Splenic Marginal Zone Lymphoma

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Classifications

ICD-O Morphology

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Pathophysiology

5

Chronic Antigenic Stimulation of Splenic Marginal Zone B Cells

Sustained antigenic drive selects and expands marginal zone B cells of the splenic white pulp. Two independent lines of evidence point to a specific, non-random antigen rather than a random founding event: strongly biased immunoglobulin heavy-chain variable gene usage, with a large fraction of cases using IGHV1-2, and an epidemiological and therapeutic association with chronic hepatitis C virus infection. A stereotyped receptor repertoire implies that the founding clone is chosen by its antigen-binding specificity, placing SMZL alongside MALT lymphoma in the family of inflammation-associated, antigen-driven B-cell neoplasms.

marginal zone B cell of spleen CL:0000845

B cell receptor signaling pathway GO:0050853 ↑ INCREASED

marginal zone of spleen UBERON:0001251 white pulp of spleen UBERON:0001959

Downstream

Disruption of Marginal Zone B-cell Identity and Quiescence Chronic proliferation under antigenic drive provides the replicative context in which NOTCH2, KLF2, and chromosome 7q lesions are acquired and selected.

Show evidence (6 references)

PMID:39280243 SUPPORT Human Clinical

"Immunogenetic investigations have revealed biases in the immunoglobulin gene repertoire, indicating a role of antigen selection."

Establishes that the biased immunoglobulin repertoire in SMZL implies antigen-driven selection of the founding clone.

PMID:39280243 SUPPORT Human Clinical

"representing 30% of all cases and 90% of IGHV1-2 users"

Quantifies IGHV1-2*04 usage at 30% of all SMZL cases, the concrete immunogenetic signature of antigen selection.

PMID:39280243 SUPPORT Human Clinical

"IGHV1-2*04 and/or del(7q) are very strong pointers for the diagnosis of SMZL"

Establishes the stereotyped receptor usage as diagnostically specific to SMZL rather than a generic B-cell finding.

+ 3 more references

Disruption of Marginal Zone B-cell Identity and Quiescence

SMZL is genetically defined by lesions in the very program that specifies marginal zone B cells and holds them quiescent. NOTCH2 signaling is required for marginal zone B-cell development, and recurrent truncating mutations clustered in the C-terminal PEST degron eliminate the degradation signal, stabilizing the activated protein and producing a sustained differentiation cue. KLF2, a transcription factor that restrains NF-kB and NOTCH output in mature B cells, is recurrently inactivated, removing that brake. Deletion of the long arm of chromosome 7 is the most frequent cytogenetic abnormality in the disease. Mutations in additional NOTCH-pathway members and in other pathways governing marginal zone development affect a majority of cases. This constellation is the mechanistic signature separating SMZL from MALT lymphoma, which reaches a comparable endpoint through BCL10-MALT1 translocations instead.

marginal zone B cell of spleen CL:0000845

Notch signaling pathway GO:0007219 ↑ INCREASED

Downstream

Constitutive NF-kB Pathway Activation Loss of KLF2-mediated restraint and gain of stabilized NOTCH2 signaling both feed forward into constitutive NF-kB activity.

Show evidence (4 references)

PMID:22891276 SUPPORT Human Clinical

"we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development"

Whole-genome sequencing establishes that SMZL recurrently mutates NOTCH2, the gene required for marginal zone B-cell development itself.

PMID:22891273 SUPPORT Human Clinical

"suggesting that deregulation of MZ B cell development pathways plays a role in the pathogenesis"

Whole-exome analysis attributes SMZL pathogenesis to deregulation of the marginal zone B-cell developmental program.

PMID:22891273 SUPPORT Human Clinical

"these include NOTCH1, SPEN, and DTX1"

Shows that additional NOTCH-pathway modulators beyond NOTCH2 are recurrently mutated, indicating pathway-level rather than single-gene deregulation.

+ 1 more reference

Constitutive NF-kB Pathway Activation

Recurrent mutations in regulators of the NF-kB pathway, most notably TNFAIP3 which encodes the negative regulator A20, converge with KLF2 loss and stabilized NOTCH2 to drive constitutive nuclear NF-kB activity. This is the shared effector node across marginal zone lymphomas: MALT lymphoma reaches it through the BCL10-MALT1 translocations, SMZL through mutation of the same pathway's regulators. Sequencing of marginal zone lymphoma treated with a BTK inhibitor found NF-kB, NOTCH, or B-cell receptor pathway genes involved in the large majority of cases, confirming that these three inputs form one convergent signaling module. Constitutive NF-kB output sustains proliferation and suppresses apoptosis without continued antigenic stimulation, which is why advanced disease no longer regresses when the antigenic driver is removed.

marginal zone B cell of spleen CL:0000845

canonical NF-kappaB signal transduction GO:0007249 ↑ INCREASED B cell proliferation GO:0042100 ↑ INCREASED apoptotic process GO:0006915 ↓ DECREASED

Downstream

Splenic White Pulp Infiltration and Hypersplenism The expanded clone colonizes and expands the splenic white pulp, then spills into marrow and blood.

Show evidence (2 references)

PMID:36947202 SUPPORT Human Clinical

"NF-κB, NOTCH, or B-cell receptor (BCR) pathway genes were implicated in samples from 16 of 18 patients (89%)."

Whole-exome sequencing of marginal zone lymphoma shows the NF-kB, NOTCH, and B-cell receptor pathways are involved in the large majority of cases.

PMID:22891273 PARTIAL Human Clinical

"given the availability of drugs that can target NOTCH, NF-κB, and other pathways deregulated in this disease"

Identifies NF-kB as one of the pathways deregulated in SMZL and therapeutically targetable; indirect support since the paper's primary finding concerns NOTCH2.

Splenic White Pulp Infiltration and Hypersplenism

The lymphoma clone expands the splenic white pulp in a characteristic micronodular pattern, effacing normal follicular architecture and spilling into the red pulp. The enlarging spleen sequesters and destroys circulating blood cells, producing cytopenias out of proportion to marrow reserve. Marrow involvement is reported in nodular, interstitial, and intrasinusoidal patterns, and the tumor cells circulate as villous lymphocytes, the feature that gave the disease its older name of splenic lymphoma with villous lymphocytes. Because a substantial share of the cytopenia is mechanical, removing the spleen historically corrected the blood counts without eradicating the lymphoma.

marginal zone B cell of spleen CL:0000845

marginal zone of spleen UBERON:0001251 white pulp of spleen UBERON:0001959 spleen UBERON:0002106

Downstream

Cytopenias and Autoimmune Complications Splenic sequestration combines with lymphoma-associated autoantibody production to produce anemia and thrombocytopenia.

Show evidence (3 references)

PMID:23712547 SUPPORT Human Clinical

"It presents with marked splenomegaly."

Confirms marked splenomegaly as the characteristic presentation produced by splenic infiltration.

PMID:22891276 SUPPORT Human Clinical

"Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level."

Confirms the spleen as the defining primary site of disease involvement.

PMID:8652403 SUPPORT Human Clinical

"SLVL is a chronic B-cell lymphoproliferative disorder characterized by splenomegaly and the presence, in peripheral blood, of lymphocytes with "villous' projections."

A 100-patient clinical series defines the disease by the pairing of splenomegaly with circulating villous lymphocytes, the two consequences of splenic infiltration and spillover.

Cytopenias and Autoimmune Complications

Anemia and thrombocytopenia in SMZL arise from two superimposed mechanisms: mechanical sequestration by the enlarged spleen, and true autoimmune destruction. The lymphoma clone and the dysregulated B-cell compartment around it generate autoantibodies, so autoimmune hemolytic anemia and immune thrombocytopenia are recognized paraneoplastic complications rather than incidental findings. This dual mechanism matters clinically because it separates patients whose counts respond to splenectomy or to lymphoma-directed therapy from those who require immunosuppression.

Show evidence (1 reference)

PMID:25201005 SUPPORT Human Clinical

"immune mediated paraneoplastic phenomena such as autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common"

Establishes autoimmune hemolytic anemia and immune thrombocytopenia as common immune-mediated paraneoplastic phenomena in SMZL.

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Histopathology

5

Micronodular white pulp expansion

The lymphoma expands the splenic white pulp as micronodular lesions, the architectural hallmark of the disease on splenic histology.

Show evidence (1 reference)

PMID:19575895 SUPPORT Human Clinical

"all of the 8 cases showed micronodular white pulp lesions"

All cases in an 8-patient clinicopathologic series showed the micronodular white pulp pattern.

Biphasic nodule architecture

Nodules classically show a biphasic structure: a central aggregate of small B cells surrounded by a peripheral rim of atypical monocytoid B cells. A minority of cases are monomorphous instead.

Show evidence (1 reference)

PMID:19575895 SUPPORT Human Clinical

"Six of them exhibited the classic biphasic appearance with central aggregates of small B cells rimmed by a peripheral zone of atypical monocytoid B cells."

