Hepatosplenic T-cell Lymphoma

1. Disease Information

Overview

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).

Key Identifiers

Common Synonyms

• Hepatosplenic gamma-delta T-cell lymphoma (γδ HSTCL)
• Hepatosplenic T-cell lymphoma, gamma-delta type
• HSTCL
• HSTL

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).

2. Etiology

Disease Causal Factors

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:

1. Somatic genetic alterations: Activating mutations in JAK-STAT pathway genes (particularly STAT5B, STAT3) and loss-of-function mutations in chromatin-modifying genes (SETD2, INO80, ARID1B) (PMID: 28122867).
2. Chromosomal abnormalities: Isochromosome 7q (iso7q) and trisomy 8 are hallmark cytogenetic lesions.
3. Chronic immune stimulation/immunosuppression: Approximately 20–30% of cases arise in the setting of chronic immunosuppression (PMID: 33064823).

Risk Factors

Immunosuppression-Associated Risk

The strongest exogenous risk factor is prolonged immunosuppressive therapy, particularly:

• Thiopurine immunomodulators (azathioprine, 6-mercaptopurine): Strong association, especially with prolonged use (≥2 years) (PMID: 21823196).
• Combination immunosuppression (thiopurines + anti-TNF agents): Synergistically increased risk, particularly in young males with inflammatory bowel disease (IBD), especially Crohn's disease (PMID: 21941193).
• Solid organ transplantation: HSTCL has been reported 4–27 years after kidney transplantation under long-term immunosuppressive therapy (PMID: 14504095).
• Hematologic malignancies: Chronic lymphocytic leukemia and other conditions requiring immunosuppressive treatment have been associated.

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).

Demographic Risk Factors

• Age: Young adults and adolescents (median age at diagnosis 20–35 years in most series, though SEER data in adults show median ~48 years)
• Sex: Strong male predominance (~2:1 to 3:1 male-to-female ratio; 63.8% male in SEER adult data)
• Race/ethnicity: Caucasian predominance (57.7%), followed by Black (20.9%), Asian/Pacific Islander (11.7%), Hispanic (9.2%) in US population data (PMID: 27099586)

EBV Status

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).

3. Phenotypes

Clinical Presentation

Quality of Life Impact

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

4. Genetic/Molecular Information

Chromosomal Abnormalities

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.

Somatic Mutations (PMID: 28122867 — McKinney et al., Cancer Discovery 2017)

McKinney et al. performed whole-exome sequencing of 68 HSTLs and identified the following recurrent mutations:

JAK-STAT Pathway Mutations

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 Gene Mutations

Chromatin-modifying genes were the most frequently mutated group, collectively affecting 62% of HSTCL cases:

Additional Epigenetic Mutations (Haematologica 2024)

Functional Consequences

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).

TCR Gene Rearrangements

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)

5. Environmental Information

Immunosuppressive Drug Exposure

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).

No Other Established Environmental Risk Factors

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

6. Mechanism / Pathophysiology

Causal Chain (Ordered Mechanistic Steps)

1. 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).

2. 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).

3. 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).

4. 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).

5. 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).

6. 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).

7. 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).

8. 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).

Molecular Pathways

• JAK-STAT pathway: Central to HSTCL pathogenesis. STAT5B and STAT3 mutations provide constitutive activation. GO: GO:0007259 (receptor signaling pathway via JAK-STAT)
• PI3K-AKT-mTOR pathway: PIK3CD mutations activate downstream AKT/mTOR signaling. GO: GO:0043491 (protein kinase B signaling)
• Chromatin remodeling/epigenetic regulation: SETD2 loss results in global H3K36me3 reduction. GO: GO:0016571 (histone methylation)
• NF-κB signaling: May contribute to survival signaling in neoplastic T cells

Cell Types Involved

Biological Processes

7. Anatomical Structures Affected

Organ Level

Tissue and Cell Level

• Splenic red pulp: Diffuse infiltration of cords and sinuses by atypical lymphocytes (UBERON:0001250)
• Hepatic sinusoids: Neoplastic cells within variably dilated sinusoids (UBERON:0001281)
• Bone marrow sinusoids: Intrasinusoidal pattern of infiltration

Key Negative Finding

• Lymph nodes are characteristically NOT involved — the absence of lymphadenopathy is a hallmark distinguishing HSTCL from most other lymphomas.

