Managing angioimmunoblastic T-cell lymphoma
A 61-year-old man with prior history of hypertension, diabetes and alcoholic cardiomyopathy presented to the clinic with night sweats, a 50-lb weight loss in the past four months and generalized erythematous rash for two years. He had at least four skin biopsies conducted that were consistent with nonspecific vasculitis and dermatitis. He was prescribed 60 mg prednisone for the past three months with minimal relief.
A computed tomography scan of the chest, abdomen and pelvis showed cervical, supraclavicular, axillary, mediastinal and retroperitoneal lymphadenopathy and a 4-cm mass in the right kidney. A biopsy of the right supraclavicular lymph node showed atypical lymphoid aggregate with mixed intermediate and large cells, abundant eosinophils and prominent proliferation of endothelial venules and follicular dendritic cells. The cells were CD3, CD5, CD7 and Bcl-6positive and CD10- and CD20-negative; consistent with the diagnosis of angioimmunoblastic T-cell lymphoma.
A staging bone marrow biopsy was normal. Blood work showed a negative Coombs test and absent hypergammaglobulinemia. His ejection fraction was estimated to be 41% by a multiple gated acquisition scan.
Source: Razaq W
How will you manage this patient?
- Treat with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)
- Treat with cyclophosphamide, etoposide, procarbazine and prednisone (CEPP)
- Treat with alemtuzumab
- Treat with fludarabine
Angioimmunoblastic T-cell lymphoma is a mature peripheral T-cell lymphoma that comprises 15% to 20% of all peripheral T-cell lymphomas and 1% to 2% of non-Hodgkins lymphomas. The disease was initially thought to be a premalignant condition and was termed as angioimmunoblastic lymphadenopathy. The pathophysiology is not fully understood, but there is enough evidence suggesting that angioimmunoblastic T-cell lymphoma develops in a serial fashion. The initial reaction can be an unbalanced immune response to an unknown stimulus followed by an oligoclonal phase that is driven by the persistence of the stimulus. It is assumed that the oligoclonal phase then undergoes a molecular change that gives rise to a malignant monoclonal population. Angioimmunoblastic T-cell lymphoma also has been linked to many viral infections like Epstein-Barr virus, cytomegalovirus and herpes type 6.
The disease preferentially affects elderly men and median age at diagnosis is about 60 years. Clinically, the course of the disease is moderate to highly aggressive, with occasional spontaneous remissions. Most patients present with generalized lymphadenopathy, hepatosplenomegaly, skin rash, fevers and weight loss. Some patients may also present with pleural effusions, ascites and/or edema. Polyclonal hypergammaglobulinemia, a positive Coombs and antinuclear antibody tests are also common lab findings.
Histological examination of the skin rash usually demonstrates a perivascular dermal infiltrate with eosinophils, plasma cells and lymphoid cells that can be mistaken for vasculitis or dermatitis. T-cell gene rearrangement studies are necessary to make the diagnosis because both T and B cells are commonly present in the specimen; however, B-cell proliferations are usually polyclonal. Lymph node biopsy reveals partial effacement of the nodal architecture with polymorphous infiltrate. The most classic finding is the aborization and proliferation of high endothelial venules along with follicular dendritic cells. Angioimmunoblastic T-cell lymphoma is derived from CD2, CD3, CD4, CD5 and CD7 positive mature helper T cells, although significant numbers of non-neoplastic T cells may coexist with the malignant population.
Angioimmunoblastic T-cell lymphoma is an aggressive T-cell lymphoma with dismal prognosis. Polychemotherapy achieves better responses than prednisone alone. Patients are usually prescribed prednisone alone for vasculitis-like skin rash before the chemotherapy with mild to moderate relief. Results from a German non-randomized trial (n=39) by Siegert et al. showed that chemotherapy with cyclophosphamide, doxorubicin, vincristine, bleomycin, procarbazine, prednisone, ifosfamide, methotrexate and etoposide (COP-BLAM / IMVP-16 regimen) demonstrated 64% complete remission with median survival of 15 months. In another non-randomized trial by Pautier et al., the data showed 60% complete response rates with five-year overall survival of only 36% when patients were treated with a CHOPlike regimen. Long-term disease free remissions are, however, reported with autologous bone marrow transplant in the first remission or in chemosensitive recurrent disease.
This patient was unique as his ejection fraction was only 41% and an anthracycline-based regimen was contraindicated. We decided to treat him with cyclophosphamide, etoposide, procarbazine and prednisone (CEPP). He had a complete response after six cycles of chemotherapy with resolution of his skin rash. Subsequently, he was referred for an autologous bone marrow transplant. He tolerated the bone marrow transplant without major adverse events. At present, he has been disease free for 30 months.
Wajeeha Razaq, MD, is a third-year HemOnc Fellow at St. Lukes Roosevelt Hospital Center in New York and a member of the HemOnc Today Editorial Board
For more information:
- Jackow CM, Cather JC, Hearne V, et al. Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion. Blood. 1997;89:32-40.
- Jacob HS. Superantigens cause super trouble: The case for insight-based medicine. Annual AOA lecture; Columbia University College of Physicians & Surgeons; January 2007.
- Pautier P, Devidas A, Delmer A, et al. Angioimmunoblastic-like T-cell non Hodgkins lymphoma: outcome after chemotherapy in 33 patients and review of the literature. Leuk Lymphoma. 1999;32:545-552.
- Siegert W. Agthe A, Griesser H, et al. Treatment of angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma using prednisone with or without the COPBLAM/IMVP-16 regimen. A multicenter study. Kiel Lymphoma Study Group. Ann Intern Med. 1992;117:364-370.
The histology (mainly helper T cells plus eosinophils) plus hypergammaglobulinemia strongly suggest that chronic absorption from skin surfaces of a CD4-stimulating antigen initiates this disorder. Initial oligoclonal proliferation then gives way to more neoplastic mutations. We and others (Jackow et al) have observed this syndrome in several patients with chronic contamination of skin with noninvasive, toxic shock syndrome toxinsecreting Staphylococcus aureus. Of great interest, toxic shock syndrome toxin is a superantigen that specifically stimulates proliferation of CD4 lymphocytes in an oligoclonal fashion. Such patients have been successfully treated with IV infusions of IV gamma globulin, monthly brief administrations of anti-Staphylococcal antibiotics and daily microbial washes (Jacob et al).
Harry S. Jacob, MD
HemOnc Today Chief Medical Editor