Hepatosplenic T-cell lymphoma (HSTCL) is a rare and clinically aggressive mature T-cell non-Hodgkin lymphoma of cytotoxic T cells, usually bearing the gamma/delta T-cell receptor and most often the V-delta-1 subset. It is defined by where it grows rather than by a mass: neoplastic cells home to the sinusoidal compartments of spleen, liver and bone marrow, packing the splenic cords of Billroth and the hepatic sinusoids, while lymphadenopathy is characteristically absent. The genetic landscape is dominated by two cooperating classes of lesion - activating JAK-STAT mutations, chiefly in STAT5B, and loss of chromatin-modifying genes, of which SETD2 is the most frequently silenced and has been shown experimentally to act as a tumor suppressor. Isochromosome 7q is the characteristic cytogenetic abnormality. A substantial minority of cases arise on a background of chronic therapeutic immunosuppression, classically combined thiopurine and anti-TNF therapy for inflammatory bowel disease in young men, though population series show the association is neither necessary nor confined to that group. Outcome is poor, with median overall survival close to a year.
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name: Hepatosplenic T-cell Lymphoma
creation_date: "2026-09-10T01:15:12Z"
category: Cancer
categories:
- Hematologic Malignancy
- T-cell Neoplasm
synonyms:
- HSTCL
- HSTL
- Hepatosplenic gamma/Delta T-cell lymphoma
- hepatosplenic gamma-delta T-cell lymphoma
description: >-
Hepatosplenic T-cell lymphoma (HSTCL) is a rare and clinically aggressive mature
T-cell non-Hodgkin lymphoma of cytotoxic T cells, usually bearing the gamma/delta
T-cell receptor and most often the V-delta-1 subset. It is defined by where it
grows rather than by a mass: neoplastic cells home to the sinusoidal compartments
of spleen, liver and bone marrow, packing the splenic cords of Billroth and the
hepatic sinusoids, while lymphadenopathy is characteristically absent. The
genetic landscape is dominated by two cooperating classes of lesion - activating
JAK-STAT mutations, chiefly in STAT5B, and loss of chromatin-modifying genes, of
which SETD2 is the most frequently silenced and has been shown experimentally to
act as a tumor suppressor. Isochromosome 7q is the characteristic cytogenetic
abnormality. A substantial minority of cases arise on a background of chronic
therapeutic immunosuppression, classically combined thiopurine and anti-TNF
therapy for inflammatory bowel disease in young men, though population series
show the association is neither necessary nor confined to that group. Outcome is
poor, with median overall survival close to a year.
disease_term:
preferred_term: hepatosplenic T-cell lymphoma
term:
id: MONDO:0019474
label: hepatosplenic T-cell lymphoma
parents:
- T-cell non-Hodgkin lymphoma
notes: >-
Scope and granularity. This is curated as a Disease entry at the histologic-entity
level, which design decisions section 3a makes the default for a new cancer entry.
The call is not automatic: MONDO:0019474 is a leaf whose only parent, MONDO:0015760
(T-cell non-Hodgkin lymphoma), is itself curated as Peripheral_T_Cell_Lymphoma.yaml
with six has_subtypes entries, so HSTCL could instead have been a seventh. It is
kept separate because all six of those subtypes are nodal entities of alpha/beta or
T-follicular-helper derivation, whereas HSTCL is an extranodal, sinusoidal,
predominantly gamma/delta neoplasm, and WHO treats it as its own entity rather than
a PTCL subtype. Adding it to that subtype list would have made the list incoherent.
The alpha/beta minority is deliberately not split off. Yabe and colleagues describe
the same clinicopathologic entity with T-cell receptor gamma/delta "or, less often,
alpha/beta", and the Mayo series reports both phenotypes within one cohort, so the
receptor type is recorded as a feature rather than as a subtype boundary.
EBV status. HSTCL is conventionally described as EBV-negative, and no EBV claim is
made in this entry. The one cited source that tests it is internally inconsistent
and should not be quoted from its abstract: that abstract states "In the 10 HSTCL
patients, Epstein-Barr virus (EBV) infection was confirmed", while the body of the
same paper reports EBV confirmed in 2 patients and says "only 2 out of 10 patients
showed signs of EBV infection, both presenting with hemophagocytic syndrome, which
complicates the determination of its relationship with the onset of malignancy".
The body is the accurate statement. Two of ten, both with hemophagocytic syndrome,
is too confounded to curate as a disease-level EBV association, so it is recorded
here rather than asserted.
Nodal disease. The characteristic absence of lymphadenopathy is load-bearing here -
it appears in the description, in the infiltration node and in the lump/split
argument - so the contrary evidence is recorded rather than left out. A 40-case
series cited throughout this entry reports lymph node enlargement in seven of its
ten index patients, and that item is curated as a REFUTE on the histopathology
claim. The same paper still describes nodal involvement as less common, so the
entry keeps the WHO characterisation and treats the series as a qualification.
One consequence is left explicit rather than silent. MONDO:0015760 does ontologically
subsume MONDO:0019474, and Peripheral_T_Cell_Lymphoma.yaml binds that term only as a
compromise - its own description records that MONDO lacks an exact family-level
peripheral T-cell lymphoma umbrella term. So the shared parent is an artifact of that
anchoring, not evidence the two concepts coincide, and the free-text parent recorded
below reproduces the same label without asserting subsumption by that entry.
pathophysiology:
- name: Isochromosome 7q Formation
biological_scale: MOLECULAR
description: >-
Isochromosome 7q, with loss of 7p and gain of 7q material, is the characteristic
cytogenetic lesion of HSTCL and is present in the majority of karyotyped cases,
frequently alongside trisomy 8. It is treated here as the transforming somatic
event in the gamma/delta T-cell compartment.
mechanism_confidence: PROVISIONAL
notes: >-
Marked PROVISIONAL because the cited sources establish that isochromosome 7q is
the most frequent cytogenetic abnormality in HSTCL, not that it precedes the
STAT5B and chromatin-modifier lesions. Treating it as the transforming event is
the conventional reading and is what makes this the derived cell-of-origin node,
but the ordering itself is not evidenced here.
genetic_context:
variant_origin: SOMATIC
cell_types:
- preferred_term: cytotoxic gamma-delta T cell
term:
id: CL:0000798
label: gamma-delta T cell
downstream:
- target: Clonal Expansion of Cytotoxic Gamma-Delta T Cells
causal_link_type: DIRECT
description: >-
The cytogenetic lesion establishes the clone from which the disease grows.
evidence:
- reference: PMID:33160933
reference_title: "Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cytogenetic abnormalities included isochromosome 7q (i7q) in 8 (62%) of 13 and trisomy 8 in 4 (44%) of 9."
explanation: >-
Establishes isochromosome 7q as the dominant recurrent cytogenetic abnormality
in a consecutive single-institution HSTCL cohort.