Six of eight cases showed the classic biphasic nodule architecture.

Red pulp infiltration

Beyond the white pulp nodules, tumor cells infiltrate the red pulp in sheets.

Show evidence (1 reference)

PMID:19575895 SUPPORT Human Clinical

"There was infiltration of tumor cells in the red pulp, sheets in appearance in all 8 cases."

All eight cases showed sheet-like red pulp infiltration in addition to the white pulp lesions.

Low proliferation index

Ki-67 immunostaining shows a low proliferation index, consistent with the indolent clinical behavior of the disease.

Show evidence (1 reference)

PMID:19575895 SUPPORT Human Clinical

"The proliferation index, as highlighted by Ki-67 immunostaining, was low"

Documents the low Ki-67 proliferation index that matches the indolent course.

Intrasinusoidal bone marrow infiltration

Marrow involvement is described in nodular, interstitial, and intrasinusoidal patterns. The intrasinusoidal component is often cited as characteristic of SMZL, but the supporting evidence available here is a single case report, so the finding is recorded without a frequency and without a diagnostic flag.

Show evidence (1 reference)

PMID:28892912 PARTIAL Human Clinical

"tumour cells in nodular, interstitial and intrasinusoidal pattern of infiltration"

Documents the intrasinusoidal marrow pattern; marked PARTIAL because this is a single case report and cannot establish how characteristic the pattern is.

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Pathograph

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Phenotypes

6

Blood 5

Lymphocytosis with Villous Lymphocytes Increased total lymphocyte count HP:0100827

Show evidence (2 references)

PMID:8652403 SUPPORT Human Clinical

"SLVL is a chronic B-cell lymphoproliferative disorder characterized by splenomegaly and the presence, in peripheral blood, of lymphocytes with "villous' projections."

A 100-patient series establishes circulating villous lymphocytes in peripheral blood as a defining feature of the disease.

PMID:8652403 PARTIAL Human Clinical

"The cytological diagnosis can be difficult in patients without an absolute lymphocytosis"

Qualifies the lymphocytosis claim by noting that some patients lack an absolute lymphocytosis, which is why no frequency band is asserted for this phenotype.

Anemia Anemia HP:0001903

Show evidence (1 reference)

PMID:25201005 PARTIAL Human Clinical

"autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common"

Supports anemia in SMZL via its autoimmune hemolytic mechanism; the mechanical sequestration contribution is not quantified in this source.

Thrombocytopenia Thrombocytopenia HP:0001873

Show evidence (1 reference)

PMID:25201005 PARTIAL Human Clinical

"autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common"

Supports thrombocytopenia in SMZL via its immune-mediated mechanism; the hypersplenic contribution is not quantified in this source.

Autoimmune Hemolytic Anemia Autoimmune hemolytic anemia HP:0001890

Show evidence (1 reference)

PMID:25201005 SUPPORT Human Clinical

"immune mediated paraneoplastic phenomena such as autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common"

Directly identifies autoimmune hemolytic anemia as a relatively common paraneoplastic phenomenon in SMZL.

Immune Thrombocytopenia Autoimmune thrombocytopenia HP:0001973

Show evidence (1 reference)

PMID:25201005 SUPPORT Human Clinical

"immune mediated paraneoplastic phenomena such as autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common"

Directly identifies autoimmune thrombocytopenia as a relatively common paraneoplastic phenomenon in SMZL.

Cardiovascular 1

Splenomegaly Splenomegaly HP:0001744

Show evidence (2 references)

PMID:23712547 SUPPORT Human Clinical

"It presents with marked splenomegaly."

Directly states that SMZL presents with marked splenomegaly.

PMID:8652403 SUPPORT Human Clinical

"SLVL is a chronic B-cell lymphoproliferative disorder characterized by splenomegaly and the presence, in peripheral blood, of lymphocytes with "villous' projections."

A 100-patient series characterizes the disease by splenomegaly, independently confirming it as the defining clinical feature.

🧬

Genetic Associations

5

NOTCH2 Mutation (Recurrent Somatic Driver)

Gene: NOTCH2 hgnc:7882 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (3 references)

PMID:22891273 SUPPORT Human Clinical

"Mutations in NOTCH2, a gene required for marginal-zone (MZ) B cell development, represent the most frequent lesion in SMZL"

Establishes NOTCH2 as the most frequent genetic lesion in SMZL and links it to marginal zone B-cell development.

PMID:22891273 SUPPORT Human Clinical

"All NOTCH2 mutations are predicted to cause impaired degradation of the NOTCH2 protein by eliminating the C-terminal PEST domain, which is required for proteasomal recruitment."

Specifies the molecular consequence of the PEST-domain mutations as impaired proteasomal degradation of NOTCH2.

PMID:22891276 SUPPORT Human Clinical

"These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation"

Independently confirms the PEST-domain clustering and truncating nature of the NOTCH2 mutations.

KLF2 Mutation (Recurrent Somatic Driver)

Gene: KLF2 hgnc:6347 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:39280243 SUPPORT Human Clinical

"identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways"

Establishes KLF2 as one of the recurrently mutated genes defining the SMZL mutational landscape.

TNFAIP3 Mutation (Recurrent Somatic Mutation)

Gene: TNFAIP3 hgnc:11896 relationship_type: COOPERATING variant_origin: SOMATIC

Show evidence (2 references)

PMID:39280243 PARTIAL Human Clinical

"TNFAIP3 7–15% Mutations resulted in a loss of NF-κB cascade inhibition in other NHLs."

Supports recurrent TNFAIP3 mutation in SMZL; marked PARTIAL because the same sentence attributes the NF-kB functional consequence to other non-Hodgkin lymphomas, not to SMZL.

PMID:36947202 PARTIAL Human Clinical

"MYD88, TNFAIP3, and KMT2D mutations correlate with PFS in patients with relapsed/refractory MZL treated with zanubrutinib."

Shows TNFAIP3 is prognostically relevant under BTK inhibition; marked PARTIAL because the cohort spans marginal zone lymphoma subtypes rather than SMZL specifically.

Deletion of Chromosome 7q (Most Frequent Cytogenetic Lesion)

relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (2 references)

PMID:39280243 SUPPORT Human Clinical

"cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7"

Establishes deletion of chromosome 7q as the recurrent cytogenetic abnormality of SMZL.

PMID:39280243 SUPPORT Human Clinical

"IGHV1-2*04 and/or del(7q) are very strong pointers for the diagnosis of SMZL"

Establishes del(7q) as one of the two strongest diagnostic pointers for SMZL.

TP53 Disruption (Adverse Prognostic Lesion)

Gene: TP53 hgnc:11998 relationship_type: MODIFIER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:39280243 SUPPORT Human Clinical

"identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways"

Establishes TP53 as one of the three recurrently mutated genes in the SMZL landscape.

💊

Medical Actions

6

Observation

Asymptomatic patients with low-risk disease can be managed expectantly. A prospective study of a risk-adapted strategy found observation to be the best approach for the lowest-risk group, making watchful waiting an evidence-based option rather than merely a default.

Show evidence (2 references)

PMID:37386877 SUPPORT Human Clinical

"observation as the best approach for patients in group A and rituximab as the best treatment for group B"

Prospective multicenter study supports observation for the lowest-risk SMZL group.

PMID:8652403 SUPPORT Human Clinical

"treatment abstention should be considered in patients with favourable prognostic factors"

An earlier 100-patient series independently reached the same conclusion that untreated observation is appropriate for favourable-risk patients.

Rituximab

Action: Pharmacotherapy NCIT:C15986

Agent: rituximab NCIT:C1702

Anti-CD20 monoclonal antibody, now the preferred first-line therapy for symptomatic SMZL. In a prospective multicenter series, rituximab-containing arms achieved a higher overall response rate than splenectomy.

Show evidence (2 references)

PMID:37386877 SUPPORT Human Clinical

"The overall response rate was higher in the rituximab chemotherapy and in the rituximab arms compared with the splenectomy arm"

Prospective multicenter data show rituximab-containing therapy outperforms splenectomy on overall response rate.

PMID:37386877 SUPPORT Human Clinical

"observation as the best approach for patients in group A and rituximab as the best treatment for group B"

Identifies rituximab as the preferred treatment for the risk group requiring therapy.

Splenectomy

Action: Splenectomy NCIT:C15328

Surgical removal of the spleen, the historical first-line treatment and still an option in patients fit for surgery. It corrects the mechanical cytopenias and relieves mass effect but does not eradicate the lymphoma, and has been largely superseded by rituximab on response-rate grounds.

Mechanism Target:

Splenic White Pulp Infiltration and Hypersplenism — Splenectomy removes the sequestering organ, correcting the mechanical component of the cytopenias.

Show evidence (2 references)

PMID:23712547 SUPPORT Human Clinical

"Splenectomy remains one of the first-line options in patients fit for surgery."

Confirms splenectomy as an established first-line option for surgically fit SMZL patients.

