γ-δ T-Cell Lymphoma With Disseminated Intravascular Coagulation and Autoimmune Hemolytic Anemia
Gamma-delta (γ-δ) T-cell lymphomas (GDTCL) are rare and aggressive cancers with specific morphologic, phenotypic, and functional properties. When discovered in 1984, the T-cell receptor (TCR) was characterized as an alpha-beta (α-β) heterodimer. The γ-δ heterodimer was discovered later, when a third rearranging gene was recognized.1
Gaulard and colleagues described the first case of peripheral neoplasm with the γ-δ TCR.2 Now the present authors report the case of a patient with an autoimmune hemolytic anemia (AIHA) with both cold and warm antibodies—an atypical presentation of this rare form of TCL. Such a case has not been previously reported.
Clinical History
A 77-year-old woman with a past medical history of osteoarthritis, gout, mitral stenosis, bioprosthetic aortic valve replacement, and obesity presented to the emergency department (ED) reporting progressive weakness, confusion, and jaundice. She had been recently discharged from
another hospital after an 18-day stay for gangrenous cholecystitis and shingles. Her home medications were metronidazole and acyclovir. In the ED, she was febrile at 100.5°. Laboratory test results revealed anemia with a hemoglobin level of 50 g/L (83 g/L in clinic 2 weeks earlier) and neutropenia with an absolute neutrophilic count of 500 cells/μL (normal range 1,520-6,370 cells/μL). She also was thrombocytopenic with a platelet count of 71x109/L (normal range 150-450×109/L).
On admission, the hematology service was consulted for pancytopenia. The pertinent workup included a lactate dehydrogenase level of 31.16 μkat/L (normal range 1.7-3.4 μkat/L), a haptoglobin level of < 1,500 mg/L (normal range 260-1,850 mg/L), and a direct bilirubin level of 13.68 μmol/L (normal range 1.7-5.1 μmol/L). A peripheral blood smear was negative for schistocytes. Fibrin split products were 40 mg/L (normal < 10 mg/L), fibrinogen level was 6.94 μmol/L (normal range 5.8-11.8 μmol/L), prothrombin time was 14.6 seconds (normal range 10-14 sec), and international normalized ratio was 1.3 (normal < 1). The concomitant decrease in fibrinogen level and increase in fibrin split product titers were consistent with the diagnosis of acute disseminated intravascular coagulation. Iron studies were consistent with anemia of chronic disease (low reticulocyte count of 0.4%) and vitamin B12 deficiency (level 195). Coombs test results were positive for both cold and warm antibodies, with cold being more prominent. Abdominal ultrasonography revealed hepatosplenomegaly (HSM).
The patient was diagnosed with AIHA with no initial obvious underlying etiology. The differential diagnosis included autoimmune disorder, lymphoproliferative disease, and drug-induced process. She also was diagnosed with sepsis, which was thought to be contributing to the pancytopenia.
Broad-spectrum antibiotics (cefepime, metronidazole) and vitamin B12 supplements were started. After a blood transfusion, the patient developed fever and hypoxia, which required transfer to the medical intensive care unit. The differentials at this time included a transfusion reaction and/or transfusion-associated circulatory overload. Intravenous immunoglobulin was started at 1 g/kg to help with cold agglutinins. Prednisone 1 mg/kg was started as well. Peripheral blood flow cytometry results were positive for an abnormal T-cell population likely consistent with T-cell lineage lymphoma. Bone marrow biopsy results were consistent with GDTCL. Computed tomography (CT) of chest/abdomen/pelvis showed bilateral lung nodules < 1 cm, HSM with multiple spleen infarcts, and a 4.7-cm right adnexal soft-tissue lesion. Liver biopsy results were consistent with GDTCL. Results of a workup for cytomegalovirus and Epstein-Barr virus were negative, as was a mycoplasma screen. The patient was diagnosed with GDTCL with hepatic involvement, and CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone) therapy was started.
Discussion
Peripheral TCL (PTCL) are a rare, typically extranodal group of malignancies. They are aggressive and generally have a poor outcome, with most patients dying of lymphoma within 2 years.3 T-cell lymphomas most commonly express the γ-δ TCR. About 2% to 4% of TCLs express the γ-δ TCR.4 In 2008, the World Health Organization recognized 2 distinct GDTCL subgroups: hepatosplenic GDTCL (HSGDTCL) and primary cutaneous GDTCL.5 As the patient presented with hepatic involvement, this discussion focused on HSGDTCL.
Hepatosplenic GDTCL are rare types of PTCL. First described as a separate TCL subgroup in the 1990 REAL (Revised European-American Lymphoma) classification,6 they are estimated to represent about 1.4% of all TCL, with about 100 cases reported in the literature.4
The GDTCL cells tend to live in mucosa, lymphoid tissue, epithelial-rich tissues (skin, gastrointestinal tract), and red pulp of spleen.7 They develop from thymic precursors in bone marrow and are CD4-/CD8- and thus known as double negative cells.8 They mimic natural killer cells, behave as cytotoxic cells, and are capable of TCR rearrangement as well as phagocytosis.9
Hepatosplenic GDTCL are usually phenotypically CD2+, CD3+, CD4-, CD5-, CD7+, CD8-, and TCR γ-δ+.10 They are rarely associated with Epstein-Barr virus infection; reported cases seem more common in Asia.11 Peak incidence is in young men (median age 20-25 years; male:female ratio 10:1). At-risk populations include the chronically immunosuppressed, including solid organ transplanted patients and patients under prolonged antigenic stimulation.12
The most common clinical features of HSGDTCL include B symptoms (fever of unknown origin, night sweats, loss of > 10% of body weight), marked HSM, and lack of lymphadenopathy. Patients often present with fever, weakness, and abdominal pain. Laboratory test results
typically show abnormal liver function and abnormal lactate dehydrogenase levels. Bone marrow is almost always involved, with possible trilineage cytopenia. Anemia and thrombocytopenia are reported in 75% and 85% of cases, respectively.13
Warm (70%) and cold auto-antibodies are the 2 classifications of AIHA.14 The AIHA can be primary, idiopathic, or a manifestation of underlying disease conditions, including non-Hodgkin lymphomas, systemic autoimmune diseases, chronic infections, postorgan transplantation, and solid tumors. It has also been reported as a complication of treatment with nucleoside analogues.15