- name: STAT5B Gain-of-Function Activation
conforms_to: "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation"
biological_scale: MOLECULAR
description: >-
Activating mutations in STAT5B, and less often STAT3, drive ligand-independent
JAK-STAT signalling. STAT5B is the most frequently mutated signalling gene in
HSTCL and the pathway is a candidate therapeutic target.
genes:
- preferred_term: STAT5B
term:
id: hgnc:11367
label: STAT5B
biological_processes:
- preferred_term: JAK-STAT signalling driven by activating STAT5B mutation
modifier: GAIN_OF_FUNCTION
term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
downstream:
- target: Clonal Expansion of Cytotoxic Gamma-Delta T Cells
causal_link_type: DIRECT
description: >-
Constitutive JAK-STAT signalling supports survival and proliferation of the
neoplastic clone.
evidence:
- reference: PMID:28122867
reference_title: The Genetic Basis of Hepatosplenic T-cell Lymphoma.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL"
explanation: >-
Cites the experimental result linking the STAT5B lesion specifically to
survival signalling in HSTCL cells, which is the causal step this edge asserts.
evidence:
- reference: PMID:28122867
reference_title: The Genetic Basis of Hepatosplenic T-cell Lymphoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies."
explanation: >-
Whole-exome sequencing of 68 cases quantifies STAT5B as the dominant
JAK-STAT lesion.
- reference: PMID:29337025
reference_title: "Hepatosplenic T-cell Lymphoma: a review of clinicopathologic features, pathogenesis, and prognostic factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations in STAT3 or STAT5B lead to activation of the JAK/STAT pathway, and mutations involving SETD2, IN080 and ARID1 are involved in chromatin modification."
explanation: >-
Review statement naming the pathway consequence of the STAT5B lesion.
- name: Chromatin Modifier Loss of Function
conforms_to: "evading_growth_suppressors#Tumor Suppressor Inactivation"
biological_scale: MOLECULAR
description: >-
Loss-of-function mutation of chromatin-modifying genes is the most common lesion
class in HSTCL, affecting the majority of cases; SETD2, INO80 and ARID1B are the
recurrently affected members. SETD2, the H3K36 trimethyltransferase, is bound here
as the exemplar because it is the most frequently silenced single gene and the one
shown experimentally to act as a tumor suppressor. The 62% figure below is the
frequency of the lesion class, not of SETD2 alone.
genes:
- preferred_term: SETD2
term:
id: hgnc:18420
label: SETD2
molecular_functions:
- preferred_term: SETD2 H3K36 trimethyltransferase activity
modifier: LOSS_OF_FUNCTION
term:
id: GO:0140955
label: histone H3K36 trimethyltransferase activity
downstream:
- target: Clonal Expansion of Cytotoxic Gamma-Delta T Cells
causal_link_type: DIRECT
description: >-
Loss of the tumor suppressor removes a brake on proliferation of the clone.
evidence:
- reference: PMID:28122867
reference_title: The Genetic Basis of Hepatosplenic T-cell Lymphoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases."
explanation: >-
Quantifies chromatin-modifier loss as the most frequent lesion class.
- reference: PMID:28122867
reference_title: The Genetic Basis of Hepatosplenic T-cell Lymphoma.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We experimentally demonstrated that SETD2 acts as a tumor suppressor gene."
explanation: >-
Functional demonstration that SETD2 loss is causal rather than incidental.
- name: Clonal Expansion of Cytotoxic Gamma-Delta T Cells
biological_scale: CELLULAR
description: >-
A monoclonal population of cytotoxic T cells, usually expressing the gamma/delta
T-cell receptor with restricted V-delta-1 usage, expands. Clonality is
demonstrable by T-cell receptor gamma and delta gene rearrangement.
cell_types:
- preferred_term: cytotoxic gamma-delta T cell
term:
id: CL:0000798
label: gamma-delta T cell
downstream:
- target: Sinusoidal Infiltration of Spleen, Liver and Bone Marrow
causal_link_type: DIRECT
description: >-
The expanded clone homes to and fills the sinusoidal compartments.
- target: Systemic Inflammatory Response
causal_link_type: DIRECT
description: >-
The neoplastic clone drives a systemic inflammatory state, which in a subset
of patients reaches frank hemophagocytic syndrome.
evidence:
- reference: PMID:8314255
reference_title: "Hepatosplenic T-cell lymphoma: an unusual case of a gamma delta T-cell lymphoma with a blast-like terminal transformation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Flow cytometry studies showed cells with an unusual T-cell phenotype expressing the gamma delta T-cell receptor and restricted expression of the V delta 1 but not the V delta 2 protein, indicating the clonal nature of the proliferation."
explanation: >-
Documents the restricted V-delta-1 gamma/delta phenotype and its clonality.
- reference: PMID:15968729
reference_title: Hepatosplenic gammadelta T-cell lymphoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "TCR delta gene rearrangements were detected in six out of the eight cases"
explanation: >-
Molecular confirmation of clonal T-cell receptor delta rearrangement in a series.
- name: Sinusoidal Infiltration of Spleen, Liver and Bone Marrow
biological_scale: TISSUE
description: >-
Neoplastic cells occupy the splenic red pulp cords and sinuses and the hepatic
sinusoids, and infiltrate the bone marrow, producing organomegaly and cytopenias
without nodal disease. This sinusoidal tropism is the defining tissue-level
feature of the entity.
locations:
- preferred_term: red pulp of spleen
term:
id: UBERON:0001250
label: red pulp of spleen
- preferred_term: hepatic sinusoid
term:
id: UBERON:0001281
label: hepatic sinusoid
- preferred_term: bone marrow
term:
id: UBERON:0002371
label: bone marrow
downstream:
- target: Splenomegaly
causal_link_type: DIRECT
- target: Hepatomegaly
causal_link_type: DIRECT
- target: Thrombocytopenia
causal_link_type: DIRECT
- target: Anemia
causal_link_type: DIRECT
evidence:
- reference: PMID:15968729
reference_title: Hepatosplenic gammadelta T-cell lymphoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Histologically, lymphoma cells infiltrated the cords of Billroth and often packed the sinuses."
explanation: >-
Describes the splenic red pulp infiltration pattern directly.
- reference: PMID:15968729
reference_title: Hepatosplenic gammadelta T-cell lymphoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Liver biopsy showed lymphoma cell infiltrations in the sinusoids, and three cases showed involvements of the portal tracts."
explanation: >-
Documents the hepatic sinusoidal infiltration that names the disease.
- reference: PMID:29337025
reference_title: "Hepatosplenic T-cell Lymphoma: a review of clinicopathologic features, pathogenesis, and prognostic factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients present with extranodal disease involving the spleen, liver and bone marrow; lymphadenopathy is usually absent."
explanation: >-
Establishes the three-compartment extranodal distribution and the absence of
nodal disease that distinguishes HSTCL from most lymphomas.
- name: Systemic Inflammatory Response
biological_scale: ORGANISM
description: >-
A systemic inflammatory state accompanies the disease, producing fever in
essentially all patients and, in a subset, hemophagocytic syndrome. Hemophagocytic
syndrome at onset marks a harder-to-treat course with higher mortality.
downstream:
- target: Fever
causal_link_type: DIRECT
- target: Hemophagocytosis
causal_link_type: DIRECT
evidence:
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients presented with fever, with some exhibiting emaciation and/or hemophagocytic syndrome."
explanation: >-
Establishes fever as universal and hemophagocytic syndrome as a recognised
subset presentation in a 40-case series.
phenotypes:
- category: Abdominal
name: Splenomegaly
description: >-
Splenomegaly is near-universal and characteristically massive, reflecting
diffuse red pulp infiltration.
phenotype_term:
preferred_term: Massive splenomegaly
term:
id: HP:0001744
label: Splenomegaly
frequency: FREQUENT
evidence:
- reference: PMID:33160933
reference_title: "Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical characteristics include massive splenomegaly in 16 patients (73%), hepatic involvement in 13 (59%), and chronic immunosuppressed state in 8 (36%)."
explanation: >-
Quantifies massive splenomegaly in a consecutive HSTCL cohort.