PMID:37386877 PARTIAL Human Clinical

"The overall response rate was higher in the rituximab chemotherapy and in the rituximab arms compared with the splenectomy arm"

Supports the displacement of splenectomy by rituximab on response rate, though lymphoma-specific survival did not differ by treatment received.

Hepatitis C Antiviral Therapy

Action: Antiviral Therapy NCIT:C16119

In hepatitis C virus-associated SMZL, therapy directed at the virus rather than at the lymphoma can induce hematologic response. This is the splenic counterpart of Helicobacter pylori eradication in gastric MALT lymphoma and is the strongest therapeutic evidence for the antigen-driven model of marginal zone lymphomagenesis.

Mechanism Target:

Chronic Antigenic Stimulation of Splenic Marginal Zone B Cells — Clearing the virus removes the chronic antigenic drive sustaining the clone, the same logic as Helicobacter pylori eradication in gastric MALT lymphoma.

Show evidence (2 references)

PMID:25273531 SUPPORT Human Clinical

"Interferon and ribavirin based treatment proved to be successful in small case series of hepatitis C virus associated splenic lymphoma with villous lymphocytes, therefore, it is suggested that antiviral treatment could be an alternative to chemo-immunotherapy."

Documents lymphoma response to antiviral therapy in hepatitis C virus-associated splenic lymphoma with villous lymphocytes.

PMID:25273531 SUPPORT Human Clinical

"The association between hepatitis C virus and certain B-cell non-Hodgkin lymphomas, such as marginal zone lymphomas, is supported by epidemiological studies."

Establishes the epidemiological basis for the hepatitis C virus association that makes antiviral therapy rational.

Bruton Tyrosine Kinase Inhibition

Action: Pharmacotherapy NCIT:C15986

Agent: zanubrutinib NCIT:C141428

BTK inhibitors block B-cell receptor signal transmission upstream of NF-kB. Zanubrutinib is used for relapsed or refractory marginal zone lymphoma after anti-CD20 therapy, and mutations in NF-kB pathway genes are associated with the response.

Mechanism Target:

Constitutive NF-kB Pathway Activation — BTK inhibition interrupts B-cell receptor signal transmission into the NF-kB pathway.

Show evidence (2 references)

PMID:36947202 SUPPORT Human Clinical

"MYD88, TNFAIP3, and KMT2D mutations correlate with PFS in patients with relapsed/refractory MZL treated with zanubrutinib."

Establishes zanubrutinib use in relapsed or refractory marginal zone lymphoma and links NF-kB pathway genotype to progression-free survival.

PMID:36947202 SUPPORT Human Clinical

"NF-κB, NOTCH, or B-cell receptor (BCR) pathway genes were implicated in samples from 16 of 18 patients (89%)."

Provides the mechanistic rationale for BTK inhibition by showing B-cell receptor and NF-kB pathway involvement in the large majority of cases.

Cladribine with or without Rituximab

Action: Pharmacotherapy NCIT:C15986

Agent: cladribine CHEBI:567361 rituximab NCIT:C1702

Cladribine (2-chlorodeoxyadenosine), a purine analog, given alone or with an anti-CD20 antibody, is an effective pharmacological option for patients who are poor surgical candidates. An extended-follow-up series of 50 SMZL patients reported an 87% overall response rate and 80% five-year progression-free survival.

Show evidence (3 references)

PMID:23712547 SUPPORT Human Clinical

"Fifty SMZL patients were treated with Cladribine"

Establishes the treated SMZL cohort for this regimen.

PMID:23712547 SUPPORT Human Clinical

"ORR was 87%"

Quantifies the overall response rate of cladribine-based therapy in SMZL.

PMID:23712547 SUPPORT Human Clinical

"After a median follow-up of 48 months, 7 of 41 responsive cases relapsed and the 5-year PFS was 80%."

Quantifies durability of response with 5-year progression-free survival.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Splenic Marginal Zone Lymphoma:

Hairy cell leukemia

Overlapping Features The classic mimic: also presents with splenomegaly and cytopenias, and its cells also have cytoplasmic projections. Distinguished by annexin A1, CD103 and CD123 expression (absent in SMZL) and by BRAF mutation.

Show evidence (2 references)

PMID:39280243 SUPPORT Human Clinical

"MYD88 for WM, BRAF for HCL, NOTCH1 and SF3B1 for CLL, PTPRD for NMZL, and MAP2K1 for HCL-V"

Gives BRAF as the molecular discriminator separating hairy cell leukemia from SMZL.

PMID:39280243 SUPPORT Human Clinical

"Lack of expression of CD103, CD123, annexin A1, and cyclin D1 serve to distinguish SMZL from other splenic lymphomas"

Gives the immunophenotypic discriminators; annexin A1, CD103 and CD123 are hairy cell leukemia markers absent in SMZL.

Hairy cell leukemia variant

Overlapping Features A separate entity from classic hairy cell leukemia, distinguished from SMZL by MAP2K1 mutation.

Show evidence (1 reference)

PMID:39280243 SUPPORT Human Clinical

"MYD88 for WM, BRAF for HCL, NOTCH1 and SF3B1 for CLL, PTPRD for NMZL, and MAP2K1 for HCL-V"

Gives MAP2K1 as the molecular discriminator for hairy cell leukemia variant.

Waldenstrom macroglobulinemia

Overlapping Features Overlaps with SMZL in its IgM paraproteinemia and marrow involvement; distinguished by MYD88 mutation.

Show evidence (1 reference)

PMID:39280243 SUPPORT Human Clinical

"MYD88 for WM, BRAF for HCL, NOTCH1 and SF3B1 for CLL, PTPRD for NMZL, and MAP2K1 for HCL-V"

Gives MYD88 as the molecular discriminator for Waldenstrom macroglobulinemia.

Chronic lymphocytic leukemia

Overlapping Features Shares the indolent clonal B-cell lymphocytosis; distinguished by CD5 expression and by NOTCH1 and SF3B1 mutation.

Show evidence (1 reference)

PMID:39280243 SUPPORT Human Clinical

"MYD88 for WM, BRAF for HCL, NOTCH1 and SF3B1 for CLL, PTPRD for NMZL, and MAP2K1 for HCL-V"

Gives NOTCH1 and SF3B1 as the molecular discriminators for chronic lymphocytic leukemia.

Nodal marginal zone lymphoma

Overlapping Features The nodal sibling within the marginal zone family; distinguished from SMZL by PTPRD mutation and by its nodal rather than splenic distribution.

Show evidence (1 reference)

PMID:39280243 SUPPORT Human Clinical

"MYD88 for WM, BRAF for HCL, NOTCH1 and SF3B1 for CLL, PTPRD for NMZL, and MAP2K1 for HCL-V"

Gives PTPRD as the molecular discriminator for nodal marginal zone lymphoma.

Splenic diffuse red pulp small B-cell lymphoma

Overlapping Features A rare splenic B-cell lymphoma that infiltrates red pulp diffusely rather than forming the micronodular white pulp lesions of SMZL. The CD200/CD180 fluorescence ratio assists separation.

Show evidence (2 references)

PMID:19575895 PARTIAL Human Clinical

"The differential diagnosis includes other small B-cell lymphomas and lymphoid hyperplasia of spleen."

Establishes that other small B-cell lymphomas of the spleen are the differential; PARTIAL because this source does not name this entity individually.

PMID:39280243 SUPPORT Human Clinical

"the CD200/CD180 median fluorescence (MFI) ratio may help to distinguish SDRPL diagnosis over HCL, SMZL, and SBLPN, where a ratio of 0.5 or less is in favour of SDRPL"

Gives the specific flow-cytometric discriminator separating SDRPL from SMZL, with its decision threshold.

🔬

Clinical Trials

1

NCT03846427 PHASE_II COMPLETED

MAGNOLIA (BGB-3111-214), a single-arm phase II study of the next-generation BTK inhibitor zanubrutinib in relapsed or refractory marginal zone lymphoma, the trial supporting BTK inhibition in this disease. Enrolment spans marginal zone lymphoma subtypes rather than SMZL alone.

Show evidence (2 references)

clinicaltrials:NCT03846427 SUPPORT

"This is a single arm study to evaluate the efficacy, safety and tolerability of zanubrutinib (BGB-3111) in participants with relapsed/refractory marginal zone lymphoma (R/R MZL)."

ClinicalTrials.gov summary confirms the design and population of the MAGNOLIA trial.

PMID:34526366 SUPPORT Human Clinical

"the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%"

Reports the primary efficacy outcome of the MAGNOLIA trial.

