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Hepatosplenic T cell lymphoma

Authors: Mario L. Marques-Piubelli, M.D., Maria C. Ferrufino-Schmidt, M.D., Roberto N. Miranda, M.D.

Editorial Board Member: Anamarija M. Perry, M.D.

Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.

Last author update: 2 May 2022

Last staff update: 2 May 2022

Copyright: 2002-2022, PathologyOutlines.com, Inc.

PubMed Search: Hepatosplenic T cell lymphoma

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Table of Contents

Cite this page: Marques-Piubelli ML, Ferrufino-Schmidt MC, Miranda RN. Hepatosplenic T cell lymphoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBhepatosplenic.html. Accessed December 9th, 2022.

Definition / general

Rare, aggressive extranodal neoplasm that originates from nonactivated cytotoxic T cells; it usually expresses the T cell receptor (TCR) γδ (gamma delta) (Ann Diagn Pathol 2017;26:16, Am J Surg Pathol 2016;40:676, Am J Surg Pathol 2017;41:82, Cancer Treat Res 2019;176:185)
First described in 1981 by Marshall Kadin as erythrophagocytic Tγ lymphoma; recognized as a distinct entity in 1994 (N Engl J Med 1981;304:648)

Essential features

Rare, aggressive extranodal neoplasm that originates from cytotoxic T cells; it usually expresses the T cell receptor (TCR) γδ (gamma delta) (Am J Surg Pathol 2017;41:82)
Hepatomegaly and splenomegaly are the most common clinical manifestations (Ann Diagn Pathol 2017;26:16)
Liver and bone marrow: sinusoidal infiltration (Histopathology 2014;64:171)
- Median bone marrow tumor burden ~30% (5 - 80%) (Am J Surg Pathol 2016;40:676)
Spleen
- Diffuse involvement; expansion of the red pulp cords and sinusoids, with atrophy or absence of white pulp (Hum Pathol 2018;74:5)
Cytology: variable
- Usually monotonous, small to intermediate size cells with pale agranular cytoplasm, round / oval nuclei, moderately condensed chromatin and inconspicuous nucleoli (Blood 2003;102:4261)

Terminology

Obsolete term: erythrophagocytic Tγ lymphoma

ICD coding

ICD-O: 9716/3 - hepatosplenic T cell lymphoma

Epidemiology

< 1% of all non-Hodgkin lymphomas and 1 - 2% of all T / NK cell lymphomas (Hum Pathol 2018;74:5, Semin Diagn Pathol 2020;37:47, Clin Lymphoma Myeloma Leuk 2021;21:106)
Most common T cell lymphoma that affects the spleen (Semin Diagn Pathol 2020;37:47)
M > F (Am J Surg Pathol 2017;41:82, Blood 2020;136:2018, Int J Gen Med 2021;14:8399)
More common in young adult men, median age ~35 years (range: 4 - 82 years) (Ann Diagn Pathol 2017;26:16, Hum Pathol 2016;50:109, Am J Surg Pathol 2016;40:676, Am J Surg Pathol 2017;41:82, Blood 2003;102:4261)
Increased incidence in the United States in the last 2 decades (Am J Hematol 2017;92:E99)

Pathophysiology

Neoplastic clonal proliferation of γδ T cells induced by the upregulation of the JAK / STAT (STAT3 and STAT5B) and PI3K signaling pathways or mutations of chromatin modifiers (SETD2, INO80 and ARID1B) (Hum Pathol 2018;74:5, Haematologica 2019;104:e104, Blood 2020;136:2018)

Etiology

Unknown in 80% of cases
Up to 20% of cases arise in a context of chronic immunosuppression (Hum Pathol 2018;74:5, Blood 2020;136:2018, Curr Opin Oncol 2021;33:406)
- Posttransplantation (kidney or liver) (Am J Clin Pathol 2000;113:487, Cancer Treat Res 2019;176:185)
- Patients with immunodysregulatory disorders (inflammatory bowel disease, rheumatoid arthritis) that are using immunosuppressive agents (mercaptopurine, azathioprine, infliximab) (Ann Diagn Pathol 2017;26:16, Am J Surg Pathol 2016;40:676, Cancer Treat Res 2019;176:185, Blood 2020;136:2018)
  - TNFα inhibitors in Crohn's disease: fourfold increased risk of lymphomas (B cell lymphomas and hepatosplenic T cell lymphoma) (Am J Gastroenterol 2013;108:99)
  - Risk factors for hepatosplenic T cell lymphoma (HSTCL) in patients with inflammatory bowel disease: male sex and long term thiopurine therapy (≥ 2 years)
Genetic predisposition and chronic antigenic stimulation