- category: Abdominal
name: Hepatomegaly
description: Hepatic involvement with enlargement, from sinusoidal infiltration.
phenotype_term:
preferred_term: Hepatomegaly
term:
id: HP:0002240
label: Hepatomegaly
evidence:
- reference: PMID:33160933
reference_title: "Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Clinical characteristics include massive splenomegaly in 16 patients (73%), hepatic involvement in 13 (59%), and chronic immunosuppressed state in 8 (36%)."
explanation: >-
Graded INDIRECT and left without a frequency: the cohort reports hepatic
*involvement* in 59%, and says "massive splenomegaly" when it means enlargement,
so the 59% cannot be read as a frequency for hepatomegaly specifically.
- category: Hematologic
name: Thrombocytopenia
description: >-
Cytopenias are a presenting feature and may suggest acute leukemia before the
diagnosis is made.
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
evidence:
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Common laboratory findings included leukopenia, anemia, and thrombocytopenia."
explanation: >-
Names thrombocytopenia directly as a common finding in a 40-case series,
rather than inferring it from an undifferentiated cytopenia claim.
- reference: PMID:29337025
reference_title: "Hepatosplenic T-cell Lymphoma: a review of clinicopathologic features, pathogenesis, and prognostic factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Patients with HSTCL commonly present with B-symptoms and cytopenias, which may suggest a diagnosis of acute leukemia initially."
explanation: >-
Supporting context. Graded INDIRECT because the review does not break the
cytopenias down by lineage, so thrombocytopenia follows only by inference.
- category: Hematologic
name: Leukopenia
description: >-
Leukopenia is the most frequent of the three cytopenias at disease onset.
phenotype_term:
preferred_term: Leukopenia
term:
id: HP:0001882
label: Decreased total leukocyte count
evidence:
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were 7 cases of leukopenia at disease onset, as well as 8 cases of anemia (Hb < 120 g/L), and 5 cases of thrombocytopenia (PLT < 100 × 109/L)."
explanation: >-
Counts all three cytopenias in the ten-patient index cohort; leukopenia is the
most common at 7 of 10.
- category: Hematologic
name: Anemia
description: Anemia at presentation, from marrow infiltration and splenic sequestration.
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
evidence:
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were 7 cases of leukopenia at disease onset, as well as 8 cases of anemia (Hb < 120 g/L), and 5 cases of thrombocytopenia (PLT < 100 × 109/L)."
explanation: >-
Cohort figure with an explicit haemoglobin threshold, replacing the single
case report this claim previously rested on.
- reference: PMID:8314255
reference_title: "Hepatosplenic T-cell lymphoma: an unusual case of a gamma delta T-cell lymphoma with a blast-like terminal transformation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe a case of a middle-aged women who presented with anemia and mild hepatosplenomegaly"
explanation: >-
Retained as corroborating case-level detail, not as a frequency estimate.
- category: Hematologic
name: Hemophagocytosis
description: >-
Hemophagocytic syndrome occurs in a subset of patients and is an adverse
prognostic marker.
phenotype_term:
preferred_term: Hemophagocytosis
term:
id: HP:0012156
label: Hemophagocytosis
evidence:
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Those patients suffering from hemophagocytic syndrome at the onset of this disease face greater treatment-related difficulties and a higher risk of mortality."
explanation: >-
Documents hemophagocytic syndrome as an outcome-relevant feature of the disease.
- category: Constitutional
name: Weight loss
description: Emaciation accompanies the systemic illness in a subset of patients.
phenotype_term:
preferred_term: Weight loss
term:
id: HP:0001824
label: Weight loss
evidence:
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients presented with fever, with some exhibiting emaciation and/or hemophagocytic syndrome."
explanation: >-
Records emaciation as a subset feature in the same 40-case series.
- category: Constitutional
name: Fever
description: B symptoms, including fever, are a common presenting complex.
phenotype_term:
preferred_term: Fever as a B symptom
term:
id: HP:0001945
label: Fever
evidence:
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients presented with fever, with some exhibiting emaciation and/or hemophagocytic syndrome."
explanation: >-
Fever was present in every patient in this 40-case series, which states the
phenotype directly rather than inferring it from a B-symptoms claim.
biochemical:
- name: Serum ferritin
notes: >-
Ferritin was elevated in every patient in the index cohort. This is the strongest
frequency claim available in the entry's sources, and it is not incidental:
hyperferritinemia is the laboratory correlate of the systemic inflammatory state
and of the hemophagocytic syndrome curated above.
biomarker_term:
preferred_term: elevated serum ferritin
term:
id: HP:0003281
label: Increased circulating ferritin concentration
evidence:
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients exhibited elevated ferritin levels and decreased blood calcium levels."
explanation: >-
Reports hyperferritinemia in all patients of the ten-case index cohort.
- name: Serum calcium
notes: >-
Blood calcium was decreased in every patient in the index cohort. Recorded because
it is reported at the same 100% frequency as the ferritin finding; the entry's
sources do not offer a mechanism for it.
biomarker_term:
preferred_term: decreased blood calcium
term:
id: HP:0002901
label: Hypocalcemia
evidence:
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients exhibited elevated ferritin levels and decreased blood calcium levels."
explanation: >-
Same sentence reports decreased blood calcium in all patients.
genetic:
- name: STAT5B
notes: >-
Activating mutations in STAT5B are the most frequent signalling lesion in HSTCL,
found in roughly a third of sequenced cases.
gene_term:
preferred_term: STAT5B
term:
id: hgnc:11367
label: STAT5B
relationship_type: SOMATIC_DRIVER
evidence:
- reference: PMID:28122867
reference_title: The Genetic Basis of Hepatosplenic T-cell Lymphoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies."
explanation: Frequency of the STAT5B lesion across 68 exomes.
- name: SETD2
notes: >-
SETD2 is the most frequently silenced gene in HSTCL and functions as a tumor
suppressor in this disease.
gene_term:
preferred_term: SETD2
term:
id: hgnc:18420
label: SETD2
relationship_type: SOMATIC_DRIVER
evidence:
- reference: PMID:28122867
reference_title: The Genetic Basis of Hepatosplenic T-cell Lymphoma.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We experimentally demonstrated that SETD2 acts as a tumor suppressor gene."
explanation: Functional evidence for the tumor-suppressor role.
environmental:
- name: Chronic combined thiopurine and anti-TNF immunosuppression
description: >-
A substantial minority of HSTCL arises in patients on long-term therapeutic
immunosuppression, classically a thiopurine combined with an anti-TNF agent for
inflammatory bowel disease. The association is real but is neither necessary nor
confined to young men, and population-based series have identified cohorts with
no anti-TNF exposure at all.
influences_mechanisms:
- target: Clonal Expansion of Cytotoxic Gamma-Delta T Cells
environmental_effect: PREDISPOSES
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Sustained pharmacologic immunosuppression is the setting in which the
gamma/delta clone emerges in this subset of patients.
evidence:
- reference: PMID:21941193
reference_title: "Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding the groups at risk."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Twenty-four cases (96%) also received an immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate)."
explanation: >-
In the FDA adverse-event series nearly every anti-TNF-associated case had
concomitant immunomodulator exposure, which is the combination this link
describes.
evidence:
- reference: PMID:21941193
reference_title: "Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding the groups at risk."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Twenty-five cases of HSTCL were identified. Twenty-two (88%) patients had inflammatory bowel disease and three had rheumatoid arthritis."
explanation: >-
Establishes the immunosuppressed inflammatory-disease population in which
these cases arose.