8. Temporal Development

Onset

• Typical age: Adolescents and young adults (median 20–35 years in most clinical series; peak 13–26 years in one pooled analysis of 360 cases)
• Onset pattern: Acute to subacute; rapid clinical deterioration over weeks to months
• HP term: HP:0011463 (Childhood onset) to HP:0003581 (Adult onset)

Progression

• Disease course: Rapidly progressive and aggressive
• Stages: No formal staging system; disease is typically disseminated at diagnosis with liver, spleen, and bone marrow involvement
• Disease duration without treatment: Weeks to months; uniformly fatal if untreated
• Blast-like transformation: A blast-like terminal transformation has been described, with acquisition of additional cytogenetic abnormalities (PMID: 8314255)

Relapse Pattern

• High relapse rate after initial chemotherapy
• Median time to progression approximately 9.5 months (PMID: 33160933)

9. Inheritance and Population

Epidemiology

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

Population Demographics

• Sex ratio: Male predominance (~2:1 to 3:1); 63.8% male in SEER data
• Age distribution: Bimodal — peak in adolescents/young adults (13–26 years) and a second peak in middle-aged adults (~48 years median in SEER adult data)
• Race/ethnicity (US SEER data): Caucasian 57.7% > Black 20.9% > Asian/Pacific Islander 11.7% > Hispanic 9.2% > Native American/Alaskan 0.6%

Genetic Inheritance

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).

10. Diagnostics

Clinical Tests

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

Histopathology and Immunohistochemistry

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:

Cytogenetics and Molecular Testing

• Conventional karyotyping: iso7q, trisomy 8
• FISH: For chromosome 7 and 8 abnormalities
• TCR gene rearrangement: Clonal γ and δ chain rearrangements
• Targeted sequencing: STAT5B, STAT3, SETD2, PIK3CD mutation analysis
• Flow cytometry: Aberrant T-cell immunophenotype (CD3+, CD4−, CD8−, TCRγδ+)

Differential Diagnosis

• Aggressive NK-cell leukemia
• T-cell large granular lymphocytic leukemia (T-LGL) — distinguishable by STAT3 predominance (75%) vs STAT5B in HSTCL (Haematologica 2024)
• T-lymphoblastic leukemia/lymphoma
• Enteropathy-associated T-cell lymphoma type II (MEITL)
• Primary cutaneous γδ T-cell lymphoma
• Splenic marginal zone lymphoma (B-cell, indolent)
• Myelodysplastic syndrome
• Infectious mononucleosis
• Hemophagocytic lymphohistiocytosis

11. Outcome/Prognosis

Survival

HSTCL carries one of the worst prognoses among all lymphoma subtypes:

• Median overall survival: 12.4 months (95% CI: 4.9–18.5 months) (PMID: 33160933)
• Median progression-free survival: 9.5 months (95% CI: 1.8–16.3 months) (PMID: 33160933)
• 5-year overall survival: Approximately 7–20% depending on series
• Nearly half of patients die within 1 year of diagnosis
• Long-term survivors (>4 years) represent approximately 18% of cases, mostly those who received allogeneic transplantation (PMID: 33160933)

With Allogeneic HSCT

• 3-year overall survival: 56–71% (depending on conditioning regimen)
• 5-year overall survival: 58–71%
• Relapse rate with TBI-based conditioning: ~13% vs ~28% without TBI
• Overall transplant mortality: 32.8% across cohort

Adverse Prognostic Factors

• Chronic immunosuppression at diagnosis
• Hemophagocytic syndrome (HP:0012156)
• Severe thrombocytopenia
• Liver involvement
• STAT5B N642H mutation (associated with higher relapse risk) (PMID: 24947020)
• Failure to achieve remission before transplantation
• Age >45 years at transplant

Favorable Prognostic Factors

• Splenectomy (diagnostic/therapeutic)
• Platinum-containing chemotherapy regimens
• Allogeneic stem cell transplantation in first remission
• Age <45 years
• Achievement of complete remission before transplant

12. Treatment

First-Line Chemotherapy

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

Stem Cell Transplantation

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.