Clinical features

Hepatomegaly and splenomegaly are the most common clinical manifestations (Ann Diagn Pathol 2017;26:16, Am J Surg Pathol 2017;41:82, Clin Lymphoma Myeloma Leuk 2021;21:106)
- 70 - 80% of patients
- Massive splenomegaly is found in most patients, defined as ≥ 6 cm below costal margin, or ≥ 20 cm in greatest dimension, or splenectomy > 1,000 g
- Abdominal discomfort
B symptoms (Am J Surg Pathol 2016;40:676)
Lymphadenopathy is uncommon (< 25%); when present, splenic peripheral lymph nodes are most commonly involved (Histopathology 2014;64:171, Blood 2020;136:2018, Semin Diagn Pathol 2020;37:47)
Peripheral blood involvement at initial presentation is uncommon
- Cytopenia or pancytopenia (Blood 2003;102:4261, Cancer Treat Res 2019;176:185, Blood 2020;136:2018):
  - Moderate anemia, thrombocytopenia and neutropenia
    - Hypersplenism, bone marrow infiltration or immune related
- Lymphocytosis in ~10% of the cases
Elevated levels of lactate dehydrogenase (LDH), β2 microglobulin and bilirubin (Hum Pathol 2018;74:5)
Bone marrow (BM) is usually involved at initial presentation (Hum Pathol 2016;50:109)
Cutaneous involvement is rare

Radiology description

CT or MRI (Blood 2020;136:2018):
- Homogeneous hepatosplenomegaly
Fluorodeoxyglucose (FDG) PET / CT (Blood 2020;136:2018):
- Diffuse FDG uptake in affected areas
  - Usually liver, spleen and bone marrow

Prognostic factors

Poor prognosis, with relapse in most cases (Am J Surg Pathol 2016;40:676)
Median overall survival (OS) is 12 months (range: 3 - 34 months) (Hum Pathol 2018;74:5, Hum Pathol 2016;50:109, Int J Gen Med 2021;14:8399)
- 3 year overall survival: 37.6%
- 5 year overall survival: 31.6%
Median progression free survival (PFS): 9.5 months 95% (CI, 1.8 - 16.3) (Clin Lymphoma Myeloma Leuk 2021;21:106)
Prognostic factors correlated with worse outcomes:
- Serum bilirubin level > 1.5 mg/dl
- Expression of TCRαβ
- Trisomy 8

Case reports

20 year old man hepatosplenic T cell lymphoma αβ subtype presenting with Coombs negative hemolytic anemia (Clin Med Insights Oncol 2015;9:123)
47 year old man with Crohn's disease on thiopurine monotherapy (World J Gastroenterol 2016;22:10465)
53 year old woman with coexisting hairy cell leukemia and hepatosplenic T cell lymphoma (Diagn Pathol 2014;9:58)
56 year old woman with hemophagocytic lymphohistiocytosis associated with hepatosplenic T cell lymphoma (Autops Case Rep 2014;4:19)
59 year old man with hepatosplenic αβ T cell lymphoma masquerading as cirrhosis (J Gastrointest Oncol 2013;4:131)
59 year old man with hepatosplenic T cell lymphoma successfully treated with PD-1 inhibitor, chidamide and chemotherapy (J Dig Dis 2022;23:50)

Treatment

No standard therapeutic guideline
- Cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), or CHOP-like, hyper CVAD (cyclophosphamide, vincristine sulfate, adriamycin and dexamethasone) or hyper CVAD-like; or non CHOP induction regimen (2' deoxycoformycin) (Ann Diagn Pathol 2017;26:16, Am J Surg Pathol 2016;40:676)
- Consolidative stem cell transplant (SCT) for eligible patients (Haematologica 2005;90:ECR14, Clin Lymphoma Myeloma Leuk 2013;13:8, Cancer Treat Res 2019;176:185, Curr Opin Oncol 2021;33:406)
- Potential target therapy: CD52, JAK1 / 2, STAT3, STAT5B and PI3KCD (Hum Pathol 2018;74:5, Cancer Treat Res 2019;176:185)

