A 41-year-old Caucasian man with a medical history of hypertension and an Eastern Cooperative Oncology Group performance status of 0 presented with abdominal pain, fatigue, and 10-pound weight loss for 2 months. He denied fevers or night sweats. On physical exam, the patient had bilateral inguinal lymphadenopathy up to 2 cm in diameter. Computed tomography (CT) scans revealed lymphadenopathy above and below the diaphragm and mild splenomegaly. Hemoglobin level was 13 g dL−1 (normal range: 13.5–16.0 g dL−1). The patient underwent an excisional biopsy of a left cervical lymph node and was discharged in stable condition.
At this time, the differential diagnosis in this mildly anemic young man with weight loss and lymphadenopathy is very broad but includes infections and autoimmune processes. Oncologic conditions, such as lymphomas, should also be evaluated.
He represented 1 week later with severe fatigue and hypotension. The patient had a hemoglobin of 5.5 g dL−1, white blood cell count of 23.7 × 109 L−1 (normal range: 3.5–11.0 × 109 L−1), and platelet count of 123 × 109 L−1 (normal range: 150–400 × 109 L−1). The differential showed 55% neutrophils, 6% bands, 20% lymphocytes, 11% monocytes, 4% eosinophils, and 2% metamyelocytes. Patient denied hemoptysis, melena, or bright red blood per rectum. Two units of packed red blood cells (RBCs) were transfused with minimal increase in his hemoglobin levels.
The hemoglobin level went from 13 to 5.5 g dL−1 in 1 week; this is an acute process. The differential includes acute bleeding or hemolysis. His blood counts also show leukocytosis and thrombocytopenia. Given the lack of response to transfusions, this could be an immune-mediated hemolytic phenomenon either primary or associated with an infectious process, such as acute EBV or Mycoplasma infection. The patient should also be worked up for gastrointestinal bleeding, although it is less likely the cause of such a marked decrease in his hemoglobin without evidence of frank hematochezia or melena.
Additonal workup showed an elevated lactate dehydrogenase (LDH) level (663 IU L−1), reticulocytosis (8.2%), and undetectable haptoglobin (<5.8 mg dL−1). A peripheral blood smear did not show schistocytosis or spherocytosis but revealed circulating myelocytes, metamyelocytes, nucleated RBCs, and RBC agglutination. Fecal occult blood test was negative.
This presentation is consistent with an acute acquired hemolytic process. The age of the patient makes congenital causes of hemolysis unlikely. The differential diagnosis includes autoimmune or drug-induced hemolysis and cryoglobulinemia. The presence of RBC agglutination supports the possibility of cryoglobulinemia. The lack of schistocytes does not support a microangiopathic process such as thrombotic thrombocytopenic purpura or disseminated intravascular coagulation. The concurrent presence of myeloid and erythroid precursors suggests a myelophthisic anemia, which could be associated with intramedullary hemolysis.
Direct Coombs test was positive for immunoglobulin G (IgG) and complement. A strong IgM cold autoantibody was also identified. These findings were consistent with warm and cold autoimmune hemolytic anemia (AIHA). A Human Immunodeficiency virus (HIV) ELISA drawn previously was reported as positive; however, his wife and he denied any behavioral risks. Serologic tests for Mycoplasma, hepatitis A, hepatitis B, hepatitis C, Cytomegalovirus, Herpes Simplex virus, Varicella zoster virus and toxoplasma were nonreactive. Epstein Barr virus (EBV) IgM was negative but IgG was elevated consistent with a past infection. His Ig levels were IgG 2,190 mgdL−1(normal range: 562–1,585 mg dL−1), IgM 855 mg dL−1(normal range: 30–246 mg dL−1), and IgA 509 mg dL−1(normal range: 72–372 mg dL−1), but no M-spike was detected by serum and urine protein electrophoresis. The patient was started on a plasmapheresis and steroids to treat cold and warm AIHA, respectively.
These laboratory data support a diagnosis of a cold and warm AIHA in this patient with a positive HIV ELISA test. Several studies have shown an association between HIV infection and an abnormal Coombs test ; however, the relationship with overt AIHA is unclear and only a handful of cases have been reported . As a sensitive test, the HIV ELISA is used for screening purposes but a Western blot test should be ordered to confirm a current HIV infection as the ELISA can be falsely positive. In fact, lymphomas and systemic lupus erythematosus, among others, can be associated with false-positive HIV ELISA tests. In patients with AIHA, warm autoantibody production can be idiopathic; however, cold antibodies are usually associated with other processes, including lymphoproliferative disorders, which should be evaluated in this patient with a positive HIV ELISA test and lymphadenopathy, as the risk of developing aggressive B-cell lymphomas (BCLs) is higher in HIV-infected individuals. The differential diagnosis for this patient's hypergammaglobulinemia also includes lymphoma, HIV infection, and autoimmune conditions. I believe the patient's lymph node excisional biopsy will be helpful on evaluating this case further.