{ }

Source YAML

click to show

name: Splenic Marginal Zone Lymphoma
creation_date: "2026-07-31T00:00:00Z"
description: >-
  Splenic marginal zone lymphoma (SMZL) is a rare, indolent mature B-cell
  non-Hodgkin lymphoma arising from the marginal zone of the splenic white pulp.
  It presents with splenomegaly, peripheral blood involvement by circulating
  villous lymphocytes, and cytopenias, with bone marrow involvement and little
  or no peripheral lymphadenopathy. Like its
  extranodal sibling MALT lymphoma, SMZL appears to begin as an antigen-driven
  process: biased immunoglobulin heavy-chain gene usage (notably IGHV1-2) and an
  association with chronic hepatitis C virus infection both point to sustained
  antigenic selection of marginal zone B cells. Where MALT lymphoma escapes
  antigen dependence through translocations that fuse or deregulate the
  BCL10-MALT1 axis, SMZL instead acquires point mutations and deletions in the
  genes that specify and restrain marginal zone B-cell identity, namely NOTCH2,
  KLF2, and the long arm of chromosome 7, together with NF-kB-activating lesions
  such as TNFAIP3. The two lymphomas therefore converge on constitutive NF-kB
  signaling by mechanistically distinct routes. Splenic infiltration and
  hypersplenism drive the cytopenias, which are frequently compounded by
  autoimmune hemolytic anemia and immune thrombocytopenia. Antiviral therapy can
  induce lymphoma regression in hepatitis C virus-associated disease, mirroring
  Helicobacter pylori eradication in gastric MALT lymphoma; splenectomy was the
  historical first-line treatment and has largely been superseded by rituximab.
categories:
- Hematologic Malignancy
- B-cell Neoplasm
- Non-Hodgkin Lymphoma
parents:
- B-cell non-Hodgkin lymphoma
- marginal zone lymphoma
disease_term:
  preferred_term: splenic marginal zone lymphoma
  term:
    id: MONDO:0019462
    label: splenic marginal zone lymphoma
synonyms:
- SMZL
- SLVL
- splenic lymphoma with villous lymphocytes
- splenic marginal zone B-cell lymphoma
- marginal zone lymphoma of the spleen
pathophysiology:
- name: Chronic Antigenic Stimulation of Splenic Marginal Zone B Cells
  conforms_to: "tumor_promoting_inflammation#Chronic Inflammatory Stimulus"
  description: >-
    Sustained antigenic drive selects and expands marginal zone B cells of the
    splenic white pulp. Two independent lines of evidence point to a specific,
    non-random antigen rather than a random founding event: strongly biased
    immunoglobulin heavy-chain variable gene usage, with a large fraction of
    cases using IGHV1-2, and an epidemiological and therapeutic association with
    chronic hepatitis C virus infection. A stereotyped receptor repertoire
    implies that the founding clone is chosen by its antigen-binding
    specificity, placing SMZL alongside MALT lymphoma in the family of
    inflammation-associated, antigen-driven B-cell neoplasms.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunogenetic investigations have revealed biases in the immunoglobulin gene repertoire, indicating a role of antigen selection."
    explanation: Establishes that the biased immunoglobulin repertoire in SMZL implies antigen-driven selection of the founding clone.
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "representing 30% of all cases and 90% of IGHV1-2 users"
    explanation: Quantifies IGHV1-2*04 usage at 30% of all SMZL cases, the concrete immunogenetic signature of antigen selection.
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IGHV1-2*04 and/or del(7q) are very strong pointers for the diagnosis of SMZL"
    explanation: Establishes the stereotyped receptor usage as diagnostically specific to SMZL rather than a generic B-cell finding.
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is significantly associated with del(7q), KLF2, and NOTCH2 mutations"
    explanation: Links the antigen-selection signature to the downstream genetic lesions, tying this node to the next one in the chain.
  - reference: PMID:34384734
    reference_title: "Repertoire of Rearranged Immunoglobulin Heavy Chain Genes in Russian Patients With B-Cell Lymphoproliferative Diseases."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "In the half of SMZL patients was identified gene IGHV1-2."
    explanation: Independent cohort corroborating the IGHV1-2 bias; retained only as secondary support since it is a small mixed B-LPD series reporting IGHV1-2 rather than the *04 allele specifically.
  - reference: PMID:25273531
    reference_title: "Non-Hodgkin lymphoma and hepatitis C: where we are and what next?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both chronic antigenic stimulation and viral lymphotropism may contribute to the evolution of the malignant clone"
    explanation: Identifies chronic antigenic stimulation as a proposed mechanism linking hepatitis C virus to marginal zone lymphomagenesis.
  cell_types:
  - preferred_term: marginal zone B cell of spleen
    term:
      id: CL:0000845
      label: marginal zone B cell of spleen
  locations:
  - preferred_term: marginal zone of spleen
    term:
      id: UBERON:0001251
      label: marginal zone of spleen
  - preferred_term: white pulp of spleen
    term:
      id: UBERON:0001959
      label: white pulp of spleen
  biological_processes:
  - preferred_term: B cell receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
  downstream:
  - target: Disruption of Marginal Zone B-cell Identity and Quiescence
    description: >-
      Chronic proliferation under antigenic drive provides the replicative
      context in which NOTCH2, KLF2, and chromosome 7q lesions are acquired and
      selected.
- name: Disruption of Marginal Zone B-cell Identity and Quiescence
  description: >-
    SMZL is genetically defined by lesions in the very program that specifies
    marginal zone B cells and holds them quiescent. NOTCH2 signaling is required
    for marginal zone B-cell development, and recurrent truncating mutations
    clustered in the C-terminal PEST degron eliminate the degradation signal,
    stabilizing the activated protein and producing a sustained differentiation
    cue. KLF2, a transcription factor that restrains NF-kB and NOTCH output in
    mature B cells, is recurrently inactivated, removing that brake. Deletion of
    the long arm of chromosome 7 is the most frequent cytogenetic abnormality in
    the disease. Mutations in additional NOTCH-pathway members and in other
    pathways governing marginal zone development affect a majority of cases.
    This constellation is the mechanistic signature separating SMZL from MALT
    lymphoma, which reaches a comparable endpoint through BCL10-MALT1
    translocations instead.
  evidence:
  - reference: PMID:22891276
    reference_title: "Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development"
    explanation: Whole-genome sequencing establishes that SMZL recurrently mutates NOTCH2, the gene required for marginal zone B-cell development itself.
  - reference: PMID:22891273
    reference_title: "The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting that deregulation of MZ B cell development pathways plays a role in the pathogenesis"
    explanation: Whole-exome analysis attributes SMZL pathogenesis to deregulation of the marginal zone B-cell developmental program.
  - reference: PMID:22891273
    reference_title: "The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these include NOTCH1, SPEN, and DTX1"
    explanation: Shows that additional NOTCH-pathway modulators beyond NOTCH2 are recurrently mutated, indicating pathway-level rather than single-gene deregulation.
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7"
    explanation: Establishes deletion of chromosome 7q as the recurrent cytogenetic lesion of SMZL.
  cell_types:
  - preferred_term: marginal zone B cell of spleen
    term:
      id: CL:0000845
      label: marginal zone B cell of spleen
  biological_processes:
  - preferred_term: Notch signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007219
      label: Notch signaling pathway
  downstream:
  - target: Constitutive NF-kB Pathway Activation
    description: >-
      Loss of KLF2-mediated restraint and gain of stabilized NOTCH2 signaling
      both feed forward into constitutive NF-kB activity.
- name: Constitutive NF-kB Pathway Activation
  conforms_to: "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation"
  description: >-
    Recurrent mutations in regulators of the NF-kB pathway, most notably TNFAIP3
    which encodes the negative regulator A20, converge with KLF2 loss and
    stabilized NOTCH2 to drive constitutive nuclear NF-kB activity. This is the
    shared effector node across marginal zone lymphomas: MALT lymphoma reaches
    it through the BCL10-MALT1 translocations, SMZL through mutation of the same
    pathway's regulators. Sequencing of marginal zone lymphoma treated with a
    BTK inhibitor found NF-kB, NOTCH, or B-cell receptor pathway genes involved
    in the large majority of cases, confirming that these three inputs form one
    convergent signaling module. Constitutive NF-kB output sustains
    proliferation and suppresses apoptosis without continued antigenic
    stimulation, which is why advanced disease no longer regresses when the
    antigenic driver is removed.
  evidence:
  - reference: PMID:36947202
    reference_title: "Molecular associations of response to the new-generation BTK inhibitor zanubrutinib in marginal zone lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NF-κB, NOTCH, or B-cell receptor (BCR) pathway genes were implicated in samples from 16 of 18 patients (89%)."
    explanation: Whole-exome sequencing of marginal zone lymphoma shows the NF-kB, NOTCH, and B-cell receptor pathways are involved in the large majority of cases.
  - reference: PMID:22891273
    reference_title: "The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "given the availability of drugs that can target NOTCH, NF-κB, and other pathways deregulated in this disease"
    explanation: Identifies NF-kB as one of the pathways deregulated in SMZL and therapeutically targetable; indirect support since the paper's primary finding concerns NOTCH2.
  cell_types:
  - preferred_term: marginal zone B cell of spleen
    term:
      id: CL:0000845
      label: marginal zone B cell of spleen
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    modifier: INCREASED
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  - preferred_term: B cell proliferation
    modifier: INCREASED
    term:
      id: GO:0042100
      label: B cell proliferation
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
  downstream:
  - target: Splenic White Pulp Infiltration and Hypersplenism
    description: >-
      The expanded clone colonizes and expands the splenic white pulp, then
      spills into marrow and blood.
- name: Splenic White Pulp Infiltration and Hypersplenism
  description: >-
    The lymphoma clone expands the splenic white pulp in a characteristic
    micronodular pattern, effacing normal follicular architecture and spilling
    into the red pulp. The enlarging spleen sequesters and destroys circulating
    blood cells, producing cytopenias out of proportion to marrow reserve.
    Marrow involvement is reported in nodular, interstitial, and intrasinusoidal
    patterns, and the tumor cells circulate as villous lymphocytes, the feature
    that gave the disease its older name of splenic lymphoma with villous
    lymphocytes. Because a substantial share of the
    cytopenia is mechanical, removing the spleen historically corrected the
    blood counts without eradicating the lymphoma.
  evidence:
  - reference: PMID:23712547
    reference_title: "Significant efficacy of 2-chlorodeoxyadenosine{+/-} rituximab in the treatment of splenic marginal zone lymphoma (SMZL): extended follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It presents with marked splenomegaly."
    explanation: Confirms marked splenomegaly as the characteristic presentation produced by splenic infiltration.
  - reference: PMID:22891276
    reference_title: "Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level."
    explanation: Confirms the spleen as the defining primary site of disease involvement.
  - reference: PMID:8652403
    reference_title: "Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SLVL is a chronic B-cell lymphoproliferative disorder characterized by splenomegaly and the presence, in peripheral blood, of lymphocytes with \"villous' projections."