Gross description

Diffuse and homogeneous, enlarged liver and spleen; without distinct macroscopic lesions; lymph nodes are usually not enlarged (Blood 2003;102:4261)

Microscopic (histologic) description

Spleen
- Diffuse involvement; expansion of the red pulp cords and sinusoids, with atrophy or absence of white pulp (Hum Pathol 2018;74:5, Blood 2020;136:2018)
- Hemophagocytosis may be present (Blood 2020;136:2018)
Liver and bone marrow: sinusoidal infiltration (Histopathology 2014;64:171, Blood 2003;102:4261, Blood 2020;136:2018)
- Median bone marrow tumor burden ~30% (5 - 80%) (Am J Surg Pathol 2016;40:676, Blood 2020;136:2018)
  - Bone marrow tumor burden directly related to neutropenia (Hum Pathol 2016;50:109)

Microscopic (histologic) images

Contributed by Roberto N. Miranda, M.D.

Bone marrow infiltration

Bone marrow with dyspoietic changes

CD3 positive

CD4 negative

CD8 negative

TCR βF1 negative

TCRγδ positive

Liver infiltration

HSTCL: CD3 positive

HSTCL: CD4 negative

CD8 positive

TIA1 positive

Cytology description

Variable
- Usually monotonous, small to intermediate size cells with pale agranular cytoplasm, round / oval nuclei, moderately condensed chromatin and inconspicuous nucleoli (Am J Surg Pathol 2016;40:676, Am J Surg Pathol 2017;41:82, Blood 2003;102:4261, Blood 2020;136:2018, Semin Diagn Pathol 2020;37:47)
  - Blastic cells (medium to large cells with high nucleus to cytoplasm ratio, fine chromatin, without nucleoli) (Am J Clin Pathol 2001;116:410)
Background trilineage dyspoietic changes in bone marrow (Hum Pathol 2016;50:109)
- Dysmegakaryopoiesis is most common: hypolobated or small size nuclei
Hemophagocytosis (< 5%) (Hum Pathol 2018;74:5, Semin Diagn Pathol 2020;37:47)

Cytology images

Contributed by Roberto N. Miranda, M.D.

Small size morphology

Intermediate size morphology

Blastic morphology

Positive stains

T cell antigens: CD2, CD3, CD7, TIA1, granzyme M, Fas ligand (Ann Diagn Pathol 2017;26:16, Hum Pathol 2016;50:109, Am J Surg Pathol 2016;40:676, Am J Surg Pathol 2017;41:82, Histopathology 2014;64:171, Blood 2003;102:4261, Blood 2020;136:2018)
CD56: 67% of cases; related to immune disorders
Ki67 variable (Hum Pathol 2018;74:5)
TCRγδ

Negative stains

CD1a, CD4, CD5, CD8, CD10, CD57, CD94, TdT, Epstein-Barr virus encoded small RNAs (EBER) (Ann Diagn Pathol 2017;26:16, Hum Pathol 2016;50:109, Am J Surg Pathol 2016;40:676, Am J Surg Pathol 2017;41:82, Histopathology 2014;64:171, Blood 2003;102:4261, Blood 2020;136:2018)
B cell antigens: CD19, CD20 and CD25
Mature and nonactivated cytotoxic T cell immunophenotype: granzyme B (albeit positive in 38% of cases) and perforin
TCRαβ (20%): when present appears to carry a poor prognosis
Follicular T cell markers (Semin Diagn Pathol 2020;37:47):
- PD-1, CD10, BCL6, CXCL13, ICOS
Rare cases negative for TCRγδ and αβ (TCR silent) (Hum Pathol 2018;74:5)

Flow cytometry description

Helpful for diagnosis (Semin Diagn Pathol 2020;37:47, Leuk Res 2021;108:106614):
- TCRγδ in 80% of cases
- CD2+, CD3+, CD7+, CD56+, KIR+
- CD94 variable
- CD4-, CD5-, CD8- and CD57- (Am J Surg Pathol 2017;41:82)
- Variable CD16 and CD94 (dim or negative)

Flow cytometry images

Contributed by Roberto N. Miranda, M.D.

