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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
Lacking specific symptoms, HSGDTCL is usually diagnosed late. The diagnosis should be suspected in young men who present with the aforementioned symptoms. However, not everyone with HSGDTCL falls in that group—the present patient was a 77-year-old woman.
Hepatosplenic GDTCL staging is similar to staging of other non-Hodgkin lymphomas. Total-body CT with contrast, bone marrow aspiration/biopsy, and direct lesion biopsy are required. Although positron emission tomography is generally thought to be as useful in TCL as in B-cell lymphomas, there is not enough evidence to support its use specifically in HSGDTCL.16 The staging classification follows the Ann Arbor system, with the majority of cases classified as stage IV.
Hepatosplenic GDTCL are aggressive tumors with a strong tendency to rapidly progress, and they are highly resistant to primary chemotherapy agents. Remission is rarely complete with use of conventional chemotherapy agents. Most patients die of the disease within 2 years of
diagnosis.12 Although the rarity of HSGDTCL has made it difficult to identify any clear prognostic factors, a correlation between thrombocytopenia severity and disease progression has been found in many studies.17 There is no standard treatment regimen. Proposed therapies
include splenectomy (for diagnosis or thrombocytopenia management), corticosteroids, alkylating agents, purine analogue, anthracycline-containing regimens, and cytarabine/cisplatin combinations. The anthracycline-based regimen most commonly used as first-line therapy is CHOP, or CHOP derivatives, with complete remission rates between 30% and 45%. However, long-term results remain disappointing (median relapse time 4 months).10 In 3 reviews, median survival was 16 months, 11 months, and 9.5 months.10,17,18 In the International T-Cell Lymphoma Project study, the 5-year failure-free survival rate was 0%, and the overall survival rate was 7%.4 In these studies, the majority of patients received some variation of CHOP-based therapy, and although positive responses were appreciated in many of the cases, they were generally short-lived.
These results have been disappointing, and other modalities have been tried—including high-dose cytarabine regimens, 2'-deoxycoformycin (pentostatin), and anti-CD52 monoclonal antibodies (alemtuzumab).19 In an HSGDTCL study, 2 of 21 patients treated with platinum/cytarabine-based induction regimens were still in remission at 42 and 52 months.17 Another study examined a variety of induction regimens used to treat HSGDTCL in 15 patients.18 Responses tended to be more durable in patients who received a dose-intense Hyper-CVIDDoxil regimen (fractionated cyclophosphamide, liposomal doxorubicin, vincristine, dexamethasone) alternated with methotrexate and cytarabine. Complete response was 50%, and median duration of complete response was 8 months. Over the past 10 years, a few case reports have described successful treatment with autologous or allogeneic stem cell transplantation.20
Conclusion
The present case represents a unique HSGDTCL presentation. To the authors’ knowledge, this is the first report of HSGDTCL presenting with acute disseminated intravascular coagulation and AIHA with both cold and warm antibodies.
Hepatosplenic GDTCL is a rare, novel disease. To understand more about this pathology, investigators need to better characterize the disease process and the manifestations. The hope is that more information will contribute to the development of more effective therapies. The unique presentation reported here may help in further characterizing and understanding this uncommon disease.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.
Click here to read the digital edition.
1. Saito H, Kranz DM, Takagaki Y, Hayday AC, Eisen HN, Tonegawa S. A third rearranged and expressed gene in a clone of cytotoxic T lymphocytes. Nature. 1984;312(5989):36-40.
2. Gaulard P, Zafrani ES, Mavier P, et al. Peripheral T-cell lymphoma presenting as predominant liver disease: a report of three cases. Hepatology. 1986;6(5):864-868.
3. Gaulard P, de Leval L. Pathology of peripheral T-cell lymphomas: where do we stand? Semin Hematol. 2014;51(1):5-16.
4. Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124-4130.
5. The International Agency for Research on Cancer. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Vol 2. 4th ed. Lyon, France: IARC Press; 2008.
6. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasm: a proposal from the International Lymphoma Study Group. Blood. 1994;84(5):1361-1392.
7. Farcet JP, Gaulard P, Marolleau JP, et al. Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta. Blood. 1990;75(11):2213-2219.
8. Bluestone JA, Khattri R, Sciammas R, Sperling AI. TCR gamma delta cells: a specialized T-cell subset in the immune system. Annu Rev Cell Dev Biol. 1995;11:307-353.
9. Holtmeier W, Kabelitz D. Gamma delta T cells link innate and adaptive immune responses. Chem Immunol Allergy. 2005;86:151-183.
10. Weidmann E. Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990. Leukemia. 2000;14(6):991-997.
11. Yu WW, Hsieh PP, Chuang SS. Cutaneous EBV-positive γδ T-cell lymphoma vs. extranodal NK/T-cell lymphoma: a case report and literature review. J Cutan Pathol. 2013;40(3):310-316.