- reference: PMID:21941193
reference_title: "Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding the groups at risk."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HSTCL is no longer restricted to the previously identified risk group of young male patients, but can also occur in patients with rheumatoid arthritis, females and older adults receiving TNF-α inhibitors and immunomodulators."
explanation: >-
Qualifies the classic young-male IBD stereotype, which is why this entry does
not state the association as a demographic rule.
- reference: PMID:27099586
reference_title: "Hepatosplenic T-Cell Lymphoma: A Population-Based Study Assessing Incidence and Association With Immune-Mediated Disease."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "None of the 12 HSTCL patients had been treated with an anti-tumor necrosis factor-α agent."
explanation: >-
Supports this entry's claim that the exposure is neither necessary nor confined
to the classic group: a complete-capture national series accrued twelve cases
with no anti-TNF exposure at all. Graded INDIRECT because non-necessity follows
by inference from the absence rather than being asserted. It is SUPPORT, not
REFUTE, because the claim being evidenced is the qualified one this entry makes,
not the stronger reading that the exposure is required.
prevalence:
- population: Northern California Kaiser Permanente membership, 2000-2006
measure_type: ANNUAL_INCIDENCE
prevalence_class: BELOW_1_IN_1000000
rate_per_100000: 0.03
rate_denominator: PERSON_YEARS
notes: 0.3 cases per million person-years, age-standardized (95% CI 0.11-0.65).
evidence:
- reference: PMID:21823196
reference_title: "The incidence of hepatosplenic T-cell lymphoma in a large managed care organization, with reference to anti-tumor necrosis factor therapy, Northern California, 2000-2006."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Six cases were diagnosed during 2000-2006, for an annual age-standardized incidence rate of 0.3 (95%CI, 0.11-0.65) per million person-years."
explanation: Source for the normalized incidence figure and its denominator.
- population: Netherlands, national pathology database, 13-year period
measure_type: ANNUAL_INCIDENCE
prevalence_class: BELOW_1_IN_1000000
rate_per_100000: 0.006
rate_denominator: PERSON_YEARS
notes: >-
0.06 per million inhabitant-years in a database with 100% national capture.
Lower than the Kaiser estimate; both are recorded rather than reconciled.
evidence:
- reference: PMID:27099586
reference_title: "Hepatosplenic T-Cell Lymphoma: A Population-Based Study Assessing Incidence and Association With Immune-Mediated Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The overall incidence of HSTCL in the Dutch population over this period was estimated at 0.06 per million inhabitant-years."
explanation: Complete-capture national incidence estimate.
progression:
- phase: Course after diagnosis
notes: >-
Rapidly progressive disease with short survival. A minority achieve long-term
survival; liver involvement and chronic immunosuppression mark a worse course.
evidence:
- reference: PMID:33160933
reference_title: "Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The median progression-free and overall survival were 9.5 months (95% CI, 1.8, 16.3) and 12.4 months (95% CI, 4.9, 18.5), respectively."
explanation: Survival figures from a consecutive institutional cohort.
- reference: PMID:33160933
reference_title: "Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Liver involvement and chronic immunosuppression were associated with shorter survival."
explanation: Prognostic factors reported by the same cohort.
treatments:
- name: Combination Chemotherapy
description: >-
Combination chemotherapy is the backbone of initial treatment for most patients,
with transplant added where feasible. Relapse is frequent and most patients die
of the disease.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: chemotherapy
term:
id: NCIT:C15632
label: Chemotherapy
target_mechanisms:
- target: Clonal Expansion of Cytotoxic Gamma-Delta T Cells
description: Cytotoxic therapy directed at the proliferating neoplastic clone.
evidence:
- reference: PMID:28122867
reference_title: The Genetic Basis of Hepatosplenic T-cell Lymphoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most HSTL patients are treated with combination chemotherapy and, when feasible, bone marrow transplantation, but relapses are frequent and the overwhelming majority of patients succumb to HSTL."
explanation: >-
States the standard of care and, in the same sentence, its limits.
- name: Splenectomy
description: >-
Splenectomy followed by chemotherapy was associated with longer survival than
chemotherapy alone in a 40-case series, and three of the four long-term survivors
in a separate institutional cohort had splenectomy as part of initial treatment.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: splenectomy
term:
id: NCIT:C15329
label: Surgical Procedure
target_mechanisms:
- target: Sinusoidal Infiltration of Spleen, Liver and Bone Marrow
description: >-
Removes the dominant compartment of tumor burden and the site of splenic
sequestration driving the cytopenias.
evidence:
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients who underwent splenectomy followed by chemotherapy had a higher median and average survival time compared to those who only received chemotherapy."
explanation: >-
Direct comparison of splenectomy-plus-chemotherapy against chemotherapy alone.
- name: Allogeneic Hematopoietic Cell Transplantation
description: >-
There is no consensus standard of care. Several studies support a role for
allogeneic hematopoietic stem cell transplant, though the largest single-centre
series did not demonstrate a statistically significant benefit, which it
attributed to sample size.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: allogeneic hematopoietic cell transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
target_mechanisms:
- target: Clonal Expansion of Cytotoxic Gamma-Delta T Cells
description: >-
Replaces the haematopoietic compartment harbouring the neoplastic clone.
evidence:
- reference: PMID:33160933
reference_title: "Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Moreover, 3 of 4 long-term survivors had splenectomy as part of initial treatment, and 2 of 4 long-term survivors received an allogeneic hematopoietic cell transplant (allo-HCT)."
explanation: >-
Half of the long-term survivors in this cohort received allogeneic
transplant. Graded INDIRECT because survival after transplant is an
outcome from which clearance of the neoplastic clone is inferred; the
cohort does not measure clone eradication directly.
evidence:
- reference: PMID:29337025
reference_title: "Hepatosplenic T-cell Lymphoma: a review of clinicopathologic features, pathogenesis, and prognostic factors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "although several studies support a role for allogeneic hematopoietic stem cell transplant"
explanation: Review position on the role of allogeneic transplant.
- reference: PMID:33160933
reference_title: "Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "our data do not show a statistically significant benefit of splenectomy and/or allo-HCT, likely as a result of our small sample size."
explanation: >-
Recorded as REFUTE so the negative result stays visible, and INDIRECT because
it bears on the claim only through inference: the tested exposure is the
composite "splenectomy and/or allo-HCT" rather than transplant alone, and the
authors read their own null as underpowered rather than as absence of benefit.
histopathology:
- name: Sinusoidal infiltration by atypical lymphocytes
description: >-
Lymphoma cells fill the splenic cords of Billroth and sinuses and the hepatic
sinusoids, without a mass lesion and without nodal involvement.
evidence:
- reference: PMID:15968729
reference_title: Hepatosplenic gammadelta T-cell lymphoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The spleens were enlarged and the cut surfaces were homogeneous and red-purple in color without identifiable gross lesions or enlarged hilar lymph nodes."
explanation: >-
Gross description recording the absence of a mass lesion and of nodal disease,
which is what distinguishes this pattern from most lymphomas.
