Hepatosplenic T-Cell Lymphoma: What to Know

Rare lymphoma occurs without lymph node enlargement

Marjan_Apostolovic/istock 

Hepatosplenic T-cell lymphoma (HSTCL) is a very rare lymphoma. Known clinically as “hepatosplenic γ δ T-cell lymphoma," this illness has only rarely been reported in the scientific literature, and so its true incidence is unknown.

HSTCL has often been seen in younger men, though cases involving women and children have also been documented. Also, there seems to be a link to increased risk of HSTCL in immunocompromised patients.

Based on published cases, HSTCL is likely to be misdiagnosed at first, and it carries a relatively poor prognosis.

Symptoms 

  • Generalized malaise
  • Fatigue
  • Symptoms of low blood counts (anemia, thrombocytopenia)
    • Anemia can produce fatigue, tiredness
    • Thrombocytopenia can cause easy bruising or bleeding
  • Constitutional symptoms, including the following:
    • Unexplained fevers
    • Weight loss without trying to lose weight
    • Night sweats that soak your shirt or sheets
  • Abdominal fullness, tightness, or pain (due to enlarged liver, enlarged spleen)
  • Lack of any detectible swollen lymph nodes
    • In contrast to many lymphomas, this one typically does not involve any detectible lymph nodes, or lumps and bumps, that you might feel under the skin in the neck, armpits, or groin.

Risk Factors

  • Male gender has been traditionally considered a risk factor based on the first published case series.
  • Continued use of immunosuppression, either currently, or in years past:
    • Organ transplant medication
    • Systemic therapy for inflammatory bowel disease (Crohn’s disease or ulcerative colitis)
  • Past medical history:
    • Kidney transplant or other solid organ transplant
    • History of malaria
    • History EBV-positive Hodgkin disease

Although the above profile has been compiled, it should be noted that descriptions of HSTCL draw on a relatively limited number of cases.

HSTCL is believed to account for less than 2 percent of all peripheral T-cell lymphomas.

Despite its unknown cause, approximately 10 to 20 percent of patients affected with this lymphoma have a previous history of chronic immune suppression, such as solid organ transplantation, lymphoproliferative disorder, inflammatory bowel disease, hepatitis B infection, or immunosuppressive therapy.

Examining Immunosuppression

In a study by Parakkal and colleagues, twenty-five cases of HSTCL were identified among patients using immunosuppressive therapy. Twenty-two (88 percent of patients) had inflammatory bowel disease and three had rheumatoid arthritis. Four cases (16 percent) were in women and four patients were above 65 years of age. Twenty-four cases (96 percent) also received an immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate). Two patients received adalimumab alone.

In the study by Deepak and colleagues, a total of 3,130,267 reports were downloaded from the FDA adverse event reporting system (2003-2010). Ninety-one cases of T-cell NHL with TNF-α inhibitors were identified in the FDA AERS and nine additional cases were identified using literature search. A total of 38 patients had rheumatoid arthritis, 36 cases had Crohn's disease, 11 had psoriasis, nine had ulcerative colitis, and six had ankylosing spondylitis.

Sixty-eight of the cases (68 percent) involved exposure to both a TNF-α inhibitor and an immunomodulator (azathioprine, 6-mercaptopurine, methotrexate, leflunomide, or cyclosporine). Hepatosplenic T-cell lymphoma (HSTCL) was the most common reported subtype, whereas mycosis fungoides/Sezary syndrome and HSTCL were identified as more common with TNF-α-inhibitor exposure.

Diagnosis

Hepatosplenic T-cell lymphoma may take a long time to diagnose, since many more common conditions may be considered first. The diagnosis is based on biopsy specimens of bone marrow, liver and/or spleen, and flow cytometry analysis.

Review of biopsy material by an expert hematopathologist is recommended.

Bone marrow biopsies typically show hypercellular (extra space taken up by cells) marrow due to the atypical lymphoid cells, but the changes have been described as subtle. Belhadj and colleagues noted the following in their 2003 report on a series of 21 patients with HSTCL:

This subtle involvement was not immediately recognized in six patients, leading to misdiagnoses of reactive hypercellular marrow in five patients and of chronic myelomonocytic leukemia in another patient with overt monocytosis at initial examination.

However this research group also noted a distinguishing characteristically sinusal pattern of infiltration on routine bone marrow biopsy: “… a peculiar sinusal distribution of tumor cells that, at initial examination, is often subtle and therefore difficult to recognize without immunohistochemistry.”

Specialized laboratory tests such as flow cytometry and immunophenotyping of biopsy specimens are essential tools for diagnosis of HSTCL, but investigators note the importance of having a high index of clinical suspicion.

Physical exam and laboratory tests may also be suggestive. Findings on physical exam, including an enlarged spleen and liver may be present. The complete blood count may show abnormalities such as thrombocytopenia (low platelet counts), anemia (low red blood cell counts), and leukopenia (low white blood cell counts. Liver tests may be essentially normal or show elevated enzymes.

Natural History and Prognosis

HSTCL is characterized by infiltration of the cancerous lymphocytes into the cavernous spaces of the liver, spleen, and bone marrow—all without enlargement of the lymph nodes, or lymphadenopathy.

The invasion of the lymphoma cells can lead to significant enlargement of the spleen and liver. Significant low counts are less common, aside from low platelet counts, which may be severe.

Up to 80 percent of people with HSTCL have the so-called B symptoms, which include fever, night sweats, and unintentional weight loss. The clinical course is highly aggressive, with median overall survival about one year from the time of diagnosis; however, there is much uncertainty regarding the potential better outcomes with earlier detection and appropriate treatment.

Autologous or allogeneic transplantation should be considered as well as patient recruitment to clinical trials. Although data to support these aggressive strategies are limited, the outcome is poor with chemotherapy alone.

Treatment

Once the diagnosis of HSTCL is confirmed and the staging work-up is complete, therapy should be initiated promptly as the disease can progress quite rapidly. No standard therapy exists owing to the rarity of this disease; however, chemotherapy regimens have been introduced based on the extrapolation of studies in other aggressive lymphomas. Hematopoietic stem cell transplant and participation in clinical trials may be among the options considered.

Sources:

Belhadj K, Reyes F, Farcet JP, et al. Hepatosplenic gammadelta T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients. Blood. 2003;102(13):4261-9.

Brinkert F, Arrenberg P, Krech T, et al. Two cases of hepatosplenic T-cell lymphoma in adolescents treated for autoimmune hepatitis. Pediatrics. 2016;138(3).pii: e20154245.

Deepak P, Sifuentes H, Sherid M, et al. T-cell non-Hodgkin's lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: results of the REFURBISH study. Am J Gastroenterol. 2013;108(1):99-105.

Parakkal D, Sifuentes H, Semer R, et al. Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding the groups at risk. Eur J Gastroenterol Hepatol 2011;23:1150–6.