    explanation: A 100-patient clinical series defines the disease by the pairing of splenomegaly with circulating villous lymphocytes, the two consequences of splenic infiltration and spillover.
  cell_types:
  - preferred_term: marginal zone B cell of spleen
    term:
      id: CL:0000845
      label: marginal zone B cell of spleen
  locations:
  - preferred_term: marginal zone of spleen
    term:
      id: UBERON:0001251
      label: marginal zone of spleen
  - preferred_term: white pulp of spleen
    term:
      id: UBERON:0001959
      label: white pulp of spleen
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  downstream:
  - target: Cytopenias and Autoimmune Complications
    description: >-
      Splenic sequestration combines with lymphoma-associated autoantibody
      production to produce anemia and thrombocytopenia.
- name: Cytopenias and Autoimmune Complications
  description: >-
    Anemia and thrombocytopenia in SMZL arise from two superimposed mechanisms:
    mechanical sequestration by the enlarged spleen, and true autoimmune
    destruction. The lymphoma clone and the dysregulated B-cell compartment
    around it generate autoantibodies, so autoimmune hemolytic anemia and immune
    thrombocytopenia are recognized paraneoplastic complications rather than
    incidental findings. This dual mechanism matters clinically because it
    separates patients whose counts respond to splenectomy or to
    lymphoma-directed therapy from those who require immunosuppression.
  evidence:
  - reference: PMID:25201005
    reference_title: "Lupus anticoagulant and thrombosis in splenic marginal zone lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "immune mediated paraneoplastic phenomena such as autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common"
    explanation: Establishes autoimmune hemolytic anemia and immune thrombocytopenia as common immune-mediated paraneoplastic phenomena in SMZL.
  notes: >-
    No biological_processes term is bound to this node deliberately. The two
    operative mechanisms here are splenic sequestration and antibody-mediated
    destruction, neither of which is apoptosis; binding GO:0006915 apoptotic
    process would be a close-enough term rather than an accurate one.
phenotypes:
- category: Clinical
  name: Splenomegaly
  description: >-
    Splenomegaly is the defining clinical feature, frequently marked and often
    the presenting complaint.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:23712547
    reference_title: "Significant efficacy of 2-chlorodeoxyadenosine{+/-} rituximab in the treatment of splenic marginal zone lymphoma (SMZL): extended follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It presents with marked splenomegaly."
    explanation: Directly states that SMZL presents with marked splenomegaly.
  - reference: PMID:8652403
    reference_title: "Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SLVL is a chronic B-cell lymphoproliferative disorder characterized by splenomegaly and the presence, in peripheral blood, of lymphocytes with \"villous' projections."
    explanation: A 100-patient series characterizes the disease by splenomegaly, independently confirming it as the defining clinical feature.
- category: Laboratory
  name: Lymphocytosis with Villous Lymphocytes
  description: >-
    Peripheral blood involvement by circulating clonal B cells bearing short
    polar cytoplasmic projections, the villous lymphocytes behind the older
    designation splenic lymphoma with villous lymphocytes. Note that an absolute
    lymphocytosis is not universal, so the villous morphology rather than the
    lymphocyte count is the diagnostic feature.
  phenotype_term:
    preferred_term: Increased total lymphocyte count
    term:
      id: HP:0100827
      label: Increased total lymphocyte count
  evidence:
  - reference: PMID:8652403
    reference_title: "Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SLVL is a chronic B-cell lymphoproliferative disorder characterized by splenomegaly and the presence, in peripheral blood, of lymphocytes with \"villous' projections."
    explanation: A 100-patient series establishes circulating villous lymphocytes in peripheral blood as a defining feature of the disease.
  - reference: PMID:8652403
    reference_title: "Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC)."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The cytological diagnosis can be difficult in patients without an absolute lymphocytosis"
    explanation: Qualifies the lymphocytosis claim by noting that some patients lack an absolute lymphocytosis, which is why no frequency band is asserted for this phenotype.
- category: Laboratory
  name: Anemia
  description: >-
    Anemia arising from splenic sequestration, marrow infiltration, or
    autoimmune hemolysis.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:25201005
    reference_title: "Lupus anticoagulant and thrombosis in splenic marginal zone lymphoma."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common"
    explanation: Supports anemia in SMZL via its autoimmune hemolytic mechanism; the mechanical sequestration contribution is not quantified in this source.
- category: Laboratory
  name: Thrombocytopenia
  description: >-
    Thrombocytopenia due to hypersplenic platelet sequestration and, in a
    subset of patients, immune-mediated platelet destruction.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:25201005
    reference_title: "Lupus anticoagulant and thrombosis in splenic marginal zone lymphoma."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common"
    explanation: Supports thrombocytopenia in SMZL via its immune-mediated mechanism; the hypersplenic contribution is not quantified in this source.
- category: Clinical
  name: Autoimmune Hemolytic Anemia
  description: >-
    Autoimmune hemolytic anemia is a recognized paraneoplastic immune
    complication of SMZL, reflecting autoantibody production by the
    dysregulated B-cell compartment.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:25201005
    reference_title: "Lupus anticoagulant and thrombosis in splenic marginal zone lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "immune mediated paraneoplastic phenomena such as autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common"
    explanation: Directly identifies autoimmune hemolytic anemia as a relatively common paraneoplastic phenomenon in SMZL.
- category: Clinical
  name: Immune Thrombocytopenia
  description: >-
    Autoimmune thrombocytopenia occurs in a subset of patients and is
    mechanistically distinct from the mechanical thrombocytopenia of
    hypersplenism.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:25201005
    reference_title: "Lupus anticoagulant and thrombosis in splenic marginal zone lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "immune mediated paraneoplastic phenomena such as autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common"
    explanation: Directly identifies autoimmune thrombocytopenia as a relatively common paraneoplastic phenomenon in SMZL.
genetic:
- name: NOTCH2 Mutation
  gene_term:
    preferred_term: NOTCH2
    term:
      id: hgnc:7882
      label: NOTCH2
  association: Recurrent Somatic Driver
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    Truncating mutations cluster in the C-terminal PEST degron and eliminate the
    proteasomal degradation signal, stabilizing activated NOTCH2. Because NOTCH2
    is required for marginal zone B-cell development, this is a lesion in the
    lineage-identity program itself. NOTCH2 mutation is restricted to SMZL among
    indolent B-cell lymphoproliferative disorders, giving it diagnostic value.
  case_fractions:
  - population: SMZL cohorts pooled in a 2024 molecular-landscape review
    case_fraction_low: 10
    case_fraction_high: 25
    notes: >-
      Reported as 10-25% of SMZL cases across pooled cohorts.
    evidence:
    - reference: PMID:39280243
      reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "KLF2 (12–42%), NOTCH2 (10–25%), and TP53 (15%) are among the most frequently mutated genes"
      explanation: Gives the NOTCH2 share of SMZL cases alongside the other recurrently mutated genes.
  evidence:
  - reference: PMID:22891273
    reference_title: "The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in NOTCH2, a gene required for marginal-zone (MZ) B cell development, represent the most frequent lesion in SMZL"
    explanation: Establishes NOTCH2 as the most frequent genetic lesion in SMZL and links it to marginal zone B-cell development.
  - reference: PMID:22891273
    reference_title: "The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All NOTCH2 mutations are predicted to cause impaired degradation of the NOTCH2 protein by eliminating the C-terminal PEST domain, which is required for proteasomal recruitment."
    explanation: Specifies the molecular consequence of the PEST-domain mutations as impaired proteasomal degradation of NOTCH2.
  - reference: PMID:22891276
    reference_title: "Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation"
    explanation: Independently confirms the PEST-domain clustering and truncating nature of the NOTCH2 mutations.
- name: KLF2 Mutation
  gene_term:
    preferred_term: KLF2
    term:
      id: hgnc:6347
      label: KLF2
  association: Recurrent Somatic Driver
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    KLF2 is the most frequently mutated gene in SMZL. It is a transcription
    factor that restrains NF-kB and NOTCH signaling in mature B cells;
    inactivation removes this brake and promotes nuclear NF-kB accumulation.
    Note that the mechanistic characterisation rests on murine knockout B cells,
    so the human mechanism is inferred from a model system even though the
    mutation frequency itself is human.
  case_fractions:
  - population: SMZL cohorts pooled in a 2024 molecular-landscape review
    case_fraction_low: 12
    case_fraction_high: 42
    notes: >-
      Reported as 12-42% of SMZL cases; the wide band reflects heterogeneity between cohorts.
    evidence:
    - reference: PMID:39280243
      reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "KLF2 12–42% Most frequent mutation in SMZL"
      explanation: Gives the KLF2 share of SMZL cases and identifies it as the most frequent mutation in the disease.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways"
    explanation: Establishes KLF2 as one of the recurrently mutated genes defining the SMZL mutational landscape.
- name: TNFAIP3 Mutation
  gene_term:
    preferred_term: TNFAIP3
    term:
      id: hgnc:11896
      label: TNFAIP3
  association: Recurrent Somatic Mutation
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  notes: >-
    TNFAIP3 encodes A20, a negative regulator of NF-kB, and is mutated in
    7-15% of SMZL. Specificity caveat: the mutation frequency is
    SMZL-specific, but the mechanistic claim that loss of A20 releases the
    NF-kB cascade is extrapolated. The source review states the functional
    consequence was shown "in other NHLs", and the supporting BTK-inhibitor
    cohort spans marginal zone lymphoma subtypes rather than SMZL alone. The
    driver role in SMZL specifically should be treated as probable rather than
    demonstrated.
  case_fractions:
  - population: SMZL cohorts pooled in a 2024 molecular-landscape review
    case_fraction_low: 7.0
    case_fraction_high: 15.0
    notes: >-
      Reported as 7-15% of SMZL cases in the review's recurrent-mutation table.
    evidence:
    - reference: PMID:39280243
      reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "TNFAIP3 7–15% Mutations resulted in a loss of NF-κB cascade inhibition in other NHLs."
      explanation: Gives the SMZL-specific TNFAIP3 mutation frequency and, in the same row, attributes the NF-kB mechanism to other NHLs rather than to SMZL.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "TNFAIP3 7–15% Mutations resulted in a loss of NF-κB cascade inhibition in other NHLs."
    explanation: Supports recurrent TNFAIP3 mutation in SMZL; marked PARTIAL because the same sentence attributes the NF-kB functional consequence to other non-Hodgkin lymphomas, not to SMZL.
  - reference: PMID:36947202
    reference_title: "Molecular associations of response to the new-generation BTK inhibitor zanubrutinib in marginal zone lymphoma."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "MYD88, TNFAIP3, and KMT2D mutations correlate with PFS in patients with relapsed/refractory MZL treated with zanubrutinib."
