~31%, commonest NHL)

Older patients (mean 60yr). ~half extranodal at presentation (marrow, GI tract). Subtypes: EBV-associated (immunosuppressed), HHV-8+immunosuppression (primary effusion lymphoma), mediastinal (young females, spreads to CNS/abdomen). Large cleaved cells, diffuse pattern, CD19+/CD20+, BCL-2 overexpression. Aggressive, widely disseminates.

Burkitt lymphoma/leukaemia

~30% of childhood NHLs. Leukaemic form = L3 ALL. 3 types: African endemic (jaw tumour, EBV-linked), sporadic (more pleomorphic, CNS infiltration, more aggressive), immunodeficiency-associated (HIV).

Morphology: intermediate cells, 2-5 nucleoli, high mitotic rate → high cell death → macrophages with debris → “starry sky” appearance. CD19+, CD10+, surface IgM. t(8;14)/t(8;22) → MYC overexpression. High-grade, very rapidly progressive.

MALToma (~8%)

H. pylori-associated (esp. gastric), extranodal sites (stomach, intestine, orbit, lung, thyroid, salivary, CNS). ~half gastric cases: t(11;18). Diffuse small B lymphocytes, CD5-negative. Good prognosis; rarely → DLBCL.

Mantle cell lymphoma (~8%)

t(11;14), BCL-1 overexpression, surface IgM/IgD (CD5+ like SLL). Older males; marrow/spleen/liver/bowel. Arises from mantle zone B-cells, indented nuclei. More aggressive than other SLL-type lymphomas.

Hairy cell leukaemia

Older males, hairy cells in blood/marrow + splenomegaly. Susceptible to M. avium intracellulare. Pancytopenia, TRAP+, CD19/20/22 + CD11/25/103. Chronic course, mean survival 4-5yr, responds to splenectomy/α-interferon/2-CDA.

Other B-cell malignancies (brief)

B-cell prolymphocytic leukaemia, splenic marginal zone lymphoma, lymphoplasmacytic lymphoma (= Waldenström’s tissue form), nodal marginal zone lymphoma.

Precursor B/T-cell ALL/lymphoma

Commonest childhood cancer <4yr. Pre-B 90%, pre-T 10%. Pre-B: usually ALL in children, early extranodal spread if leukaemic. Pre-T: mediastinal mass+pleural effusion (thymic origin), rapid → leukaemia, more aggressive than B-cell form. Indistinguishable morphologically — need immunophenotyping. Lymphoblasts >20%, PAS+.

HD vs NHL

See Hodgkin Lymphoma table — HD: mostly B, localised, extranodal/marrow rare, better prognosis. NHL: 90%B/10%T, disseminated, extranodal/marrow common, worse prognosis.

Clinical relevance

Starry-sky pattern (Burkitt) = high mitotic rate → high cell death → macrophage clearance, directly explains the histology. Translocation triad — t(8;14)/MYC (Burkitt), t(14;18)/BCL-2 (follicular), t(11;14)/BCL-1 (mantle cell) — high-yield, easy to mix up, anchor each to its gene. MALT lymphoma can regress with H. pylori eradication alone — rare malignancy treatable via its infectious trigger. Precursor T-cell ALL’s mediastinal-mass presentation directly reflects thymic origin of T-cell precursors.

Overview

Non-Hodgkin lymphomas (NHLs) and the related lymphoid leukaemias are a large, heterogeneous group of neoplasms of lymphoid tissue and blood — far more common than Hodgkin lymphoma (62% vs 8% of all lymphoid neoplasms). Unlike HD’s single accepted classification, NHL has multiple recognised subtypes under the WHO scheme; this note covers the clinically important examples in detail, with brief mention of the rest. (Chronic lymphocytic leukaemia/small lymphocytic lymphoma is covered separately — see Chronic Lymphocytic Leukaemia.)

Follicular Lymphoma

Comprises about 22% of all NHLs. Occurs in older individuals, presenting with painless, characteristically waxing-and-waning peripheral lymphadenopathy; extranodal involvement is infrequent (unlike diffuse lymphomas).

Morphology: follicular/nodular growth pattern on lymph node biopsy; tumour cell nuclei range from predominantly small cleaved (more common, infrequent mitoses, slow-growing, low grade) to predominantly large cleaved (high proliferation, rapidly progressive, high grade). Positive for pan-B markers CD19, CD20, plus BCL-2 expression (distinguishes neoplastic follicles from normal germinal centres, which are BCL-2 negative). Characteristic cytogenetic abnormality: t(14;18). Peripheral blood involvement is uncommon (unlike SLL); bone marrow infiltration, when present, is typically paratrabecular.

