Hepatosplenic T-cell lymphoma

What every physician needs to know:

Hepatosplenic T-cell lymphoma (HSTCL) accounts for 1.4% of all known peripheral T-cell lymphoma. This is an aggressive lymphoma that primarily affects young adults (median 34 years of age) with a strong male predominance. HSTCL is usually comprised of a clonal expansion of a T-cell subset called gammadelta T-cells. The gammadelta references the T-cell receptor subunits that are expressed on the T-cell surface. The majority of T-cells express the alpha-beta subunits, whereas gammadelta T-cells are thought to reside mostly in mucocutaneous regions. This entity was previously named hepatosplenic gammadelta T-cell lymphoma, but clinically similar cases expressing an alpha-beta T-cell receptor are now described.

This disease appears to be often associated with immune suppression, particularly inflammatory bowel disease, often in the setting of therapy with tumor necrosis factor alpha antagonists. However, cases have occurred with other immunosuppressive therapy for inflammatory bowel disease and anti-TNF (tumor necrosis factor) drugs rarely have been the sole immunosuppressive therapy administered prior to diagnosis.

As suggested by the name, the key characteristic of HSTCL is almost always the finding of marked hepatosplenomegaly without concomitant lymphadenopathy. The bone marrow is frequently involved. Other associated presenting symptoms may be anemia, thrombocytopenia, B symptoms, neutropenia, hematophagocytic syndrome, as well as a possible elevation in the absolute lymphocyte count.

The diagnosis may be made at the time of splenectomy for presumed idiopathic thrombocytopenic purpura, by core needle biopsy of the liver for work-up of the associated liver abnormalities, or at times by a bone marrow biopsy. The diagnosis is often difficult to make and it is important to note that uncommon benign situations (post solid organ transplant, self-limiting viral illness, Epstein-Barr virus [EBV] viremia) may be accompanied by an incidental finding of increased circulating gamma delta T-cells and their presence alone is not sufficient for the diagnosis. Review of biopsy material by an expert hematopathologist is recommended.

Once the diagnosis of HSTCL is confirmed and the staging work-up is complete, therapy should be initiated promptly as this disease can progress quite rapidly. Patients are typically quite symptomatic and frequently have spent the work-up process in the hospital due to fevers and concerns of infection. Referral to a hospital with expertise in treating such aggressive lymphomas should be considered, given the rarity and unique management of these patients.

Are you sure your patient has hepatosplenic T-cell lymphoma? What should you expect to find?

You should expect to find:

Sinusoidal infiltration of malignant T-cell in the liver and bone marrow
Clonal T-cells and/or abnormal T-cells in abnormal numbers in liver, marrow, spleen, and sometimes blood

All of the below are common features but none are essential for the diagnosis:

Male
Hepatosplenomegaly
Thrombocytopenia
Anemia
Lack of lymphadenopathy
History of inflammatory bowel disease or immunosuppression
B symptoms (unexplained fevers, unintentional weight loss, and soak the shirt/bed sweats)
Cytogenetic analysis showing isochromosome 7

Beware of other conditions that can mimic hepatosplenic T-cell lymphoma:

Other conditions that can mimic HSTCL:

Acute viral hepatitis
Leptospirosis
Veno-occlusive disease
Idiopathic thrombocytopenic purpura
Hemophagocytic syndrome
Benign or reactive increase in circulating gammadelta T-cells

Which individuals are most at risk for developing hepatosplenic T-cell lymphoma:

Individuals most at risk:

Male
History of inflammatory bowel disease, particularly if on systemic immunosuppressive therapy
History of ongoing use of immunosuppression (solid organ transplant or bone marrow transplant)
History of Hodgkin lymphoma
History of malarial infection

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Complete blood count (CBC)

Early presentation: Single lineage depression (leukopenia, anemia, thrombocytopenia) that often results in further risk based testing
Late presentation: Pancytopenia as a result of bone marrow infiltration and suppression by HSTCL or hematophagocytosis

Complete metabolic panel (CMP)

High BUN/Cr (blood urea nitrogen/creatinine ratio: Highly catabolic state)
Hypoalbuminemia: Likely a result of negative acute phase reactant and/or poor synthetic function
Transaminitis (elevated alanine transaminase [ALT]/aspartate transaminase [AST]: Often elevated but usually less than 1,000)
Cholestatic (elevated alkaline phosphatase and bilirubin: While the portal triad typically remains uninvolved, subsequent disease infiltration results in accumulation of unconjugated bilirubin)

Prothrombin time (PT)/international normalized ratio (INR)

Elevated: Secondary to poor synthetic function

Lactate dehydrogenase (LDH)

Elevated: As a result of high cellular turnover

Ferritin

Elevated: Acute phase reactant but should be less than 1,000; if greater than 1,000, consider concomitant hemophagocytic syndrome

Bone marrow/peripheral flow cytometry

Immunophenotyping: CD2+, CD3+, CD4-, CD5-, CD7+, CD8-
In addition to a diagnostic lymphoma panel, request betaF-1 (negative) , gammadelta (positive) and CD52 antibody testing (rare alpha beta expressing cases will stain positive for Beta F1 and negative for gamma)

Bone marrow/peripheral cytogenetics/fluorescence in situ hybridization (FISH)

Isochromosome 7q and trisomy 8 are commonly seen but not diagnostic

Molecular studies

Frequently, analysis of the T-cell receptor for gammadelta gene rearrangement demonstrating clonality can clinch the diagnosis.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of hepatosplenic T-cell lymphoma?