    explanation: Shows TNFAIP3 is prognostically relevant under BTK inhibition; marked PARTIAL because the cohort spans marginal zone lymphoma subtypes rather than SMZL specifically.
- name: Deletion of Chromosome 7q
  association: Most Frequent Cytogenetic Lesion
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    Deletion of the long arm of chromosome 7, most often 7q31-32, is the single
    most frequent recurrent lesion in SMZL, more common than any individual
    point-mutated gene. No gene_term is bound because the lesion is a
    multi-gene chromosomal region rather than a single gene; the minimally
    deleted region removes both coding genes and microRNAs, and no single
    driver within it has been established. Together with IGHV1-2*04 usage it is
    one of the two strongest diagnostic pointers for SMZL.
  case_fractions:
  - population: SMZL cohorts pooled in a 2024 molecular-landscape review
    case_fraction_percent: 40.0
    notes: >-
      Reported as approximately 40% of SMZL cases.
    evidence:
    - reference: PMID:39280243
      reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "del(7q) (approximately 40% cases)"
      explanation: Gives the del(7q) share of SMZL cases.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7"
    explanation: Establishes deletion of chromosome 7q as the recurrent cytogenetic abnormality of SMZL.
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IGHV1-2*04 and/or del(7q) are very strong pointers for the diagnosis of SMZL"
    explanation: Establishes del(7q) as one of the two strongest diagnostic pointers for SMZL.
- name: TP53 Disruption
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Adverse Prognostic Lesion
  relationship_type: MODIFIER
  variant_origin: SOMATIC
  notes: >-
    TP53 is among the recurrently mutated genes in SMZL and is associated with
    inferior outcome and with histological transformation to large cell
    lymphoma.
  case_fractions:
  - population: SMZL cohorts pooled in a 2024 molecular-landscape review
    case_fraction_percent: 15.0
    notes: >-
      Reported as 15% of SMZL cases; a flowchart caption in the same review gives 10-15%.
    evidence:
    - reference: PMID:39280243
      reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "KLF2 (12–42%), NOTCH2 (10–25%), and TP53 (15%) are among the most frequently mutated genes"
      explanation: Gives the TP53 share of SMZL cases.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways"
    explanation: Establishes TP53 as one of the three recurrently mutated genes in the SMZL landscape.
prevalence:
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.13
  notes: >-
    Reported annual incidence of 0.13 per 100,000 individuals, i.e. 1.3 per
    million, placing SMZL in the 1-9 per million band.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with an incidence rate of 0.13 per 100,000 individuals per year"
    explanation: Gives the annual incidence of SMZL as a population rate.
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    SMZL accounts for fewer than 2% of lymphoid neoplasms. This is a case-mix
    fraction among lymphoid malignancies rather than a population rate, so no
    normalized rate per 100,000 is recorded.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Splenic marginal zone lymphoma (SMZL) is a rare, predominantly indolent B-cell lymphoma constituting fewer than 2% of lymphoid neoplasms."
    explanation: Provides the share of lymphoid neoplasms accounted for by SMZL and characterizes the disease as rare.
progression:
- phase: Indolent phase
  notes: >-
    Most patients follow a prolonged indolent course. A substantial minority,
    however, have materially shorter survival despite available treatment,
    which is why risk stratification rather than uniform therapy governs
    management.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "around 30% of patients have a shorter survival despite currently available treatments"
    explanation: Quantifies the minority of SMZL patients whose disease does not follow the expected indolent course.
  - reference: PMID:8652403
    reference_title: "Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SLVL is a disease of the elderly with a relatively benign clinical course."
    explanation: Characterizes the typical course as indolent and establishes the older adult age distribution.
  - reference: PMID:8652403
    reference_title: "Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the present series the 5-year overall survival was 78%."
    explanation: Quantifies survival in a 100-patient series, giving a concrete measure of the indolent course.
- phase: Histological transformation to large cell lymphoma
  notes: >-
    A minority of cases undergo histological transformation to a large cell
    lymphoma, which carries a markedly worse prognosis and represents the main
    lethal endpoint of the disease. The source review is internally
    inconsistent on the rate: its abstract and body give 5-15%, while Table 1
    gives 10-20% into DLBCL. Both figures are recorded rather than silently
    reconciled, the same treatment applied to the KLF2 case-fraction
    discrepancy.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the prognosis is especially poor for the 5-15% of cases that transform to a large cell lymphoma"
    explanation: Quantifies the transformation rate and its prognostic impact, per the review's abstract and body text.
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Transformation 10–20% into DLBCL"
    explanation: Table 1 of the same review gives a higher transformation rate than its body text; recorded as PARTIAL to make the intra-paper discrepancy explicit rather than picking one figure.
treatments:
- name: Observation
  description: >-
    Asymptomatic patients with low-risk disease can be managed expectantly. A
    prospective study of a risk-adapted strategy found observation to be the
    best approach for the lowest-risk group, making watchful waiting an
    evidence-based option rather than merely a default.
  evidence:
  - reference: PMID:37386877
    reference_title: "Low-risk HPLLs/ABC score patients with splenic marginal zone lymphoma can be safely managed without treatment: Results from a prospective Spanish study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "observation as the best approach for patients in group A and rituximab as the best treatment for group B"
    explanation: Prospective multicenter study supports observation for the lowest-risk SMZL group.
  - reference: PMID:8652403
    reference_title: "Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment abstention should be considered in patients with favourable prognostic factors"
    explanation: An earlier 100-patient series independently reached the same conclusion that untreated observation is appropriate for favourable-risk patients.
- name: Rituximab
  description: >-
    Anti-CD20 monoclonal antibody, now the preferred first-line therapy for
    symptomatic SMZL. In a prospective multicenter series, rituximab-containing
    arms achieved a higher overall response rate than splenectomy.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  evidence:
  - reference: PMID:37386877
    reference_title: "Low-risk HPLLs/ABC score patients with splenic marginal zone lymphoma can be safely managed without treatment: Results from a prospective Spanish study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall response rate was higher in the rituximab chemotherapy and in the rituximab arms compared with the splenectomy arm"
    explanation: Prospective multicenter data show rituximab-containing therapy outperforms splenectomy on overall response rate.
  - reference: PMID:37386877
    reference_title: "Low-risk HPLLs/ABC score patients with splenic marginal zone lymphoma can be safely managed without treatment: Results from a prospective Spanish study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "observation as the best approach for patients in group A and rituximab as the best treatment for group B"
    explanation: Identifies rituximab as the preferred treatment for the risk group requiring therapy.
- name: Splenectomy
  description: >-
    Surgical removal of the spleen, the historical first-line treatment and
    still an option in patients fit for surgery. It corrects the mechanical
    cytopenias and relieves mass effect but does not eradicate the lymphoma, and
    has been largely superseded by rituximab on response-rate grounds.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  evidence:
  - reference: PMID:23712547
    reference_title: "Significant efficacy of 2-chlorodeoxyadenosine{+/-} rituximab in the treatment of splenic marginal zone lymphoma (SMZL): extended follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Splenectomy remains one of the first-line options in patients fit for surgery."
    explanation: Confirms splenectomy as an established first-line option for surgically fit SMZL patients.
  - reference: PMID:37386877
    reference_title: "Low-risk HPLLs/ABC score patients with splenic marginal zone lymphoma can be safely managed without treatment: Results from a prospective Spanish study."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall response rate was higher in the rituximab chemotherapy and in the rituximab arms compared with the splenectomy arm"
    explanation: Supports the displacement of splenectomy by rituximab on response rate, though lymphoma-specific survival did not differ by treatment received.
  target_mechanisms:
  - target: Splenic White Pulp Infiltration and Hypersplenism
    description: >-
      Splenectomy removes the sequestering organ, correcting the mechanical
      component of the cytopenias.
- name: Hepatitis C Antiviral Therapy
  description: >-
    In hepatitis C virus-associated SMZL, therapy directed at the virus rather
    than at the lymphoma can induce hematologic response. This is the splenic
    counterpart of Helicobacter pylori eradication in gastric MALT lymphoma and
    is the strongest therapeutic evidence for the antigen-driven model of
    marginal zone lymphomagenesis.
  treatment_term:
    preferred_term: Antiviral Therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
  evidence:
  - reference: PMID:25273531
    reference_title: "Non-Hodgkin lymphoma and hepatitis C: where we are and what next?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interferon and ribavirin based treatment proved to be successful in small case series of hepatitis C virus associated splenic lymphoma with villous lymphocytes, therefore, it is suggested that antiviral treatment could be an alternative to chemo-immunotherapy."
    explanation: Documents lymphoma response to antiviral therapy in hepatitis C virus-associated splenic lymphoma with villous lymphocytes.
  - reference: PMID:25273531
    reference_title: "Non-Hodgkin lymphoma and hepatitis C: where we are and what next?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The association between hepatitis C virus and certain B-cell non-Hodgkin lymphomas, such as marginal zone lymphomas, is supported by epidemiological studies."
    explanation: Establishes the epidemiological basis for the hepatitis C virus association that makes antiviral therapy rational.
  target_mechanisms:
  - target: Chronic Antigenic Stimulation of Splenic Marginal Zone B Cells
    description: >-
      Clearing the virus removes the chronic antigenic drive sustaining the
      clone, the same logic as Helicobacter pylori eradication in gastric MALT
      lymphoma.
- name: Bruton Tyrosine Kinase Inhibition
  description: >-
    BTK inhibitors block B-cell receptor signal transmission upstream of NF-kB.
    Zanubrutinib is used for relapsed or refractory marginal zone lymphoma after
    anti-CD20 therapy, and mutations in NF-kB pathway genes are associated with
    the response.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: zanubrutinib
      term:
        id: NCIT:C141428
        label: Zanubrutinib
  evidence:
  - reference: PMID:36947202
    reference_title: "Molecular associations of response to the new-generation BTK inhibitor zanubrutinib in marginal zone lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYD88, TNFAIP3, and KMT2D mutations correlate with PFS in patients with relapsed/refractory MZL treated with zanubrutinib."
    explanation: Establishes zanubrutinib use in relapsed or refractory marginal zone lymphoma and links NF-kB pathway genotype to progression-free survival.