12. Tripodo C, Iannitto E, Florena AM, et al. Gamma-delta T-cell lymphomas. Nat Rev Clin Oncol. 2009;6(12):707-717.
13. Foppoli M, Ferreri AJM. Gamma-delta T-cell lymphomas. Eur J Haematol. 2015;94(3):206-218.
14. Hoffbrand AV, Catovsky D, Tuddenham EGD, Green AR, eds. Postgraduate Haematology. 6th ed. Oxford, England: Wiley-Blackwell; 2011.
15. Valent P, Lechner K. Diagnosis and treatment of autoimmune haemolytic anaemias in adults: a clinical review. Wien Klin Wochenschr. 2008;120(5-6):136-151.
16. Khong PL, Pang CB, Liang R, Kwong YL, Au WY. Fluorine-18 fluorodeoxyglucose positron emission tomography in mature T-cell and natural killer cell malignancies. Ann Hematol. 2008;87(8):613-621.
17. 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):4261-4269.
18. Falchook GS, Vega F, Dang NH, et al. Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment. Ann Oncol. 2009;20(6):1080-1085.
19. Konuma T, Ooi J, Takahashi S, et al. Allogeneic stem cell transplantation for hepatosplenic
gammadelta T-cell lymphoma. Leuk Lymphoma. 2007;48(3):630-632.
20. Ferreri AJ, Govi S, Pileri SA. Hepatosplenic gamma-delta T-cell lymphoma. Crit
Rev Oncol Hematol. 2012;83(2):283-292.
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
Lacking specific symptoms, HSGDTCL is usually diagnosed late. The diagnosis should be suspected in young men who present with the aforementioned symptoms. However, not everyone with HSGDTCL falls in that group—the present patient was a 77-year-old woman.
Hepatosplenic GDTCL staging is similar to staging of other non-Hodgkin lymphomas. Total-body CT with contrast, bone marrow aspiration/biopsy, and direct lesion biopsy are required. Although positron emission tomography is generally thought to be as useful in TCL as in B-cell lymphomas, there is not enough evidence to support its use specifically in HSGDTCL.16 The staging classification follows the Ann Arbor system, with the majority of cases classified as stage IV.
Hepatosplenic GDTCL are aggressive tumors with a strong tendency to rapidly progress, and they are highly resistant to primary chemotherapy agents. Remission is rarely complete with use of conventional chemotherapy agents. Most patients die of the disease within 2 years of
diagnosis.12 Although the rarity of HSGDTCL has made it difficult to identify any clear prognostic factors, a correlation between thrombocytopenia severity and disease progression has been found in many studies.17 There is no standard treatment regimen. Proposed therapies
include splenectomy (for diagnosis or thrombocytopenia management), corticosteroids, alkylating agents, purine analogue, anthracycline-containing regimens, and cytarabine/cisplatin combinations. The anthracycline-based regimen most commonly used as first-line therapy is CHOP, or CHOP derivatives, with complete remission rates between 30% and 45%. However, long-term results remain disappointing (median relapse time 4 months).10 In 3 reviews, median survival was 16 months, 11 months, and 9.5 months.10,17,18 In the International T-Cell Lymphoma Project study, the 5-year failure-free survival rate was 0%, and the overall survival rate was 7%.4 In these studies, the majority of patients received some variation of CHOP-based therapy, and although positive responses were appreciated in many of the cases, they were generally short-lived.
These results have been disappointing, and other modalities have been tried—including high-dose cytarabine regimens, 2'-deoxycoformycin (pentostatin), and anti-CD52 monoclonal antibodies (alemtuzumab).19 In an HSGDTCL study, 2 of 21 patients treated with platinum/cytarabine-based induction regimens were still in remission at 42 and 52 months.17 Another study examined a variety of induction regimens used to treat HSGDTCL in 15 patients.18 Responses tended to be more durable in patients who received a dose-intense Hyper-CVIDDoxil regimen (fractionated cyclophosphamide, liposomal doxorubicin, vincristine, dexamethasone) alternated with methotrexate and cytarabine. Complete response was 50%, and median duration of complete response was 8 months. Over the past 10 years, a few case reports have described successful treatment with autologous or allogeneic stem cell transplantation.20
Conclusion
The present case represents a unique HSGDTCL presentation. To the authors’ knowledge, this is the first report of HSGDTCL presenting with acute disseminated intravascular coagulation and AIHA with both cold and warm antibodies.
Hepatosplenic GDTCL is a rare, novel disease. To understand more about this pathology, investigators need to better characterize the disease process and the manifestations. The hope is that more information will contribute to the development of more effective therapies. The unique presentation reported here may help in further characterizing and understanding this uncommon disease.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.