Ultrasound

Documents both hepatic/splenic architecture, size, and flow.

Computer tomography (CT)

Helpful to demonstrate lack of locoregional lymphadenopathy.

If you decide the patient has hepatosplenic T-cell lymphoma, what therapies should you initiate immediately?

Intravenous hydration, allopurinol (renally dosed)

Consideration of transfer/referral to center with experience in treating these rare aggressive lymphomas.

Institution of combination chemotherapy as below.

More definitive therapies?

While there is no standard induction chemotherapy for the treatment of HSTCL, it is generally felt that CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like therapies are less likely to result in adequate disease eradication. Anecdotally, etoposide has been felt to be an important drug given its success as a single agent in hemophagocytic syndrome. Therefore, several etoposide containing high intensity regimens have been of notable utility including ICE (ifosfamide, carboplatin, etoposide), IVAC (ifosfamide, etoposide, and high-dose cytarabine), EPOCH (etoposide, doxorubicin, vincristine, prednisone, and cyclophosphamide), and ESHAP (etoposide, the steroid methylprednisolone, high-dose cytarabine [Ara-C], and cisplatin).

Other regimens such as DHAP (dihydroxyacetone phosphate) and hyper-CVAD have also been used successfully to induce remissions. Many believe these conventional therapies alone are unlikely to be curative and kinetic failures (evidence of regrowth between cycles) are seen. Consolidative therapy with high dose therapy and stem cell transplantation in first remission is recommended. Allogeneic stem cell transplantation is generally preferred when possible, but long term remissions have occurred with autologous stem cells, when no donor source was available.

What other therapies are helpful for reducing complications?

While undergoing intensive chemotherapy should consider:

Antiviral: Acyclovir
Antifungal: Fluconazole
Anti-PCP (pneumocystis pneumonia):Trimethoprim/sulfamethoxazole (Bactrim DS [double strength])
Frequent monitoring of complete blood count (CBC) for transfusion requirements
The role of central nervous system (CNS) prophylaxis is unknown

What should you tell the patient and the family about prognosis?

The work-up that may precede the diagnosis HSTCL is often prolonged, as the diagnosis is often difficult to confirm and infection may be initially suspected. This can take an emotional toll on all parties involved.

Historically this is a very poor prognosis disease. However, with the earlier recognition of the disease, the understanding of the limitations of CHOP therapy, and the early implementation of high dose therapy and stem cell transplantation, more patients are achieving long term remission than in previous times. Therefore, the patient and family should approach this with cautious optimism as the treatment is difficult but cure is possible.

Given the propensity of this disease to relapse quickly off therapy, human leukocyte antigen (HLA) typing of the patient and siblings, as well as a consultation with an allogeneic stem cell transplantation team, should be considered early in the treatment course.

What if scenarios.

As discussed above, an initial chemosensitive response with large percentage tumor bulk reduction is commonly seen after the initial cycle; however, subsequent close monitoring for signs/symptoms of chemorefractory disease is often necessary for further cycles. In patients who do not respond adequately to initial therapy or relapse, anecdotal responses with drugs such as alemtuzumab (this is a reason to check CD52 status at diagnosis), pentostatin, and pralatrexate are reported.

Pathophysiology

Please see introduction.

What other clinical manifestations may help me to diagnose hepatosplenic T-cell lymphoma?

The first step is to consider the diagnosis

Hepatosplenomegaly in a patient with inflammatory bowel disease or other history of immunosuppression should raise the question of HSTCL.

A similar presentation in an otherwise healthy individual in whom no other source is identified should be considered for a liver or bone marrow biopsy.

What other additional laboratory studies may be ordered?

Other studies:

Uric acid
Lactic acid
Haptoglobin
HLA typing (patient & siblings), once diagnosis confirmed

What’s the evidence?

Gaulard, P, Belhadj, K, Reyes, F. “Gamma delta T-cell lymphomas”. Semin Hematol.. vol. 40. 2003. pp. 233-243. [A nice review of the clinicopathologic characteristics of HSTCL.]

Falchook, GS, Vega, F, Dang, NH. “Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment”. Ann Oncol.. vol. 20. 2009. pp. 1080-5. [Relatively large retrospective series from MD Anderson in patients with HSTCL.]

Tey, SK, Marlton, PV, Hawley, CM, Norris, D, Gill, DS. “Post-transplant hepatosplenic T-cell lymphoma successfully treated with HyperCVAD regimen”. Am J Hematol.. vol. 83. 2008. pp. 330-333. [A report of a single patient treated with hyperCVAD and a review of the literature.]

Corazzelli, G, Capobianco, G, Russo, F, Frigeri, F, Aldinucci, D, Pinto, A. “Pentostatin (2'-deoxycoformycin) for the treatment of hepatosplenic gammadelta T-cell lymphomas”. Haematologica.. vol. 90. 2005. pp. e39-e41. [Small case series of patients with refractory disease treated with single agent pentostatin.]

Konuma, T, Ooi, J, Takahashi, S. “Allogeneic stem cell transplantation for hepatosplenic gammadelta T-cell lymphoma”. Leuk Lymphoma.. vol. 48. 2007. pp. 630-632. [Case report of a single patient treated with an allogeneic stem cell transplantation with extensive literature review.]

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