Paraneoplastic Phenomena and Diagnostic Challenges in Angioimmunoblastic T-Cell Lymphoma (AITL): Report of Two Cases and Review of the Literature

Case Series

Case 1. The first case was a 74-year-old man who presented with a two-week history of fatigue, dyspnea and night sweats. He had a past medical history of ischemic cardiomyopathy and classical Hodgkin's lymphoma stage IIIB first diagnosed in 1997. After having been treated initially with four cycles of Cyclophosphamid, Oncovin, Procabazin, Prednison (COPP) and Adriamycin, Bleomycin, Vinblastin, Dacarbazin (ABVD) the patient attained a complete remission (CR). Re-treatment with ABVD followed by involved-field radiotherapy (30 Gy) for a stage IIIB relapse nine years later (2006) again resulted in sustained CR. At the current admission (2010), the patient showed clinical signs of newly-onset congestive heart failure (NYHA IV) and asymptomatic pleural effusions. No pathological lymphadenopathy was found, neither clinically nor on a whole-body computed tomographie (CT) scan, but the presence of mild splenomegaly (13.8×5.5 cm) and small amounts of ascites were detected. Serum sodium levels were decreased to 121 mmol/l (normal range=133-145 mmol/l), with a plasma osmolarity of 261 mOsmol/kg per H₂O (normal range=280-295 mOsmol/kg), while his urine osmolarity was 231 mOsmol/kg per H₂O (normal range=420-1220 mOsmol/kg) and urine sodium concentration of 40 mmol/l (normal range=10-226 mmol/l). Clinically, the patient was hypervolemic and plasma anti-diuretic hormone (ADH) concentration was 1 pM/l (normal range, 0-13 pM/l). Liver and renal function parameters were all within normal ranges.

Hence, the diagnosis of hypotonic hyper-hydration as a consequence of congestive heart failure was made, whereas a syndrome of inappropriate anti-diuretic hormone (SIADH) was considered unlike. Hyponatremia was successfully corrected by sodium chloride supplementation and fluid restriction, and the patient was discharged with an improved, cardiologically-recompensated performance status. However, three weeks later, he was re-admitted due to pronounced hypo-osmolar hyponatremia and newly-found grade IV neutropenia. The results of his blood analysis were as follows: white blood cell count (WBC) of 0.8×10⁹/l, normochromic anemia with a red blood cell count (RBC) of 3.28×10¹²/l, hemoglobin concentration 10 g/l, platelet count of 157,000×10⁹/l. In addition, the patient displayed hypogammaglobulinemia (IgG 480 mg/dl) and mildly elevated lactate dehydrogenase (LDH) of 277 U/L (normal range=100-250 U/l). Bone marrow aspirate including immunophenotyping as well as bone marrow histology showed normal cellularity, but severe agranulocytosis. There were no morphological or immunohistochemical signs of dysplasia in any of the three cell lines, nor was lymphoma infiltration detectable. Thus, a diagnosis of reactive granulocytopenia was rendered. However, clonal T-cell receptor rearrangement [as assessed by polymerase chain reaction (PCR)] was detected in bone marrow and peripheral blood. Moreover, despite normal bone marrow metaphase cytogenetics, interphase fluorescence in situ hybridization (FISH) using a set of probes suitable for detection of a suspected low-risk myelodysplastic syndrome identified trisomy 5 and tetrasomy 5, respectively, in 40% of the interphases [Figure 1; trisomy 5 (left) and tetrasomy 4 (right) are shown in (E), trisomy 3 is shown in (F)].

In the subsequent three weeks, the patient rapidly developed severe dyspnea due to increased pleural and peritoneal effusions and worsening congestive heart failure refractory to treatment with diuretics and neuro-humeral therapy. The patient had generalized pathological lymphadenopathy and splenomegaly. Re-biopsy of the bone marrow showed infiltration of AITL (Figure 1; A-D). Immunohistochemical analysis of AITL in the bone marrow revealed nodules with fibrosis surrounded by large numbers of eosinophils (Figure 1A); the neoplastic infiltrate was positive for CD5 (Figure 1B), CD4 (Figure 1C) more than CD8 (see insert), programmed death-1 (PD1) (Figure 1D) and CD10 as assessed by immunohistochemistry and flow cytometry. However, shortly after the diagnosis (and 10 weeks after the first symptoms), the patient died of refractory volume overload. Immunohistochemical analyses of lymph nodes from the autopsy showed effacement of the lymph node architecture with diffuse infiltration of CD5+, CD2+, CD10+ T-cells around sinusoidal veins typical of AITL. Recurrence of the previous classical Hodgkin's lymphoma was definitively excluded.