Positivity for CD2, TCRγδ and CD56

Molecular / cytogenetics description

Gamma delta origin: biallelic rearrangement of TRG (Am J Surg Pathol 2017;41:82, Blood 2003;102:4261)
Chromatin modifying genes (~60%): SETD2, INO80, TET3 and SMARCA2 (Hum Pathol 2018;74:5, Blood 2020;136:2018)
Mutations in JAK / STAT pathway
- STAT3 (10%) and STAT5B (30%) mutations
RHOA, CD28 and CCR4 are usually absent (more common in other T cell lymphomas) (PLoS One 2014;9:e102977)
DNA methylation profiling (Haematologica 2019;104:e104)
- Hypermethylated genes: CD5, BCL11B, CXCR6, GIMAP7
- Hypomethylated genes: ADARB1, NFIC, NR1H3, ST3GAL3
Mutation of PIK3CD in up to 10% of cases (Cancer Discov 2017;7:369)
Aberrant karyotype (67%)
Isochromosome (7q) or ring chromosome 7 (Ann Diagn Pathol 2017;26:16, Genes Chromosomes Cancer 2002;33:243, Cancer Treat Res 2019;176:185, Blood 2020;136:2018)
- ~50% of cases
- Primary chromosomal aberration
- Loss of 7p22.1p14.1
- Gain of 7q22.11q31.1
Trisomy 8 is usually present (Hum Pathol 2016;50:109, Am J Surg Pathol 2016;40:676, Blood 2020;136:2018)
- ~ 70% of cases
- Secondary event
- If present at time of diagnosis, there is a significantly shorter overall survival and progression free survival

Sample pathology report

Bone marrow (right iliac crest) core and clot specimen; aspirate smears and peripheral blood:
- Hepatosplenic T cell lymphoma
- Flow cytometry immunophenotype demonstrated aberrant T cells with loss of CD4 and CD8, positive for T cell receptor gamma delta chain (see comment)
- Comment: According to clinical records, patient is a 28 year old man who has a history of Crohn's disease, for which he was receiving azathioprine and tumor necrosis alpha receptor antagonist. Patient reports malaise and fever for 3 months. On physical exam, patient had massive splenomegaly (8 cm below costal margin) and hepatomegaly. Laboratory findings showed leukopenia, severe anemia and thrombocytopenia. Additional testing proved negative for antiglobulin testing, negative for HIV, hepatitis B, hepatitis C and HTLV1.
- Bone marrow core biopsy and clot sections show similar features. There is 70% cellularity with trilineage hematopoiesis. Megakaryocytes are adequate in number and range from small, hypolobated forms to megakaryocytes of normal size and shape. There are scattered small clusters of small to intermediate size lymphocytes with hyperchromatic nuclei with irregular nuclear contours.
- Bone marrow aspirate smears show trilineage hematopoiesis with mild dysmegakaryopoiesis. There are approximately 15% lymphocytes, of small to intermediate size, with clear and agranular cytoplasm and central hyperchromatic nuclei with irregular nuclear contours.
- Immunohistochemical studies were performed in bone marrow core biopsy and the T cell marker CD3 highlights lymphocytes in an interstitial and sinusoidal pattern, representing approximately 10% of marrow cells. Atypical lymphocytes are also highlighted with CD2, CD7, CD56, TIA1 and granzyme M. The T cell receptor gamma delta is positive in lymphocytes, while the T cell receptor alpha beta (βF1 clone) is negative. CD4 and CD8 are negative in atypical lymphocytes. The following markers are also negative in lymphocytes: CD1a, CD5, CD10, CD57, EBER (EBV in situ hybridization), TCL1 and TdT.
- Concurrent flow cytometry immunophenotype demonstrates that approximately 15% of marrow cells are T lymphocytes, positive for CD2, CD7, CD52, CD56 and T cell receptor gamma delta. The atypical lymphocytes are negative for CD4, CD5, CD8, CD57 and T cell receptor alpha beta. The B lymphocytes are polytypic.
- Molecular testing revealed monoclonal T cell receptor gene rearrangement of gamma (V gamma 4 family) and beta chains. Next generation sequencing showed mutation of STAT5B. The specimen was negative for IGH gene rearrangement.
- Cytogenetic analysis revealed isochromosome 7 and trisomy 8
- Clinical correlation and followup is recommended.