About half of low-grade cases eventually transform into diffuse large B-cell lymphoma over their indolent course. Median survival 7–9 years.

Diffuse Large B-Cell Lymphoma (DLBCL)

The most common NHL subtype (~31%), occurring in older patients (mean age 60). May present as nodal or extranodal disease — about half have extranodal involvement at presentation, particularly bone marrow and the alimentary tract; a primary CNS form also occurs.

Distinct clinicopathologic subtypes:

• EBV-associated — implicated in immunosuppressed patients (AIDS, organ transplant).
• HHV-8-associated with immunosuppression — presents with effusion (primary effusion lymphoma).
• Mediastinal large B-cell lymphoma — young females, prominent mediastinal involvement, frequently spreads to CNS and abdominal viscera.

Morphology: the diffuse counterpart of follicular large cleaved cell lymphoma — large cleaved cells in a diffuse pattern, pale abundant cytoplasm, prominent 1–2 nucleoli. Positive for pan-B markers (CD19, CD20), surface immunoglobulin overexpression, and BCL-2 overexpression. Aggressive, disseminates widely.

Burkitt Lymphoma/Leukaemia

Uncommon in adults but comprises about 30% of childhood NHLs; the corresponding leukaemic form corresponds to L3 ALL (FAB grouping). Three subgroups:

1. African endemic — first described in African children; classically presents as a jaw tumour spreading to bone marrow and meninges; etiologically linked to EBV.
2. Sporadic — cells resemble endemic Burkitt but more pleomorphic, sometimes multinucleated; propensity for CNS infiltration; more aggressive than the endemic form.
3. Immunodeficiency-associated — seen with HIV infection.

Morphology: histologically similar across all three subtypes — intermediate-sized, non-cleaved, homogeneous tumour cells; round-to-oval nuclei with 2–5 nucleoli; basophilic cytoplasm with lipid vacuolation; very high mitotic rate and correspondingly high cell death. Numerous macrophages containing phagocytosed tumour debris are scattered through the background, producing the classic “starry sky” appearance. The leukaemic form shows monomorphic medium-sized cells with round nuclei, frequent mitoses, multiple nucleoli, and vacuolated basophilic cytoplasm.

Immunophenotype: CD19+, CD10+, surface IgM. Cytogenetics: t(8;14) or t(8;22), involving the MYC gene on chromosome 8, with MYC protein overexpression driving transformation. Burkitt lymphoma is a high-grade, very rapidly progressive tumour.

Extranodal Marginal Zone B-Cell Lymphoma of MALT Type (MALToma)

About 8% of NHLs. Kept as a separate WHO category (rather than folded into SLL) for two reasons: its etiologic association with H. pylori (most frequently as gastric MALT lymphoma) and its characteristic extranodal sites (stomach, intestine, orbit, lung, thyroid, salivary glands, CNS). About half of gastric MALT lymphomas show t(11;18). Median age 60; usually stays localised to the organ of origin, may spread to regional nodes.

Morphology: diffuse infiltration by monoclonal small B lymphocytes, CD5-negative.

Generally good prognosis; rarely more aggressive or transforms into DLBCL.

Mantle Cell Lymphoma

About 8% of NHLs. Distinguished from SLL by the characteristic t(11;14) translocation and overexpression of BCL-1 and surface IgM/IgD (both SLL and mantle cell lymphoma are CD5-positive, however). Occurs in older males; involves bone marrow, spleen, liver, bowel.

Morphology: arises from B-cells of the follicular mantle zone; diffuse or nodular pattern, somewhat indented nuclei. More aggressive than other SLL-type lymphomas.

Hairy Cell Leukaemia

An uncommon B-cell malignancy in older males, characterised by “hairy cells” in blood/marrow and splenomegaly (previously named leukaemic reticuloendotheliosis for its reticuloendothelial-organ infiltration). Patients are susceptible to M. avium intracellulare infection.

Morphology: pancytopenia (marrow failure + splenic sequestration); characteristic hairy cytoplasmic projections best seen on phase-contrast microscopy but also visible on routine smears; positive tartrate-resistant acid phosphatase (TRAP) staining. B-cell origin confirmed by CD19, CD20, CD22 (plus CD11, CD25, CD103).