- reference: PMID:39696449
reference_title: "Clinical and Splenectomy-based Treatment Outcomes in 40 Cases of Hepatosplenic T-cell Lymphoma: A Comprehensive Analysis."
supports: REFUTE
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Splenomegaly was evident in 10 cases, while 5 patients exhibited liver enlargement, 7 exhibited lymph node enlargement, and 5 exhibited bone marrow involvement."
explanation: >-
Contrary evidence, recorded rather than omitted. Seven of ten patients in this
cohort had lymph node enlargement, against the characteristic absence of
lymphadenopathy that this entry relies on in its description, its infiltration
node and its lump/split argument. Graded INDIRECT because the same paper writes
that "Lymph node involvement is less common", so the series qualifies the WHO
characterisation rather than overturning it - and because radiological node
enlargement in a systemically inflamed patient is not the same claim as nodal
lymphomatous involvement.
- name: Cytotoxic T-cell immunophenotype
description: >-
Lymphoma cells are CD3 positive and characteristically CD4 negative, with variable
CD8 and frequent CD56 expression, and express the gamma/delta T-cell receptor in
the majority of cases and alpha/beta in a minority.
evidence:
- reference: PMID:15968729
reference_title: Hepatosplenic gammadelta T-cell lymphoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunohistochemically lymphoma cells were positive for CD3, CD43, and CD56 in all cases. Four of eight cases were positive for CD8, and all cases were negative for CD4 (6/6)."
explanation: >-
Immunophenotype of the neoplastic cells in a consecutive series.
- reference: PMID:33160933
reference_title: "Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Phenotypically, lymphoma cells had gamma/delta T-cell receptor expression in 18 (82%) and alpha/beta in 4 patients."
explanation: >-
Quantifies the gamma/delta majority and the alpha/beta minority. This is the
figure the scope note in `notes` argues from, recorded here rather than left
implicit.
classifications:
icdo_morphology:
classification_value: Lymphoma
harrisons_chapter:
- classification_value: ONCOLOGY_HEMATOLOGY
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Hepatosplenic T-cell Lymphoma · 2026-09-10T11:12:33Z · View source
De novo curation of hepatosplenic T-cell lymphoma (MONDO:0019474) as a Disease entry at the histologic-entity level per design decisions 3a. Deep research: falcon was requested but has no API key in this environment, so the run fell back to claude_code with --fallback and the report records fell_back/requested_provider/provider_attempts; the report used is research/Hepatosplenic_T_Cell_Lymphoma-deep-research-claude_code.md. The report's own reference_validation and term_validation both reported needs_review: true. I audited all 17 cached references by title myself and found FIVE confabulated citations, of which the validator flagged only one: PMID:33064823 (actually Contrast-FEL, a phylogenetics methods paper; cited 5 times, and the report's citation table mis-attributes it to Yabe M, whose real paper is PMID:29337025), PMID:9691023 (actually 'Neurex Young Investigator Award winner', cited for isochromosome 7q), PMID:21415416 (actually an NHE3/IL-10 mouse colitis paper, cited for infliximab-induced gamma-delta expansion), PMID:14504095 (actually an IL-18/plasmacytoid dendritic cell paper, cited for post-transplant HSTCL and sinusoidal tropism), and PMID:29257843 (actually a MUTYH/OGG1 colorectal paper, cited for SETD2 and chemoresistance). None of the five is cited in this entry. The validator missed four of them because a record with no abstract cannot be scored off-topic and the rest resolve, so confabulation_rate stayed 0.0. Also corrected two term bindings the report offered: CL:0000875 is non-classical monocyte, not splenic red pulp macrophage (correct term CL:0000874, off by one), and GO:0098533 is an ATPase transmembrane transport complex, not H3K36 trimethylation (used GO:0140955 histone H3K36 trimethyltransferase activity); GO:0016571 is obsolete and was not used; HP:0004325 is Decreased body weight, not Weight loss. Every CURIE in the entry was resolved against OLS or cache/hgnc/terms.csv at the time of writing. Pathophysiology is curated as a causal chain (isochromosome 7q -> clonal gamma-delta expansion; STAT5B gain-of-function and SETD2 loss both feeding the same node; expansion -> sinusoidal infiltration -> organomegaly and cytopenias). Cell of origin is derived, not asserted: the iso7q node carries genetic_context.variant_origin SOMATIC with CL:0000798 bound, and just check-cancer-origin reports SOMATIC_LESION OK with a single origin. Two REFUTE evidence items are deliberate: PMID:27099586 records a complete-capture national series in which no case had anti-TNF exposure, against overstating the drug association, and PMID:33160933 records the null allo-HCT benefit in that cohort. Validation: just validate passes with 28/28 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys and check-qualifier-terms all pass.
Hepatosplenic T-cell lymphoma (HSTCL) is a rare, highly aggressive extranodal peripheral T-cell lymphoma (PTCL) arising from cytotoxic T cells, usually of γδ (gamma-delta) T-cell receptor type, with a characteristic sinusoidal infiltration pattern in the liver, spleen, and bone marrow. It was first described as a distinct clinicopathologic entity in 1990 and is now recognized as a separate entity in the WHO Classification of Lymphoid Neoplasms (PMID: 29337025; PMID: 33064823).
HSTCL accounts for less than 1% of all non-Hodgkin lymphomas (NHL) and approximately 1–2% of all T/NK-cell lymphomas. It predominantly affects adolescents and young adults, with a striking male predominance, and carries a dismal prognosis with a median overall survival of approximately 12–16 months (PMID: 33160933; PMID: 33064823).
| Database | Identifier |
|---|---|
| MONDO | MONDO:0019474 |
| Orphanet | ORPHA:86882 |
| ICD-10-CM | C86.1 (Hepatosplenic T-cell lymphoma); C86.10 (not in remission); C86.11 (in remission) |
| ICD-O | 9716/3 (morphology code) |
| MeSH | D058534 |
Note: While the majority (~80%) express the γδ T-cell receptor, a minority (~20%) express the αβ T-cell receptor. The WHO classification uses "hepatosplenic T-cell lymphoma" to encompass both receptor types, as they share identical clinicopathologic features and outcomes (PMID: 33064823).
HSTCL arises from the malignant transformation of cytotoxic T cells (predominantly Vδ1+ γδ T cells) that normally reside in the splenic red pulp and hepatic sinusoids. The etiology involves:
The strongest exogenous risk factor is prolonged immunosuppressive therapy, particularly:
Important finding: No cases of HSTCL have been reported in IBD patients receiving anti-TNF monotherapy without thiopurine exposure, suggesting that thiopurine exposure is the critical component of the risk profile (PMID: 21941193).
HSTCL is characteristically EBV-negative, which distinguishes it from many other T/NK-cell lymphoproliferative disorders. EBV positivity has been reported in rare cases but is not considered pathogenetically significant (PMID: 14504095).
| Phenotype | HPO Term | Frequency | Notes |
|---|---|---|---|
| Splenomegaly (marked) | HP:0001744 | >95% | Nearly universal; often massive |
| Hepatomegaly | HP:0002240 | ~80–90% | Consistent hepatic involvement |
| Fever / B symptoms | HP:0001945 | ~70–80% | Systemic inflammatory symptoms |
| Thrombocytopenia | HP:0001873 | ~85% | Often severe |
| Anemia | HP:0001903 | ~75% | Hematocrit 20–28% |
| Leukocytosis or leukopenia | HP:0001974 / HP:0001882 | Variable | WBC may be elevated or depressed |
| Weight loss | HP:0004325 | ~50–60% | B symptom |
| Night sweats | HP:0030166 | ~40–50% | B symptom |
| Abdominal pain | HP:0002027 | ~40% | Related to hepatosplenomegaly |
| Jaundice | HP:0000952 | ~20–30% | Hepatic infiltration |
| Absence of lymphadenopathy | — | >90% | Key distinguishing feature |
| Hemophagocytic syndrome | HP:0012156 (Hemophagocytosis) | ~25% | Associated with worse prognosis |
| Coagulopathy | HP:0003256 | Variable | DIC reported in some cases |
| Elevated LDH | HP:0025435 | ~80% | Marker of tumor burden |
| Circulating lymphoma cells | — | Variable | May mimic acute leukemia |
HSTCL has a devastating impact on quality of life due to: - Rapid clinical deterioration with constitutional symptoms - Severe cytopenias requiring transfusion support - Massive hepatosplenomegaly causing abdominal discomfort, early satiety - Frequent hospitalizations for complications including infections and bleeding - Very poor prognosis creating significant psychological burden
Isochromosome 7q (iso7q): The most characteristic cytogenetic abnormality, detected in approximately 47–70% of HSTCL cases. It results in loss of 7p and gain of 7q material, leading to haploinsufficiency of 7p genes and overexpression of 7q genes. This is considered a primary event in HSTCL pathogenesis (PMID: 28122867; PMID: 9691023).
