Lymphoma & related disorders

Mature T/NK cell disorders

Aggressive NK/T cell disorders

Hepatosplenic T cell lymphoma

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

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

Topic Completed: 12 December 2019

Minor changes: 25 May 2021

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

PubMed Search: Hepatosplenic T cell lymphoma[TI] pathology

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Table of Contents

Cite this page: Marques-Piubelli M, Ferrufino-Schmidt M, Miranda R. Hepatosplenic T cell lymphoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBhepatosplenic.html. Accessed January 21st, 2022.

Definition / general

Rare, aggressive extranodal neoplasm that originates from 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)
First described in 1981 by Marshall Kadin as "erythrophagocytic Tγ Lymphoma"; recognized as a distinct entity in 1994 (Hum Pathol 2018;74:5, Blood 2003;102:4261)

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)

ICD coding

ICD-0: 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)
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 cell induced by up regulation of the JAK / STAT (STAT3 and STAT5B) pathway or mutations of chromatin modifiers (SETD2, INO80 and ARID1B) (Hum Pathol 2018;74:5)

Etiology

Unknown in 80% of cases
Up to 20% of cases arise in a context of chronic immunosuppression (Hum Pathol 2018;74:5)
- Posttransplantation (kidney or liver) (Am J Clin Pathol 2000;113:487)
- Patients with immunodysregulatory disorders (inflammatory bowel disease, rheumatoid arthritis) using immunosuppressive agents (mercaptopurine, azathioprine, infliximab) (Ann Diagn Pathol 2017;26:16, Am J Surg Pathol 2016;40:676)
  - 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)
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)
- 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
B symptoms (Am J Surg Pathol 2016;40:676)
Lymphadenopathy is uncommon (< 25%); when present, splenic peripheral lymph nodes are the most commonly compromised (Histopathology 2014;64:171)
Peripheral blood involvement at initial presentation is uncommon
- Cytopenia or pancytopenia: moderate anemia, thrombocytopenia and neutropenia (Blood 2003;102:4261)
  - Pathogenesis not well defined
- Severity correlates with disease progression
Elevated levels of lactate dehydrogenase (LDH), β2 microglobulin and bilirubin (Hum Pathol 2018;74:5)
Bone marrow (BM) usually involved at initial presentation (Hum Pathol 2016;50:109)
Cutaneous involvement is rare

Prognostic factors

Poor prognosis, with relapse in most of the cases (Am J Surg Pathol 2016;40:676)
Median overall survival (OS) is 12 months (range: 3 to 34 months) (Hum Pathol 2018;74:5, Hum Pathol 2016;50:109)
Prognostic factors
- Serum bilirubin level > 1.5 mg/dl
- Expression of TCRαβ
- Trisomy 8
Cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like (hyper CVAD cyclophosphamide, vincristine sulfate, adriamycin and dexamethasone or hyper-CVAD-like) (Ann Diagn Pathol 2017;26:16, Am J Surg Pathol 2016;40:676)
Non CHOP induction regimen (2' deoxycoformycin) and consolidative stem cell transplant (SCT) (Haematologica 2005;90:ECR14, Clin Lymphoma Myeloma Leuk 2013;13:8)
Potential target therapy: JAK1 / 2, STAT3, STAT5B and PI3KCD (Hum Pathol 2018;74:5)

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)

Gross description

Diffuse and homogeneous enlarged liver and spleen; without distinct macroscopic lesions (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)
Liver and bone marrow: sinusoidal infiltration (Histopathology 2014;64:171, Blood 2003;102:4261)
- Median bone marrow tumor burden ~30% (5 - 80%) (Am J Surg Pathol 2016;40:676)
  - 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 infiltration by hepatosplenic T cell lymphoma

Bone marrow dyspoietic changes

Small size cells (bone marrow aspirate)

Intermediate size cells (bone marrow aspirate)

Blastic morphology (bone marrow aspirate)

CD3 sinusoidal pattern

CD4 negative

CD8 negative

TCR βF1 negative

TCRγδ positive

Liver portal infiltration

Liver sinusoidal infiltration

Liver sinusoidal pattern CD3

Kupffer cells CD4 positive

Lymphoma cells CD8 positive

Lymphoma cells 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)
  - Blastic cells (medium to large cells with high nucleus cytoplasm ratio, fine chromatin and without nucleoli) (Am J Clin Pathol 2001;116:410)
Background trilineage dyspoietic changes in bone marrow (Hum Pathol 2016;50:109)
- Dysmegakaryopoiesis is more common: hypolobated or small size nuclei
Hemophagocytosis (< 5%) (Hum Pathol 2018;74:5)

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)
CD56: 2/3 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)
B cell antigens: CD19, CD20 and CD25
Mature and nonactivated cytotoxic T cell immunophenotype: Granzyme B and Perforin negative
TCRαβ (20%): when present appears to carry a poor prognosis
Rare cases negative for TCRγδ and αβ (TCR silent) (Hum Pathol 2018;74:5)

Flow cytometry description

Helpful for diagnosis
TCRγδ in 80% cases
CD2+, CD3+, CD7+, CD56+, KIR+
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.

Flow cytometry of hepatosplenic T cell lymphoma

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)
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)
Mutation of PIK3CD in up to 10% of cases (Cancer Discov 2017;7:369)
Aberrant karyotype (2/3)
Isochromosome (7q) or ring chromosome 7 (Ann Diagn Pathol 2017;26:16, Genes Chromosomes Cancer 2002;33:243)
- ~50% cases
- Primary chromosomal aberration
- Loss of 7p22.1p14.1
- Gain 7q22.11q31.1
Trisomy 8 is usually present (Hum Pathol 2016;50:109, Am J Surg Pathol 2016;40:676)
- ~ 70% cases
- Secondary event
- If present at time of diagnosis, have a significantly shorter overall survival and progression free survival (PFS)

Molecular / cytogenetics images

Images hosted on other servers:

PCR for TCRγ

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 male, who has a history of Crohn's disease for which he was receiving azathioprine and tumor necrosis alpha receptor antagonist. Patient refers that 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 are 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 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
Aggressive NK cell leukemia / lymphoma
- Azurophilic granules in cytoplasm
- CD3-, TCR- and EBV+
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

Board review style question #1

Which of the following immunophenotypic pattern correspond 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