Case 2. The second case was a 72-year-old woman presenting with a one-week history of dyspnea and B symptoms. She had a medical history of a metabolic syndrome and a chronic obstructive pulmonary disease. CT of the chest showed prominent mediastinal and axillary lymphadenopathy (2.2×1.4 cm) as well as splenomegaly (5.7×15 cm). Further laboratory analyses revealed a WBC of 2.3×10⁹/l (30% neutrophils, 40% lymphocytes, 17% eosinophils), normochromic normocytic anemia with an RBC of 3.79×10¹²/l, haemoglobin concentration 8.9 g/l, platelet count of 100,000×10⁹/l and LDH of 275 U/l. Serum electrophoresis showed polyclonal hypergammaglobulinemia of 2.7 g/dl. Direct Coomb's test (DCT) was positive with the presence of a warm antibody (IgG), but there were no signs of active hemolysis. Bone marrow biopsy with cytological, immunophenotypic and immunohistochemistry assessment showed no lymphoma infiltration and no evidence of hemophagocytosis. Conventional cytogenetics and FISH analyses of the bone marrow were also normal. However, molecular analyses showed clonal T-cell receptor rearrangements. Due to worsening dyspnea, anti-obstructive treatment, including systemic steroids, had to be initiated, upon which the lymphadenopathy disappeared completely within a few days and the B symptoms resolved.

The patient was discharged after her perfomance status improved on the basis of a tight follow-up schedule. Within two weeks, however, her performance status deteriorated rapidly (B symptoms, dyspnea and reoccurrence of generalized lymphadenopathy) and she had to be re-admitted. Fludeoxyglucose positron emission tomographies (FDG PET) scan was performed showing prominent generalized lymphadenopathy, diffuse spleen infiltration and enhanced FDG uptake in the marrow, suggestive for bone marrow infiltration (Figure 1G, H and I). Laboratory findings also disclosed significant hyponatremia (115 mmol/l) and severe disseminated intravascular coagulopathy (DIC; prothrombin time: 26%, partial thromboplastin time: >200 s, fibrinogen: <40 mg/dl, D-dimer: >33.818 μg/l), impeding diagnostic lymph node biopsy. Other conditions causing an activated coagulation system, e.g. hepatic failure, sepsis or thrombotic thrombocytopenic purpura, were excluded. DIC was refractory to high-dose glucocorticoid therapy and symptomatic treatment, including repeated administration of fresh-frozen plasma, resulting in a fatal gastrointestinal bleeding. Post-mortem examination finally confirmed AITL in lymph node analyses, showing a partial effacement of the normal lymph node architecture by a predominantly paracortical infiltrate of CD4⁺, CD5⁺ and CD10⁺ lymphocytes. There was a markedly increased lymph node neovascularization with small clusters of follicular dendritic cells surrounding the blood vessels. PCR performed in the analyzed lymphatic tissues showed pathological T-cell receptor rearrangement proving T-cell clonality.

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Figure 1.

Immunhistochemical analysis of angioimmunoblastic T-cell lymphoma (AITL) in the bone marrow composed of nodules with fibrosis surrounded by large numbers of eosinophils (A); the neoplastic infiltrate was positive for CD5 (B), CD4 (C) more than CD8 (see inset) and programmed death-1 (PD1) (D). Trisomy 5 (left) and tetrasomy 4 (right) are shown in (E). Trisomy 3 is shown in (F). Fludeoxyglucose positron emission tomography scan of the second case showing prominent generalized lymphadenopathy, diffuse splenic infiltration and enhanced bone marrow activity suggestive of bone marrow infiltration (G, H and I).