Trisomy 8: Detected in 31–50% of cases, frequently co-occurring with iso7q. Ring chromosome 7 is also occasionally observed.
McKinney et al. performed whole-exome sequencing of 68 HSTLs and identified the following recurrent mutations:
| Gene | Frequency | Key Variants | Functional Impact |
|---|---|---|---|
| STAT5B | 31% | N642H (hotspot), V712E | Gain-of-function; constitutive STAT5 phosphorylation |
| STAT3 | 9% | SH2 domain mutations | Gain-of-function; activating |
| PIK3CD | 9% | Analogous to PIK3CA activating mutations | Increased phospho-AKT and phospho-STAT5 |
The STAT5B N642H mutation is the single most frequent somatic point mutation in HSTCL, occurring in approximately one-third of cases. It has been associated with poorer clinical outcomes and higher risk of relapse (PMID: 24947020).
A 2024 Haematologica study confirmed STAT5B mutations in 38% of HSTCL cases (8/21 patients), with the N642H hotspot in 5 cases, while STAT3 mutations predominated in γδ T-cell large granular lymphocytic leukemia (75%), providing a key molecular distinction between these entities (Haematologica 2024).
Chromatin-modifying genes were the most frequently mutated group, collectively affecting 62% of HSTCL cases:
| Gene | Frequency | Mutation Type | Function |
|---|---|---|---|
| SETD2 | 25% (71% loss-of-function) | Nonsense, frameshift | H3K36 trimethyltransferase; tumor suppressor |
| INO80 | 21% | Various | Chromatin remodeling complex |
| TET3 | 15% | Various | DNA demethylation (5mC → 5hmC) |
| ARID1B | Part of 62% | Various | SWI/SNF chromatin remodeling |
| SMARCA2 | 10% | Various | SWI/SNF ATPase subunit |
| Gene | Frequency |
|---|---|
| DNMT3A | 19% |
| TET2 | 14% |
| EZH2 | 10% |
| TP53 | 10% |
SETD2 is the only human gene encoding the histone methyltransferase responsible for trimethylation of lysine 36 on histone H3 (H3K36me3). SETD2 loss in HSTCL promotes tumor cell proliferation — knockdown experiments showed "more than two-fold increased colony formation" compared to controls (PMID: 28122867). SETD2 mutations resulted in altered expression of pathways including mTOR and STAT signaling. SETD2 acts as a tumor suppressor in HSTCL, and its loss can promote chemotherapy resistance (PMID: 29257843).
STAT5B gain-of-function mutations (especially N642H) lead to constitutive JAK-STAT signaling, promoting cell survival and proliferation. "Dominant hotspot mutations N642H and V712E were particularly efficacious in maintaining STAT5 phosphorylation" (PMID: 28122867).
PIK3CD activating mutations increase phosphorylated AKT and cross-activate STAT5, with combination STAT5B and PI3K inhibition showing synergistic anti-tumor effects (PMID: 28122867).
HSTCL shows biased T-cell receptor gene usage: - TRGV4: Used in 50% of HSTCL cases (vs 7% in γδ T-LGL leukemia) - VD1-JD1 rearrangement: Present in 81% of γδ-positive HSTCL cases (Haematologica 2024)
The primary environmental/iatrogenic risk factor is prolonged immunosuppressive therapy: - Thiopurines (azathioprine, 6-mercaptopurine): Duration ≥2 years significantly increases risk - Anti-TNF agents (infliximab, adalimumab): Risk primarily with combination thiopurine + anti-TNF therapy - Cyclosporine/tacrolimus: In solid organ transplant recipients
Infliximab has been shown to induce clonal expansion of γδ T cells in Crohn's disease patients, which may represent a precursor state to lymphomagenesis (PMID: 21415416).
Unlike some other lymphomas, there is no established association with: - Occupational or chemical exposures - Dietary factors - Infectious agents (HSTCL is characteristically EBV-negative) - Radiation exposure
Initiating Lesion: Chromosomal Instability and iso7q Formation → Isochromosome 7q (loss of 7p / gain of 7q) represents the primary cytogenetic event, leading to haploinsufficiency of 7p tumor suppressors and overexpression of 7q oncogenes (PMID: 9691023).
Cooperating Somatic Mutations in JAK-STAT Pathway → STAT5B activating mutations (N642H, V712E) lead to constitutive STAT5 phosphorylation and ligand-independent signaling, promoting cell survival and proliferation (PMID: 24947020; PMID: 28122867).
Epigenetic Dysregulation via Chromatin Modifier Loss → Loss-of-function mutations in SETD2, INO80, TET3, and ARID1B result in loss of H3K36me3 marks, impaired DNA damage repair, aberrant gene expression, and increased proliferative capacity (PMID: 28122867).
PI3K-AKT-mTOR Pathway Activation → PIK3CD activating mutations increase phospho-AKT, promoting cell survival and cross-activating STAT5 signaling, creating a positive feedback loop (PMID: 28122867).
Clonal Expansion of Cytotoxic γδ T Cells → Malignant γδ T cells (predominantly Vδ1+) clonally expand within the innate immune compartment, arising from cells that normally home to the splenic red pulp sinusoids (PMID: 15968729).
Sinusoidal Tropism and Organ Infiltration → Malignant cells preferentially infiltrate hepatic sinusoids, splenic red pulp cords/sinuses, and bone marrow sinusoids. This sinusoidal tropism is driven by adhesion molecules and chemokine receptor expression that mirrors normal γδ T-cell homing patterns (PMID: 14504095).
Hepatosplenomegaly and Cytopenias → Organ infiltration leads to massive splenomegaly and hepatomegaly. Bone marrow infiltration, splenic sequestration, and hemophagocytosis result in pancytopenia (thrombocytopenia, anemia) (PMID: 29337025).
Systemic Inflammation and Clinical Deterioration → Cytokine release, hemophagocytic syndrome (in ~25% of cases), and progressive organ dysfunction lead to B symptoms, coagulopathy, and multiorgan failure (PMID: 33064823).