Click here to read the digital edition.
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
Lacking specific symptoms, HSGDTCL is usually diagnosed late. The diagnosis should be suspected in young men who present with the aforementioned symptoms. However, not everyone with HSGDTCL falls in that group—the present patient was a 77-year-old woman.
Hepatosplenic GDTCL staging is similar to staging of other non-Hodgkin lymphomas. Total-body CT with contrast, bone marrow aspiration/biopsy, and direct lesion biopsy are required. Although positron emission tomography is generally thought to be as useful in TCL as in B-cell lymphomas, there is not enough evidence to support its use specifically in HSGDTCL.16 The staging classification follows the Ann Arbor system, with the majority of cases classified as stage IV.
Hepatosplenic GDTCL are aggressive tumors with a strong tendency to rapidly progress, and they are highly resistant to primary chemotherapy agents. Remission is rarely complete with use of conventional chemotherapy agents. Most patients die of the disease within 2 years of
diagnosis.12 Although the rarity of HSGDTCL has made it difficult to identify any clear prognostic factors, a correlation between thrombocytopenia severity and disease progression has been found in many studies.17 There is no standard treatment regimen. Proposed therapies
include splenectomy (for diagnosis or thrombocytopenia management), corticosteroids, alkylating agents, purine analogue, anthracycline-containing regimens, and cytarabine/cisplatin combinations. The anthracycline-based regimen most commonly used as first-line therapy is CHOP, or CHOP derivatives, with complete remission rates between 30% and 45%. However, long-term results remain disappointing (median relapse time 4 months).10 In 3 reviews, median survival was 16 months, 11 months, and 9.5 months.10,17,18 In the International T-Cell Lymphoma Project study, the 5-year failure-free survival rate was 0%, and the overall survival rate was 7%.4 In these studies, the majority of patients received some variation of CHOP-based therapy, and although positive responses were appreciated in many of the cases, they were generally short-lived.
These results have been disappointing, and other modalities have been tried—including high-dose cytarabine regimens, 2'-deoxycoformycin (pentostatin), and anti-CD52 monoclonal antibodies (alemtuzumab).19 In an HSGDTCL study, 2 of 21 patients treated with platinum/cytarabine-based induction regimens were still in remission at 42 and 52 months.17 Another study examined a variety of induction regimens used to treat HSGDTCL in 15 patients.18 Responses tended to be more durable in patients who received a dose-intense Hyper-CVIDDoxil regimen (fractionated cyclophosphamide, liposomal doxorubicin, vincristine, dexamethasone) alternated with methotrexate and cytarabine. Complete response was 50%, and median duration of complete response was 8 months. Over the past 10 years, a few case reports have described successful treatment with autologous or allogeneic stem cell transplantation.20
Conclusion
The present case represents a unique HSGDTCL presentation. To the authors’ knowledge, this is the first report of HSGDTCL presenting with acute disseminated intravascular coagulation and AIHA with both cold and warm antibodies.
Hepatosplenic GDTCL is a rare, novel disease. To understand more about this pathology, investigators need to better characterize the disease process and the manifestations. The hope is that more information will contribute to the development of more effective therapies. The unique presentation reported here may help in further characterizing and understanding this uncommon disease.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.
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1. Saito H, Kranz DM, Takagaki Y, Hayday AC, Eisen HN, Tonegawa S. A third rearranged and expressed gene in a clone of cytotoxic T lymphocytes. Nature. 1984;312(5989):36-40.
2. Gaulard P, Zafrani ES, Mavier P, et al. Peripheral T-cell lymphoma presenting as predominant liver disease: a report of three cases. Hepatology. 1986;6(5):864-868.
3. Gaulard P, de Leval L. Pathology of peripheral T-cell lymphomas: where do we stand? Semin Hematol. 2014;51(1):5-16.
4. Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124-4130.
5. The International Agency for Research on Cancer. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Vol 2. 4th ed. Lyon, France: IARC Press; 2008.
6. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasm: a proposal from the International Lymphoma Study Group. Blood. 1994;84(5):1361-1392.
7. Farcet JP, Gaulard P, Marolleau JP, et al. Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta. Blood. 1990;75(11):2213-2219.
8. Bluestone JA, Khattri R, Sciammas R, Sperling AI. TCR gamma delta cells: a specialized T-cell subset in the immune system. Annu Rev Cell Dev Biol. 1995;11:307-353.
9. Holtmeier W, Kabelitz D. Gamma delta T cells link innate and adaptive immune responses. Chem Immunol Allergy. 2005;86:151-183.
10. Weidmann E. Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990. Leukemia. 2000;14(6):991-997.
11. Yu WW, Hsieh PP, Chuang SS. Cutaneous EBV-positive γδ T-cell lymphoma vs. extranodal NK/T-cell lymphoma: a case report and literature review. J Cutan Pathol. 2013;40(3):310-316.