Splenectomy (NCIT:C15329 — Surgical Procedure)

• Serves both diagnostic and therapeutic purposes
• Associated with survival benefit in retrospective analyses
• Can improve cytopenias and reduce tumor burden

Experimental and Targeted Therapies

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)

Treatment Algorithm Summary

1. Diagnosis confirmed → Intensive platinum-based induction (ICE/IVAC/DHAP)
2. Response achieved → Proceed to allogeneic HSCT in first remission
3. Refractory disease → Consider alternative salvage regimens; still proceed to allo-HSCT if possible
4. Not transplant-eligible → Palliative chemotherapy; clinical trial enrollment

NCIT Treatment Terms

• NCIT:C15632 — Chemotherapy
• NCIT:C15431 — Hematopoietic Cell Transplantation
• NCIT:C15329 — Surgical Procedure (splenectomy)
• NCIT:C15986 — Pharmacotherapy
• NCIT:C93352 — Targeted Therapy (for JAK inhibitors/investigational agents)

13. Prevention

Primary Prevention

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

Secondary Prevention (Screening)

• No population-based screening exists given extreme rarity
• Surveillance in high-risk populations: Regular CBC monitoring in patients on long-term thiopurines, particularly young males with IBD
• Prompt workup of unexplained hepatosplenomegaly and cytopenias in immunosuppressed patients

Tertiary Prevention

• Post-transplant surveillance for relapse
• Regular imaging and laboratory monitoring after allo-HSCT

14. Other Species / Natural Disease

There is no well-characterized naturally occurring animal counterpart of HSTCL. The disease appears to be unique to humans. However:

• γδ T cells are conserved across mammals and birds
• T-cell lymphomas with hepatosplenic involvement have been reported rarely in dogs and cats, but these do not replicate the specific γδ sinusoidal pattern of human HSTCL

15. Model Organisms

Mouse Models

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

Cell Lines

• Limited number of HSTCL cell lines available
• DERL-2 and DERL-7 are among the few established human HSTCL cell lines used for in vitro studies

Xenograft Models

• Patient-derived xenograft (PDX) models in immunodeficient mice have been used for drug testing
• Primary HSTCL patient samples have been tested ex vivo for JAK inhibitor sensitivity (PMID: 42007450)

Key References

Summary

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)

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Quotes not found in the cited source

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• PMID:28122867 (abstract only): "Dominant hotspot mutations N642H and V712E were particularly efficacious in maintaining STAT5 phosphorylation"
• closest text in source: "In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL"

References that may not be about this subject

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.
• shared terms: gene

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.

Quotes that could not be checked

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• 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"
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Terms the report names something else

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 lymphoma
• HP:0001945 (1 mention) - the report calls it "Fever / B symptoms"; HP calls it Fever
• HP:0025435 (1 mention) - the report calls it "Elevated LDH"; HP calls it Increased circulating lactate dehydrogenase concentration
• CL:0000875 (1 mention) - the report calls it "Splenic red pulp macrophage"; CL calls it non-classical monocyte
• GO:0098533 (1 mention) - the report calls it "Histone H3-K36 trimethylation"; GO calls it ATPase dependent transmembrane transport complex
• UBERON:0001281 (1 mention) - the report calls it "Hepatic sinusoids: Neoplastic cells within variably dilated sinusoids"; UBERON calls it hepatic sinusoid**

Obsolete terms

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)

Terms whose name is worth a second look

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 Splenomegaly
• HP:0004325 (1 mention) - the report calls it "Weight loss"; HP calls it Decreased body weight, and lists "Low weight" among its other names
• HP:0012156 (2 mentions) - the report calls it "Hemophagocytosis", "Hemophagocytic syndrome"; HP calls it Hemophagocytosis
• HP:0003256 (1 mention) - the report calls it "Coagulopathy"; HP calls it Abnormality of the coagulation cascade, and lists "Coagulopathy" among its other names
• GO: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 names
• CL: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 names
• CL:0000235 (1 mention) - the report calls it "Kupffer cell / macrophage"; CL calls it macrophage
• CL:0002092 (1 mention) - the report calls it "Bone marrow hematopoietic cell"; CL calls it bone marrow cell
• GO:0043066 (1 mention) - the report calls it "Anti-apoptosis / negative regulation of apoptotic process"; GO calls it negative regulation of apoptotic process
• UBERON: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 names
• NCIT:C11197 (1 mention) - the report calls it "CHOP Regimen"; NCIT calls it FOLFOX Regimen

Terms named inconsistently

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• HP:0012156 - called "Hemophagocytosis", "Hemophagocytic syndrome"

Prefixes with no resolver

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.