Chronic course; mean survival 4–5 years; responds to splenectomy, α-interferon, and 2-chlorodeoxyadenosine (2-CDA).

Other B-Cell Malignancies (Brief Mention)

• B-cell prolymphocytic leukaemia — large B lymphocytes with prominent nucleoli in blood/marrow; leucocytosis with splenomegaly and lymphadenopathy.
• Splenic marginal zone lymphoma — small monoclonal B lymphocytes infiltrating splenic white pulp; slow, indolent course.
• Lymphoplasmacytic lymphoma — the tissue manifestation of Waldenström’s macroglobulinaemia; IgM-secreting monoclonal cells infiltrating nodes, spleen, marrow, sometimes blood; indolent; proposed hepatitis C association.
• Nodal marginal zone lymphoma (monocytoid B-cell lymphoma) — uncommon, aggressive; often disseminated at presentation with marrow involvement and a leukaemic picture.

Precursor B/T-Cell Lymphoblastic Leukaemia/Lymphoma (Acute Lymphoblastic Leukaemia)

Arises from precursor (pre-B or pre-T) lymphoid cells — the most common childhood cancer under age 4, ~4% of all lymphoid malignancies overall. Pre-B ALL accounts for 90% of cases, pre-T for the remaining 10%; stage of differentiation does not correlate with aggressiveness.

• Precursor B-cell — usually presents as ALL in children; rarely as lymphoma, which then rapidly transforms into leukaemia; leukaemic presentation shows early extranodal spread (lymphadenopathy, hepatosplenomegaly, CNS infiltration, testicular enlargement, cutaneous infiltration), plus infections from cytopenia.
• Precursor T-cell — often presents as a mediastinal mass with pleural effusion (reflecting thymic differentiation of T-cell precursors), progressing rapidly to leukaemia; bone marrow failure features (anaemia, neutropenia, thrombocytopenia) plus lymphadenopathy, hepatosplenomegaly, CNS involvement. More aggressive than the B-cell counterpart.

Morphologically indistinguishable from one another on routine smear — diagnosis rests on immunophenotyping. Peripheral blood/marrow shows lymphoblasts (>20% typically) with round-to-convoluted nuclei, high N:C ratio, no cytoplasmic granularity; PAS cytochemical stain positive in immature lymphoid cells.

Hodgkin vs Non-Hodgkin Lymphoma

See the comparison table in Hodgkin Lymphoma — key distinguishing features are cell derivation (mostly B in HD vs 90% B/10% T in NHL), pattern of spread (localised/contiguous in HD vs disseminated in NHL), extranodal and marrow involvement (uncommon in HD, common in NHL), and overall prognosis (better in HD).

Clinical Relevance

• Burkitt lymphoma’s “starry sky” appearance is a directly testable histologic pattern with a clear mechanistic explanation — the very high mitotic rate driving equally high cell death, cleared by macrophages that create the pale “stars” against the dark tumour-cell “sky.”
• The t(8;14)/MYC translocation in Burkitt, t(14;18)/BCL-2 in follicular lymphoma, and t(11;14)/BCL-1 in mantle cell lymphoma form a genuinely useful triad of “translocation → oncogene → lymphoma subtype” associations that are each independently high-yield and easy to confuse with one another if not anchored to their specific gene.
• MALT lymphoma’s association with H. pylori is clinically important beyond diagnosis — early-stage gastric MALT lymphoma can regress with H. pylori eradication therapy alone, a rare example of a malignancy treatable by treating its infectious trigger.
• Precursor T-cell ALL/lymphoma’s tendency to present as a mediastinal mass follows directly from where T-cell precursors normally differentiate (the thymus) — the anatomic presentation is a direct readout of the cell of origin’s normal developmental site.

No Rendered Diagram for This Topic

NHL is a broad classification of distinct entities (follicular, DLBCL, Burkitt, MALToma, mantle cell, hairy cell, precursor ALL/lymphoma) rather than a single shared mechanism — each subtype has its own defining translocation and immunophenotype, best captured as a comparison table rather than a process diagram.

Hand-Draw Suggestion

Draw a quick recall table with three columns — Subtype / Translocation (gene) / One distinguishing feature — and fill in Burkitt (t(8;14), MYC, starry sky), follicular (t(14;18), BCL-2, waxing-waning nodes), and mantle cell (t(11;14), BCL-1, CD5+). This triad is the highest-yield part of the topic and benefits from active recall more than a diagram.

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