12. Tripodo C, Iannitto E, Florena AM, et al. Gamma-delta T-cell lymphomas. Nat Rev Clin Oncol. 2009;6(12):707-717.
13. Foppoli M, Ferreri AJM. Gamma-delta T-cell lymphomas. Eur J Haematol. 2015;94(3):206-218.
14. Hoffbrand AV, Catovsky D, Tuddenham EGD, Green AR, eds. Postgraduate Haematology. 6th ed. Oxford, England: Wiley-Blackwell; 2011.
15. Valent P, Lechner K. Diagnosis and treatment of autoimmune haemolytic anaemias in adults: a clinical review. Wien Klin Wochenschr. 2008;120(5-6):136-151.
16. Khong PL, Pang CB, Liang R, Kwong YL, Au WY. Fluorine-18 fluorodeoxyglucose positron emission tomography in mature T-cell and natural killer cell malignancies. Ann Hematol. 2008;87(8):613-621.
17. 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):4261-4269.
18. Falchook GS, Vega F, Dang NH, et al. Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment. Ann Oncol. 2009;20(6):1080-1085.
19. Konuma T, Ooi J, Takahashi S, et al. Allogeneic stem cell transplantation for hepatosplenic
gammadelta T-cell lymphoma. Leuk Lymphoma. 2007;48(3):630-632.
20. Ferreri AJ, Govi S, Pileri SA. Hepatosplenic gamma-delta T-cell lymphoma. Crit
Rev Oncol Hematol. 2012;83(2):283-292.
1. Saito H, Kranz DM, Takagaki Y, Hayday AC, Eisen HN, Tonegawa S. A third rearranged and expressed gene in a clone of cytotoxic T lymphocytes. Nature. 1984;312(5989):36-40.
2. Gaulard P, Zafrani ES, Mavier P, et al. Peripheral T-cell lymphoma presenting as predominant liver disease: a report of three cases. Hepatology. 1986;6(5):864-868.
3. Gaulard P, de Leval L. Pathology of peripheral T-cell lymphomas: where do we stand? Semin Hematol. 2014;51(1):5-16.
4. Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124-4130.
5. The International Agency for Research on Cancer. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Vol 2. 4th ed. Lyon, France: IARC Press; 2008.
6. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasm: a proposal from the International Lymphoma Study Group. Blood. 1994;84(5):1361-1392.
7. Farcet JP, Gaulard P, Marolleau JP, et al. Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta. Blood. 1990;75(11):2213-2219.
8. Bluestone JA, Khattri R, Sciammas R, Sperling AI. TCR gamma delta cells: a specialized T-cell subset in the immune system. Annu Rev Cell Dev Biol. 1995;11:307-353.
9. Holtmeier W, Kabelitz D. Gamma delta T cells link innate and adaptive immune responses. Chem Immunol Allergy. 2005;86:151-183.
10. Weidmann E. Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990. Leukemia. 2000;14(6):991-997.
11. Yu WW, Hsieh PP, Chuang SS. Cutaneous EBV-positive γδ T-cell lymphoma vs. extranodal NK/T-cell lymphoma: a case report and literature review. J Cutan Pathol. 2013;40(3):310-316.
12. Tripodo C, Iannitto E, Florena AM, et al. Gamma-delta T-cell lymphomas. Nat Rev Clin Oncol. 2009;6(12):707-717.
13. Foppoli M, Ferreri AJM. Gamma-delta T-cell lymphomas. Eur J Haematol. 2015;94(3):206-218.
14. Hoffbrand AV, Catovsky D, Tuddenham EGD, Green AR, eds. Postgraduate Haematology. 6th ed. Oxford, England: Wiley-Blackwell; 2011.
15. Valent P, Lechner K. Diagnosis and treatment of autoimmune haemolytic anaemias in adults: a clinical review. Wien Klin Wochenschr. 2008;120(5-6):136-151.
16. Khong PL, Pang CB, Liang R, Kwong YL, Au WY. Fluorine-18 fluorodeoxyglucose positron emission tomography in mature T-cell and natural killer cell malignancies. Ann Hematol. 2008;87(8):613-621.
17. 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):4261-4269.
18. Falchook GS, Vega F, Dang NH, et al. Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment. Ann Oncol. 2009;20(6):1080-1085.
19. Konuma T, Ooi J, Takahashi S, et al. Allogeneic stem cell transplantation for hepatosplenic
gammadelta T-cell lymphoma. Leuk Lymphoma. 2007;48(3):630-632.
20. Ferreri AJ, Govi S, Pileri SA. Hepatosplenic gamma-delta T-cell lymphoma. Crit
Rev Oncol Hematol. 2012;83(2):283-292.