  - reference: PMID:36947202
    reference_title: "Molecular associations of response to the new-generation BTK inhibitor zanubrutinib in marginal zone lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NF-κB, NOTCH, or B-cell receptor (BCR) pathway genes were implicated in samples from 16 of 18 patients (89%)."
    explanation: Provides the mechanistic rationale for BTK inhibition by showing B-cell receptor and NF-kB pathway involvement in the large majority of cases.
  target_mechanisms:
  - target: Constitutive NF-kB Pathway Activation
    description: >-
      BTK inhibition interrupts B-cell receptor signal transmission into the
      NF-kB pathway.
- name: Cladribine with or without Rituximab
  description: >-
    Cladribine (2-chlorodeoxyadenosine), a purine analog, given alone or with an
    anti-CD20 antibody, is an effective pharmacological option for patients who
    are poor surgical candidates. An extended-follow-up series of 50 SMZL
    patients reported an 87% overall response rate and 80% five-year
    progression-free survival.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cladribine
      term:
        id: CHEBI:567361
        label: cladribine
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  evidence:
  - reference: PMID:23712547
    reference_title: "Significant efficacy of 2-chlorodeoxyadenosine{+/-} rituximab in the treatment of splenic marginal zone lymphoma (SMZL): extended follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty SMZL patients were treated with Cladribine"
    explanation: Establishes the treated SMZL cohort for this regimen.
  - reference: PMID:23712547
    reference_title: "Significant efficacy of 2-chlorodeoxyadenosine{+/-} rituximab in the treatment of splenic marginal zone lymphoma (SMZL): extended follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ORR was 87%"
    explanation: Quantifies the overall response rate of cladribine-based therapy in SMZL.
  - reference: PMID:23712547
    reference_title: "Significant efficacy of 2-chlorodeoxyadenosine{+/-} rituximab in the treatment of splenic marginal zone lymphoma (SMZL): extended follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After a median follow-up of 48 months, 7 of 41 responsive cases relapsed and the 5-year PFS was 80%."
    explanation: Quantifies durability of response with 5-year progression-free survival.
diagnosis:
- name: Immunophenotyping
  description: >-
    Diagnosis is made by combining clinical findings, lymphocyte morphology,
    bone marrow histology, and immunophenotype, because splenectomy is now
    rarely performed for diagnostic purposes. The characteristic profile is a
    CD20-positive clonal B-cell population lacking the markers that define the
    principal mimics, so the diagnosis is substantially one of exclusion by
    marker panel.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "diagnosis is usually based on a combination of clinical findings, lymphocyte morphology, bone marrow histology, immunohistochemical and immunophenotypic features"
    explanation: States the composite basis on which SMZL is diagnosed in the absence of splenic histology.
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The typical immunophenotype includes surface expression of IgM, CD20, CD27, CD49d, and variable expression of IgD, CD5, CD11c, and CD25"
    explanation: Gives the positive arm of the diagnostic immunophenotype.
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lack of expression of CD103, CD123, annexin A1, and cyclin D1 serve to distinguish SMZL from other splenic lymphomas"
    explanation: Gives the exclusionary arm of the panel, the markers whose absence separates SMZL from hairy cell leukemia and mantle cell lymphoma.
  - reference: PMID:8652403
    reference_title: "Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "B-cells expressed CD19+, CD20+, CD22+, CD24+ and DBA44+, whereas the expression of CD5, CD10 and CD25 was usually negative."
    explanation: Independent 100-patient series giving the concordant B-cell marker profile.
differential_diagnoses:
- name: Hairy cell leukemia
  description: >-
    The classic mimic: also presents with splenomegaly and cytopenias, and its
    cells also have cytoplasmic projections. Distinguished by annexin A1, CD103
    and CD123 expression (absent in SMZL) and by BRAF mutation.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYD88 for WM, BRAF for HCL, NOTCH1 and SF3B1 for CLL, PTPRD for NMZL, and MAP2K1 for HCL-V"
    explanation: Gives BRAF as the molecular discriminator separating hairy cell leukemia from SMZL.
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lack of expression of CD103, CD123, annexin A1, and cyclin D1 serve to distinguish SMZL from other splenic lymphomas"
    explanation: Gives the immunophenotypic discriminators; annexin A1, CD103 and CD123 are hairy cell leukemia markers absent in SMZL.
- name: Hairy cell leukemia variant
  description: >-
    A separate entity from classic hairy cell leukemia, distinguished from SMZL
    by MAP2K1 mutation.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYD88 for WM, BRAF for HCL, NOTCH1 and SF3B1 for CLL, PTPRD for NMZL, and MAP2K1 for HCL-V"
    explanation: Gives MAP2K1 as the molecular discriminator for hairy cell leukemia variant.
- name: Waldenstrom macroglobulinemia
  description: >-
    Overlaps with SMZL in its IgM paraproteinemia and marrow involvement;
    distinguished by MYD88 mutation.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYD88 for WM, BRAF for HCL, NOTCH1 and SF3B1 for CLL, PTPRD for NMZL, and MAP2K1 for HCL-V"
    explanation: Gives MYD88 as the molecular discriminator for Waldenstrom macroglobulinemia.
- name: Chronic lymphocytic leukemia
  description: >-
    Shares the indolent clonal B-cell lymphocytosis; distinguished by CD5
    expression and by NOTCH1 and SF3B1 mutation.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYD88 for WM, BRAF for HCL, NOTCH1 and SF3B1 for CLL, PTPRD for NMZL, and MAP2K1 for HCL-V"
    explanation: Gives NOTCH1 and SF3B1 as the molecular discriminators for chronic lymphocytic leukemia.
- name: Nodal marginal zone lymphoma
  description: >-
    The nodal sibling within the marginal zone family; distinguished from SMZL
    by PTPRD mutation and by its nodal rather than splenic distribution.
  evidence:
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYD88 for WM, BRAF for HCL, NOTCH1 and SF3B1 for CLL, PTPRD for NMZL, and MAP2K1 for HCL-V"
    explanation: Gives PTPRD as the molecular discriminator for nodal marginal zone lymphoma.
- name: Splenic diffuse red pulp small B-cell lymphoma
  description: >-
    A rare splenic B-cell lymphoma that infiltrates red pulp diffusely rather
    than forming the micronodular white pulp lesions of SMZL. The CD200/CD180
    fluorescence ratio assists separation.
  evidence:
  - reference: PMID:19575895
    reference_title: "[Clinicopathologic study of splenic marginal zone B-cell lymphoma]."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The differential diagnosis includes other small B-cell lymphomas and lymphoid hyperplasia of spleen."
    explanation: Establishes that other small B-cell lymphomas of the spleen are the differential; PARTIAL because this source does not name this entity individually.
  - reference: PMID:39280243
    reference_title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the CD200/CD180 median fluorescence (MFI) ratio may help to distinguish SDRPL diagnosis over HCL, SMZL, and SBLPN, where a ratio of 0.5 or less is in favour of SDRPL"
    explanation: Gives the specific flow-cytometric discriminator separating SDRPL from SMZL, with its decision threshold.
histopathology:
- name: Micronodular white pulp expansion
  diagnostic: true
  description: >-
    The lymphoma expands the splenic white pulp as micronodular lesions, the
    architectural hallmark of the disease on splenic histology.
  evidence:
  - reference: PMID:19575895
    reference_title: "[Clinicopathologic study of splenic marginal zone B-cell lymphoma]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all of the 8 cases showed micronodular white pulp lesions"
    explanation: All cases in an 8-patient clinicopathologic series showed the micronodular white pulp pattern.
- name: Biphasic nodule architecture
  description: >-
    Nodules classically show a biphasic structure: a central aggregate of small
    B cells surrounded by a peripheral rim of atypical monocytoid B cells. A
    minority of cases are monomorphous instead.
  evidence:
  - reference: PMID:19575895
    reference_title: "[Clinicopathologic study of splenic marginal zone B-cell lymphoma]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six of them exhibited the classic biphasic appearance with central aggregates of small B cells rimmed by a peripheral zone of atypical monocytoid B cells."
    explanation: Six of eight cases showed the classic biphasic nodule architecture.
- name: Red pulp infiltration
  description: >-
    Beyond the white pulp nodules, tumor cells infiltrate the red pulp in
    sheets.
  evidence:
  - reference: PMID:19575895
    reference_title: "[Clinicopathologic study of splenic marginal zone B-cell lymphoma]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was infiltration of tumor cells in the red pulp, sheets in appearance in all 8 cases."
    explanation: All eight cases showed sheet-like red pulp infiltration in addition to the white pulp lesions.
- name: Low proliferation index
  description: >-
    Ki-67 immunostaining shows a low proliferation index, consistent with the
    indolent clinical behavior of the disease.
  evidence:
  - reference: PMID:19575895
    reference_title: "[Clinicopathologic study of splenic marginal zone B-cell lymphoma]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proliferation index, as highlighted by Ki-67 immunostaining, was low"
    explanation: Documents the low Ki-67 proliferation index that matches the indolent course.
- name: Intrasinusoidal bone marrow infiltration
  description: >-
    Marrow involvement is described in nodular, interstitial, and
    intrasinusoidal patterns. The intrasinusoidal component is often cited as
    characteristic of SMZL, but the supporting evidence available here is a
    single case report, so the finding is recorded without a frequency and
    without a diagnostic flag.
  evidence:
  - reference: PMID:28892912
    reference_title: "Important Diagnostic Clues for Diagnosing Splenic Marginal Zone Lymphoma in Absence of Splenic Histology."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "tumour cells in nodular, interstitial and intrasinusoidal pattern of infiltration"
    explanation: Documents the intrasinusoidal marrow pattern; marked PARTIAL because this is a single case report and cannot establish how characteristic the pattern is.
classifications:
  icdo_morphology:
    classification_value: Lymphoma
clinical_trials:
- name: NCT03846427
  phase: PHASE_II
  status: COMPLETED
  description: >-
    MAGNOLIA (BGB-3111-214), a single-arm phase II study of the next-generation
    BTK inhibitor zanubrutinib in relapsed or refractory marginal zone lymphoma,
    the trial supporting BTK inhibition in this disease. Enrolment spans
    marginal zone lymphoma subtypes rather than SMZL alone.
  evidence:
  - reference: clinicaltrials:NCT03846427
    supports: SUPPORT
    snippet: "This is a single arm study to evaluate the efficacy, safety and tolerability of zanubrutinib (BGB-3111) in participants with relapsed/refractory marginal zone lymphoma (R/R MZL)."
    explanation: ClinicalTrials.gov summary confirms the design and population of the MAGNOLIA trial.
  - reference: PMID:34526366
    reference_title: "The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%"
    explanation: Reports the primary efficacy outcome of the MAGNOLIA trial.
references:
- reference: PMID:39280243
  title: "The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications."
- reference: PMID:22891273
  title: "The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development."
- reference: PMID:22891276
  title: "Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma."
- reference: PMID:8652403
  title: "Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC)."
- reference: PMID:19575895
  title: "[Clinicopathologic study of splenic marginal zone B-cell lymphoma]."
- reference: PMID:34526366
  title: "The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma."