Differential diagnosis

T cell large granular lymphocytic (LGL) leukemia (Am J Clin Pathol 2015;144:607, Am J Surg Pathol 2017;41:82):
- Elderly patients
- Absent or mild splenomegaly
- Liver may be involved but not enlarged
- Neoplastic lymphocytes with azurophilic granules and hyperchromatic nuclei
- Expression of CD5, CD8, CD57, granzyme B and TCRαβ
- Diagnostic challenge in cases of γδ T LGL:
  - When compared with HSTCL, has a higher presence of azurophilic granules and unlikely to have massive splenomegaly
  - Marrow infiltration is interstitial and may be focally sinusoidal but without expanding sinuses
Aggressive NK cell leukemia / lymphoma:
- Azurophilic granules in cytoplasm
- CD3-, TCR- and EBV+
T cell prolymphocytic leukemia (Blood 2019;134:1132):
- Increased white blood cells, LDH and beta 2 microglobulin
- Small to medium lymphocytes with cytoplasmic projections and variable prominent central nucleolus
- Lymphadenopathy is more common
- CD2+, CD3+, CD4+, CD5+, CD7+, CD8-, TCL1 variable
- Karyotype: inv14q or t(14;14)(q11;q32)
T cell lymphoblastic leukemia / lymphoma (Haematologica 2020;105:2524):
- Lymphadenopathy is more common
- Blastic morphology
  - Small to medium lymphoblasts with scant cytoplasm, delicate chromatin, indistinct nucleoli and convoluted nuclear membrane
  - TdT+, CD99+, CD1a+
Splenic marginal zone lymphoma:
- Infiltration of white pulp and secondarily red pulp
- Small sized lymphocytes with abundant pale cytoplasm in spleen and villous lymphocytes in peripheral blood
Chronic active EBV infection (Blood 2020;136:2018):
- Bone marrow infiltration of EBV+ small to intermediate sized lymphocytes (B, T or NK cells)
- Hemophagocytosis may be present
- No significant lymphocytic atypia or phenotypic abnormalities
Nonsplenic cytotoxic T cell lymphoma with γδ+ phenotype (Histopathology 2014;64:171):
- Skin involvement
- Absence of hepatosplenomegaly

Additional references

Medeiros: Diagnostic Pathology - Lymph Nodes and Extranodal Lymphomas, 2nd Edition, 2017, Medeiros: Ioachim's Lymph Node Pathology, 5th Edition, 2021

Board review style question #1

Which of the following immunophenotypic patterns corresponds to hepatosplenic T cell lymphoma?

CD2+, CD3+, CD4+, CD5-, TIA1+, granzyme B+, TCRγδ+
CD2+, CD3+, CD4-, CD5-, TIA1+, granzyme M+, TCRγδ+
CD2+, CD3-, CD4+, CD5+, CD7+, CD8+, TCRγδ+
CD2+, CD3-, CD4+, CD5+, CD7-, CD8-, TCRγδ+
CD2-, CD3-, CD4-, CD5+, CD7-, CD8-, TCRγδ+

Board review style answer #1

B. CD2+, CD3+, CD4-, CD5-, TIA1+, granzyme M+, TCRγδ+

Comment here

Reference: Hepatosplenic T cell lymphoma

Board review style question #2

Which of the following cytogenetic and molecular abnormalities are found in hepatosplenic T cell lymphoma?

Del(6q) and RHOA1 mutation
Inversion 14 and TCL1 rearrangement
Isochromosome 7 and STAT5B mutation
t(2;5) and JAK / STAT activation
6p25 and DUSP22 / IRF4

Board review style answer #2

C. Isochromosome 7 and STAT5B mutation

Comment here

Reference: Hepatosplenic T cell lymphoma

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