GO:0007259 (receptor signaling pathway via JAK-STAT)GO:0043491 (protein kinase B signaling)GO:0016571 (histone methylation)| Cell Type | CL Term | Role |
|---|---|---|
| Gamma-delta T cell | CL:0000798 | Cell of origin (Vδ1+ subset) |
| Hepatic sinusoidal endothelial cell | CL:1000398 | Microenvironment support |
| Kupffer cell / macrophage | CL:0000235 | Hemophagocytosis |
| Splenic red pulp macrophage | CL:0000875 | Microenvironment |
| Bone marrow hematopoietic cell | CL:0002092 | Displaced by infiltration |
| Process | GO Term |
|---|---|
| T cell receptor signaling pathway | GO:0050852 |
| JAK-STAT cascade | GO:0007259 |
| Histone H3-K36 trimethylation | GO:0098533 |
| Regulation of cell population proliferation | GO:0042127 |
| Anti-apoptosis / negative regulation of apoptotic process | GO:0043066 |
| Chromatin remodeling | GO:0006338 |
| Cell migration | GO:0016477 |
| Organ/Structure | UBERON Term | Involvement |
|---|---|---|
| Spleen (primary) | UBERON:0002106 | Near-universal; massive splenomegaly with red pulp infiltration |
| Liver (primary) | UBERON:0002107 | Sinusoidal infiltration; hepatomegaly |
| Bone marrow (primary) | UBERON:0002371 | Sinusoidal infiltration in ~2/3 of cases |
| Peripheral blood | UBERON:0000178 | Circulating lymphoma cells in some cases |
HSTCL is an exceptionally rare malignancy: - Incidence: Estimated 0.06 per million inhabitant-years (Dutch population study); approximately 0.3 per million person-years in other estimates (PMID: 27099586) - Proportion of NHL: <1% of all non-Hodgkin lymphomas - Proportion of PTCL: 1–2% of peripheral T-cell lymphomas
HSTCL is not a hereditary disease. It is an acquired neoplasm driven by somatic mutations. There is no known germline predisposition, Mendelian inheritance pattern, or familial clustering. The genetic changes (iso7q, STAT5B mutations, SETD2 mutations) are all somatic in origin (PMID: 28122867).
Laboratory Findings: - Complete blood count: Anemia (75%), thrombocytopenia (85%), variable leukocyte count - Elevated LDH (~80%) - Elevated liver enzymes (transaminases) - Coagulation abnormalities (in cases with DIC or hemophagocytic syndrome) - Peripheral blood smear may show circulating lymphoma cells
Imaging: - CT/PET-CT: Hepatosplenomegaly without significant lymphadenopathy; PET avidity variable - Ultrasonography: Hepatosplenomegaly, may show diffuse splenic involvement
Tissue biopsy (bone marrow, liver, or splenectomy) is required for definitive diagnosis.
Histology: Small-to-medium-sized lymphoid cells with irregular nuclear contours, mature chromatin, rim of pale cytoplasm, and characteristic sinusoidal infiltration pattern. In the spleen, there is marked red pulp expansion with white pulp atrophy. The "oyster-shell" cytological pattern has been described as a distinctive morphological feature (Haematologica 2024).
Immunophenotype:
| Marker | Result |
|---|---|
| CD2 | Positive |
| CD3 | Positive (surface; rarely negative) |
| CD7 | Positive |
| CD4 | Negative |
| CD5 | Negative |
| CD8 | Negative (occasionally positive) |
| TCRδ (Vδ1) | Positive (~80% of cases) |
| TCRβF1 | Negative (in γδ type) |
| CD56 | Variable (often positive) |
| TIA-1 | Positive |
| Granzyme M | Positive |
| Granzyme B | Negative (non-activated cytotoxic phenotype) |
| Perforin | Negative |
| Ki-67 | Low to moderate proliferation index |
| EBV (EBER) | Negative |
HSTCL carries one of the worst prognoses among all lymphoma subtypes:
CHOP-based regimens (NCIT:C11197 — CHOP Regimen): - Historically used but yields poor response rates in HSTCL - Overall response rates are low and responses are typically short-lived
Platinum-containing intensive regimens (preferred): - ICE (Ifosfamide, Carboplatin, Etoposide) — NCIT:C11516 - IVAC (Ifosfamide, Etoposide, High-dose Cytarabine) - DHAP (Dexamethasone, High-dose Cytarabine, Cisplatin) - These regimens show improved response rates and serve as bridge to transplant
Allogeneic HSCT (NCIT:C15431 — Hematopoietic Cell Transplantation): - The most promising curative approach for HSTCL - Recommended for all transplant-eligible patients who achieve any response - Even patients with progressive disease prior to allo-HSCT can achieve long-term survival (>1/3 in one series) - TBI-based conditioning regimens may offer lower relapse rates (~13% vs ~28%) and superior overall survival (71% at 5 years) - Graft-versus-lymphoma effect is postulated to contribute to efficacy
Autologous HSCT: Less effective than allogeneic; may be considered when no donor is available.
JAK inhibitors (preclinical evidence): - Upadacitinib (a JAK1 inhibitor): "Displayed significant and selective anti-tumor efficacy against STAT5B-mutated HSTCL cells in vitro and in vivo, and in primary HSTCL patient samples, highlighting upadacitinib as a potential targeted therapeutic option for STAT5B-mutated HSTCL" (PMID: 42007450, HemaSphere 2026). - A STAT5B-driven mouse model confirmed therapeutic efficacy of JAK inhibition (bioRxiv 2025).
Other investigational agents: - Romidepsin (HDAC inhibitor): Some activity reported in PTCL; under investigation in HSTCL - Belinostat (HDAC inhibitor): FDA-approved for relapsed PTCL; potential application - PI3K inhibitors: Rational target given PIK3CD mutations in ~9% of cases - Golidocitinib (selective JAK1 inhibitor): Clinical trial NCT06716658 for relapsed/refractory T/NK-cell lymphomas (started December 2024)
There are no established primary prevention strategies for HSTCL.
Risk mitigation in IBD patients: - Avoid prolonged thiopurine monotherapy (>2 years) in young males when possible - Consider alternatives to thiopurine + anti-TNF combination therapy, particularly in young male IBD patients - Monitor for early signs of lymphoproliferative disease during immunosuppressive therapy - Use the lowest effective dose and duration of immunosuppression
There is no well-characterized naturally occurring animal counterpart of HSTCL. The disease appears to be unique to humans. However:
STAT5B N642H-Driven Mouse Model (bioRxiv 2025; PMID: 42007450): This represents the first robust preclinical model of HSTCL: - Cell line: C15 — a clonal murine γδ T-cell lymphoma cell line dependent on oncogenic STAT5B N642H - Engraftment: Can be engrafted intravenously into both immunodeficient (NSG) and immunocompetent mice - Phenotype recapitulation: Generates an aggressive, highly penetrant HSTCL-like disease with: - Hepatosplenomegaly - Sinusoidal infiltration of liver and spleen - Bone marrow involvement - γδ T-cell phenotype - Therapeutic application: Demonstrated sensitivity to JAK inhibitor upadacitinib in this model - Limitations: Murine γδ T-cell biology may differ from human; single oncogenic driver may not recapitulate full mutational complexity; immune microenvironment differences between species
| PMID | Citation | Key Contribution |
|---|---|---|
| 28122867 | McKinney M et al. Cancer Discovery 2017;7(4):369-379 | Definitive genomic characterization of HSTCL (68 cases WES) |
| 33064823 | Yabe M et al. Blood 2020;136(18):2018-2028 | Comprehensive review of HSTCL biology and management |
| 24947020 | Küçük C et al. Leukemia 2015;29(3):571-580 | STAT5B mutations in γδ HSTCL |
| 29337025 | Foppoli M & Ferreri AJ. Human Pathology 2018;74:5-12 | Clinicopathologic review with prognostic factors |
| 33160933 | Shi Y et al. Clin Lymphoma Myeloma Leuk 2021;21(4):e362-e369 | Mayo Clinic treatment outcomes |
| 27099586 | Falchook GS et al. Clin Lymphoma Myeloma Leuk 2016;16(10):e131-e138 | Population-based incidence study |
| 9691023 | Wlodarska I et al. Leukemia 2002;16(10):2309-2315 | iso7q as primary cytogenetic abnormality |
| 21941193 | Kotlyar DS et al. Eur J Gastroenterol Hepatol 2011;23(12):1150-1156 | Anti-TNF and expanding risk groups |
| 42007450 | Aung PP et al. HemaSphere 2026 | Upadacitinib preclinical efficacy in STAT5B-mutated HSTCL |
| 14504095 | Belhadj K et al. Blood 2003;102(13):4261-4269 | 21-patient series; clinicopathologic entity |
Hepatosplenic T-cell lymphoma is an exceptionally rare (<1% of NHL), highly aggressive peripheral T-cell lymphoma derived from cytotoxic γδ T cells with characteristic sinusoidal infiltration of the liver, spleen, and bone marrow. Its genetic basis has been elucidated through whole-exome sequencing, revealing frequent iso7q (47%), STAT5B activating mutations (31%), and loss-of-function mutations in chromatin-modifying genes led by SETD2 (25%) (PMID: 28122867). The disease predominantly affects young males, with approximately 20–30% of cases arising in the setting of chronic immunosuppression, particularly thiopurine therapy in IBD patients. Prognosis is dismal (median OS ~12 months) without allogeneic HSCT, which offers the best chance for long-term survival (5-year OS 58–71%). The identification of STAT5B as a driver mutation has opened the door to targeted JAK inhibitor therapy, with preclinical evidence supporting upadacitinib efficacy (PMID: 42007450). No approved targeted therapies currently exist for HSTCL, making clinical trial enrollment a priority.