📚

References & Deep Research

References

6

PMID:39280243

The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications.

No top-level findings curated for this source.

PMID:22891273

The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development.

No top-level findings curated for this source.

PMID:22891276

Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma.

No top-level findings curated for this source.

PMID:8652403

Splenic lymphoma with villous lymphocytes: clinical presentation, biology and prognostic factors in a series of 100 patients. Groupe Francais d'Hématologie Cellulaire (GFHC).

No top-level findings curated for this source.

PMID:19575895

[Clinicopathologic study of splenic marginal zone B-cell lymphoma].

No top-level findings curated for this source.

PMID:34526366

The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma.

No top-level findings curated for this source.

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1

Claude Code ▸

Two corrections to Appendix A while I'm here:

claude-haiku-4-5-20251001, claude-opus-5[1m] 2026-07-31T15:38:46.955618

The background OAK lookup died partway through (it was still pulling down the UBERON/GO sqlite files and got cut off), but it coughed up its UBERON half before it went. One real addition for the report:

Newly verified ✅ — UBERON:0001959 white pulp of spleen. That's a good one to have, since the white pulp is exactly where SMZL sets up — worth using on the anatomical nodes alongside UBERON:0002106 spleen.

Two corrections to Appendix A while I'm here: - UBERON:0001969 in my table is blood plasma, not white pulp — I pulled it from the cache grep and it's fine as a label, just not a term you want for this entry. - UBERON:0002370 is thymus. It was in my verification batch as a control-ish lookup and doesn't belong anywhere in an SMZL entry. Ignore it.

Still unverified, same as I flagged: the marginal zone of spleen UBERON term (the search timed out both times), plus red pulp and splenic hilar lymph node. The GO half of the job never ran at all — but that's a non-issue, since all eight GO terms in Appendix A came from the repo's own cache/go/, which is a stronger check anyway.

Nothing else in the report changes.

Splenic Marginal Zone Lymphoma

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