Pathologic findings from the excisional lymph node biopsy showed a preserved nodal architecture with scattered reactive cortical lymphoid follicles, occasionally surrounded by clear monocytoid cells (Fig.1A,B). There was focal expansion of the paracortex by a mixed population of small lymphocytes, histiocytes, plasma cells, and immunoblasts (Fig.1C). Paracortical vascular proliferation was also identified. Immunostains for CD20 highlighted germinal center B-cells and few paracortical immunoblasts (Fig.1D). Numerous CD10-positive cells were seen in a perifollicular distribution (Fig.1E) that coexpressed CD3 (Fig.1F) and CD4 (Fig.1G), but were negative for CD5, CD7, CD8 (Fig.1H), BCL6, and MUM1/IRF4. The paracortical regions demonstrated a moderately high proliferation index (Ki-67 ∼ 60%; Fig.1I). Anaplastic lymphoma kinase and EBV latent membrane protein-1 were negative. Flow cytometry detected an aberrant T-cell population with loss of CD7 and coexpression of CD10 and CD25. Polymerase chain reaction (PCR) studies revealed two minor T-cell receptor (TCR) beta bands and one TCR gamma band as well as genomic EBV. PCR for IgH gene rearrangements was negative. The morphologic, immunophenotypic, and molecular findings were consistent with angioimmunoblastic T-cell lymphoma (AITL).
AITL is indeed a unifying diagnosis in this challenging case. AITL can present with protean symptoms. In this case, this patient's lymphadenopathy, weight loss, hypergammaglobulinemia, and AIHA can be fully explained by AITL. From the pathological perspective, AITL is a T-cell lymphoma that frequently develops with a coincident population of EBV-positive, CD20-positive B-cells that can be clonal, posing a diagnostic difficulty in which AITL is confused with a T-cell-rich BCL. An additional concern is the possibility of a concurrent diffuse large BCL (DLBCL) occasionally seen in patients with AITL; however, in this case, there was an absence of sheets of large CD20-positive cells and clonal Ig heavy chain gene rearrangements were not identified by PCR testing. Additionally, the coexpression of CD3 and CD4 with loss of CD7 and the presence of TCR gene rearrangements in the malignant cells strongly support a T-cell lymphoma. The presence of CD10 and the morphological features such as paracortical vascular proliferation are consistent with AITL. The relationship between AITL and a positive HIV ELISA in this case is intriguing. Although HIV infection has been mostly associated to the development of aggressive BCLs, there may be up to a 15-fold increase in the risk of T-cell lymphomas . Nonetheless, T-cell lymphomas are a rare occurrence in HIV-infected individuals with less than a 100 cases reported in the literature. Furthermore, in a recent series of 51 patients with HIV-associated T-cell lymphoma, only two patients had AITL . Based on this patient's diagnosis, staging and risk-stratification should include CT scans of the chest, abdomen, and pelvis, bone marrow biopsy and aspirate, LDH levels and an evaluation of cardiac function.
A bone marrow biopsy revealed marked hypercellularity (95%) with trilineage hyperplasia. Few interstitial lymphoid aggregates were noted consisting of a mixture of CD20+ B-cells and CD3+/CD5+ T-cells with partial loss of CD7 in T-cell clusters. Molecular studies performed on bone marrow biopsy were negative for TCR gene rearrangement. The patient was considered stage IV due to a likely bone marrow involvement by AITL. His International Prognostic Index (IPI) score was high-intermediate at 3. His Prognostic Index for Peripheral T-cell Lymphoma (PIT) score was 2. CT scans done previously showed generalized adenopathy without apparent extranodal involvement. His LDH levels had decreased to 412 IU L−1. The HIV Western blot came back negative. His CD4+ cell count and CD4+/CD8+ ratio were normal, and his HIV viral load was undetectable.
Bone marrow involvement by lymphoma affects staging and risk-stratification. In this case, the results from the bone marrow biopsy were not definitive; however, the degree of hypercellularity and the loss of CD7 expression in the lymphoid aggregates make a strong case for lymphomatous involvement. The IPI score does not use bone marrow involvement per se as a prognostic factor but bone marrow involvement is considered an extranodal site and would categorize a patient as stage IV, an adverse prognostic factor in the IPI . On the other hand, the PIT score includes bone marrow involvement as one of the prognostic factors . In DLBCL, bone marrow involvement has been associated with central nervous system affection and prophylactic intrathecal chemotherapy could be administered; however, this is not a common practice for T-cell lymphomas. Interestingly, his HIV Western blot was negative, and there was no additional evidence of HIV infection. To the best of our knowledge, only one case in the literature had reported a false-positive HIV ELISA test in the setting of AITL . Nonetheless, HIV testing should be routinely done in any patient with a diagnosis of lymphoma.
Because of the presence of a heavy background of CD20-positive B-cells and ongoing AIHA, the patient was started therapy with rituximab &!hyphen;cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), recovering dramatically after one cycle, and being discharged in stable condition. He completed six cycles of R-CHOP as an outpatient. His only complication was a grade 2 peripheral neuropathy. A possitron emission tomography (PET)/CT scan done after finishing R-CHOP showed no evidence of 18-F fluorodeoxyglucose-avid disease. His HIV ELISA was negative and bone marrow biopsy demonstrated no abnormalities. The patient was then referred for autologous stem cell transplantation (ASCT) in first remission. He was mobilized with subcutaneous filgrastim and plerixafor. The conditioning regimen consisted of cyclophosphamide, carmustine, and etoposide, without total body irradiation (TBI). He experienced no major complications during his hospital course and has since done well without evidence of recurrent disease 24 months after diagnosis.