Case Study: 48-Year-Old Woman With Weight Loss, Hepatomegaly, and Splenomegaly

A 48-year-old woman with no significant medical history presented with a two-month history of abdominal fullness and 11.3 kg weight loss. She reported generalized abdominal pain and denied fever, night sweats, diarrhea, nausea, or vomiting. She denied any alcohol or illicit drug use. Physical examination revealed diffuse abdominal tenderness with hepatomegaly and splenomegaly. Her initial laboratory and imaging results are provided in the Table.

Computed tomography of the abdomen and pelvis showed findings consistent with hepatic cirrhosis along with portal hypertension, splenomegaly, and minimal ascites.

Given the imaging findings, the decision was made to proceed with a liver biopsy, which demonstrated marked infiltration by atypical lymphocytes in a multifocal nodular as well as prominent intrasinusoidal distribution. Flow cytometric examination demonstrated CD8⁺, CD57⁺, and T-cell receptor (TCR) beta-positive lymphocytes. TCR rearrangement was positive by immunohistochemistry. Fluorescence in situ hybridization testing was negative for isochromosome 7q. A bone marrow biopsy confirmed the presence of the same lymphocyte population involving 15 percent of the marrow with normal cytogenetics.

What is the most likely diagnosis?

1. Hepatosplenic T-cell lymphoma
2. Aggressive natural killer cell large granular lymphocytic (NK-LGL) leukemia
3. T-cell large granular lymphocytic (T-LGL) leukemia
4. Chronic NK lymphocytosis
5. T-cell lymphoproliferative disorder (LPD)

Answer: C

LGL leukemia is an uncommon disorder affecting one in 10 million people in the United States, with a median age of 60 years at presentation.¹ LGL leukemia can be of T- or NK-cell lineage. Patients with T-LGL leukemia usually present with symptoms related to neutropenia such as fever and recurrent bacterial infections; however, one third of the patients are asymptomatic. They can also present with other B-like symptoms such as fatigue, weight loss, and drenching night sweats. Most cases of T-LGL leukemia are associated with autoimmune or connective tissue disorders, most commonly rheumatoid arthritis in 40 percent of cases. It can also be associated with hematologic disorders such as myelodysplastic syndrome, autoimmune cytopenias, and Hodgkin lymphoma.

Patients with T-LGL leukemia usually have a modestly increased LGL count, higher than 2,000 LGLs/µL in most patients (normal range, 200-400 LGLs/µL), and the absolute lymphocyte count can be increased or normal.¹ The bone marrow is involved in 90 percent of cases, and bone marrow biopsy and aspirate are only needed in patients with atypical presentations (as in the patient described here) or in patients with a low LGL count. Immunophenotypic studies are needed to establish the diagnosis and typically reveal T-LGLs that express CD3, CD8, CD16, and CD57, but do not usually express CD4, CD56, or CD28. Identification of clonally rearranged TCR genes is a key factor in the diagnosis of T-LGL leukemia. Most cases are alpha/beta variants, while fewer than 10 percent being gamma/delta variants.

Asymptomatic patients do not require treatment and can be closely monitored.² Treatment is reserved for patients with symptoms due to cytopenias or associated autoimmune disorders. Immunosuppressive therapy with methotrexate, cyclophosphamide, or cyclosporine constitutes the mainstay of treatment for LGL leukemia. The choice of treatment is based on the clinical setting, the presenting symptoms, and associated conditions. For example, if a patient presents with rheumatoid arthritis and T-LGL leukemia, then methotrexate (10 mg/m² weekly) plus prednisone (1 mg/kg/d for a month followed by a taper) would be the preferred treatment.

The response to treatment should be evaluated with history, physical examination, and complete blood count with differential.² Complete remission is defined as a complete normalization of blood counts in the setting of a circulating LGL count of less than 500 LGLs/µL. Patients with at least a partial response should be continued on their current therapy until treatment failure or until the maximum number of months has elapsed for that regimen, whichever is shorter.

In summary, T-LGL leukemia is an uncommon disease that presents in the sixth decade with symptoms of neutropenia and is most often associated with rheumatoid arthritis. The diagnosis is made based on immunophenotypic features of T-LGLs (CD8⁺, CD57⁺, TCR alpha/beta⁺). Treatment when indicated is usually with immunosuppressive agents such as methotrexate, cyclophosphamide, and cyclosporine.

References:

1. Lamy T, Moignet A, Loughran Jr TP. LGL leukemia: from pathogenesis to treatment. Blood. 2017;129:1082-1094.
2. Lamy T, Loughran Jr TP. How I treat LGL leukemia. Blood. 2011;117:2764-2774.

Case contributed by Dr. Fawzi Abu Rous, PGY-IV Hematology and Oncology Fellow, Henry Ford Cancer Institute, Detroit, MI, and Dr. Nino Balanchivadze, PGY-V Hematology and Oncology Fellow, Henry Ford Cancer Institute, Detroit, MI.