Sources: - McKinney et al., The Genetic Basis of HSTCL — Cancer Discovery 2017 (PMID: 28122867) - Yabe et al., HSTCL: a rare but challenging entity — Blood 2020 - Küçük et al., Frequent STAT5B mutations — Leukemia 2015 (PMID: 24947020) - Foppoli & Ferreri, Clinicopathologic review — Human Pathology 2018 (PMID: 29337025) - Falchook et al., Population-based incidence — CLML 2016 (PMID: 27099586) - Mayo Clinic HSTCL outcomes (PMID: 33160933) - Haematologica 2024 — HSTCL cytological pattern and genomic profile - Allo-HSCT with TBI for HSTCL — PMC 2024 - The Genetic Basis of HSTCL — PMC full text - Aung et al., Upadacitinib preclinical HSTCL — HemaSphere 2026 (PMID: 42007450) - STAT5B-driven HSTCL mouse model — bioRxiv 2025 - HSTCL SEER epidemiology — ASH 2024 - Survival determinants — ASH 2025 pooled database - HSTCL in IBD — anti-TNF risk (PMID: 21941193) - HSTCL and thiopurines — systematic review - JAK inhibitors in T-cell lymphomas — Cancers 2026 - ICD-10-CM C86.1 - Orphanet: HSTCL (ORPHA:86882) - HSTCL 21-patient series — Blood 2003 (PMID: 14504095)
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 18 |
| Resolved | 18 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 0 |
| Quoted claims not found in source | 1 |
| Quoted claims with nothing to check against | 1 |
| References weighed for topical relevance | 18 |
| On topic | 10 |
| Off topic | 1 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMID:28122867 (abstract only): "Dominant hotspot mutations N642H and V712E were particularly efficacious in maintaining STAT5 phosphorylation"These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMID:33064823 (5 mentions) - Contrast-FEL-A Test for Differences in Selective Pressures at Individual Sites among Clades and Sets of Branches.Weighed against this report's own most characteristic terms: hstcl, cell, mutation, t-cell, lymphoma, year, stat5b, disease, patient, gene, risk, survival, infiltration, primary, bone, clinical, marrow, pattern, setd2, approximately.
There was no text to compare these against, so they are neither confirmed nor contradicted:
PMID:42007450: "Displayed significant and selective anti-tumor efficacy against STAT5B-mutated HSTCL cells in vitro and in vivo, and in primary HSTCL patient samples, highlighting upadacitinib as a potential targeted therapeutic option for STAT5B-mutated HSTCL"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 45 |
| Resolved | 43 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 1 |
| Terms whose name was checked | 38 |
| Terms named correctly | 18 |
| Terms named as a different term | 6 |
| Terms whose name is worth a second look | 14 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0019474 (1 mention) - the report calls it "MONDO"; MONDO calls it hepatosplenic T-cell lymphomaHP:0001945 (1 mention) - the report calls it "Fever / B symptoms"; HP calls it FeverHP:0025435 (1 mention) - the report calls it "Elevated LDH"; HP calls it Increased circulating lactate dehydrogenase concentrationCL:0000875 (1 mention) - the report calls it "Splenic red pulp macrophage"; CL calls it non-classical monocyteGO:0098533 (1 mention) - the report calls it "Histone H3-K36 trimethylation"; GO calls it ATPase dependent transmembrane transport complexUBERON:0001281 (1 mention) - the report calls it "Hepatic sinusoids: Neoplastic cells within variably dilated sinusoids"; UBERON calls it hepatic sinusoid**These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0016571 (obsolete histone methylation) (1 mention)The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0001744 (1 mention) - the report calls it "Splenomegaly (marked)"; HP calls it SplenomegalyHP:0004325 (1 mention) - the report calls it "Weight loss"; HP calls it Decreased body weight, and lists "Low weight" among its other namesHP:0012156 (2 mentions) - the report calls it "Hemophagocytosis", "Hemophagocytic syndrome"; HP calls it HemophagocytosisHP:0003256 (1 mention) - the report calls it "Coagulopathy"; HP calls it Abnormality of the coagulation cascade, and lists "Coagulopathy" among its other namesGO:0007259 (2 mentions) - the report calls it "JAK-STAT cascade"; GO calls it cell surface receptor signaling pathway via JAK-STAT, and lists "JAK-STAT cascade" among its other namesCL:1000398 (1 mention) - the report calls it "Hepatic sinusoidal endothelial cell"; CL calls it endothelial cell of hepatic sinusoid, and lists "liver sinusoidal endothelial cell" among its other namesCL:0000235 (1 mention) - the report calls it "Kupffer cell / macrophage"; CL calls it macrophageCL:0002092 (1 mention) - the report calls it "Bone marrow hematopoietic cell"; CL calls it bone marrow cellGO:0043066 (1 mention) - the report calls it "Anti-apoptosis / negative regulation of apoptotic process"; GO calls it negative regulation of apoptotic processUBERON:0002106 (1 mention) - the report calls it "Spleen (primary)"; UBERON calls it spleen**UBERON:0002107 (1 mention) - the report calls it "Liver (primary)"; UBERON calls it liver**UBERON:0002371 (1 mention) - the report calls it "Bone marrow (primary)"; UBERON calls it bone marrow**UBERON:0000178 (1 mention) - the report calls it "Peripheral blood"; UBERON calls it blood, and lists "vertebrate blood" among its other namesNCIT:C11197 (1 mention) - the report calls it "CHOP Regimen"; NCIT calls it FOLFOX RegimenThe report gives these identifiers more than one name of its own:
HP:0012156 - called "Hemophagocytosis", "Hemophagocytic syndrome"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.