Lymphoma & related disorders
Mature T/NK cell disorders
Aggressive NK/T cell disorders
Hepatosplenic
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: 5 July 2020
Copyright: 2002-2020, PathologyOutlines.com, Inc.
PubMed Search: Hepatosplenic T cell lymphoma[TI] pathology
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Pathophysiology | Etiology | Clinical features | Prognostic factors | Case reports | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Flow cytometry description | Flow cytometry images | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review answer #1 | Board review style question #2 | Board review answer #2Cite this page: Marques-Piubelli M, Ferrufino-Schmidt M, Miranda R. Hepatosplenic. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBhepatosplenic.html. Accessed August 6th, 2020.
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
- Cytopenia or pancytopenia: moderate anemia, thrombocytopenia and neutropenia (Blood 2003;102:4261)
- 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)
- Median bone marrow tumor burden ~30% (5 - 80%) (Am J Surg Pathol 2016;40:676)
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)
- 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)
- 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
- Nonsplenic cytotoxic T cell lymphoma with γδ+ phenotype (Histopathology 2014;64:171)
- Skin involvement
- Absence of hepatosplenomegaly
Additional references
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 answer #1
B. CD2+, CD3+, CD4-, CD5-, TIA1+, Granzyme M+, TCRγδ+
Reference: Lymphoma and plasma cell neoplasms - Hepatosplenic T cell lymphoma
Comment here
Reference: Lymphoma and plasma cell neoplasms - Hepatosplenic T cell lymphoma
Comment here
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 answer #2
C. Isochromosome 7 and STAT5B mutation
Reference: Lymphoma and plasma cell neoplasms - Hepatosplenic T cell lymphoma
Comment here
Reference: Lymphoma and plasma cell neoplasms - Hepatosplenic T cell lymphoma
Comment here
