Clinical spectrum, evolution, and management of autoimmune cytopenias associated with angioimmunoblastic T-cell lymphoma.

OBJECTIVE: Angioimmunoblastic T-cell lymphoma (AITL) is frequently associated with autoimmune cytopenia (AIC). Whether such patients have a particular phenotype and require particular management is unclear. METHOD: Angioimmunoblastic T-cell lymphoma patients from the multicentric database of the Lymphoma Study Association presenting with AIC during disease course were included and matched to AITL patients without AIC (1/5 ratio). RESULTS: At diagnosis, AIC patients (n = 28) had more spleen and bone marrow involvement (54% vs 19% and 71% vs 34%, P < 0.001), Epstein-Barr virus replication (89% vs 39%, P < 0.001), gamma globulin titers (median 23 vs 15 g/L, P = 0.002), and proliferating B cells and plasmablasts in biopsies, as compared to control patients (n = 136). The 28 AIC patients had 41 episodes of AIC, diagnosed concomitantly with AITL in 23 (82%) cases. After a median follow-up of 24 months (range 3-155), 10 patients relapsed, all associated with AITL relapse. CONCLUSION: Our results provide new insight into AIC associated with AITL by highlighting the significant interplay between AITL and B-cell activation leading to subsequent autoimmunity.

Cutaneous angioimmunoblastic T-cell lymphoma: Epstein-Barr virus positivity and its effects on clinicopathologic features.

BACKGROUND: Epstein-Barr virus (EBV) positivity frequently presents in patients with nodal angioimmunoblastic T-cell lymphoma (AITL). However, the presence of EBV in skin lesions and its clinicopathologic significance have not been evaluated. OBJECTIVE: To analyze the clinical and histopathologic features of cutaneous AITL and evaluate EBV positivity in skin tissue and its effects on clinicopathologic features of AITL. METHODS: Clinicopathologic variables in patients with cutaneous AITL were analyzed and compared depending on EBV in situ hybridization status in skin lesions by using patients' medical records. RESULTS: Of the 86 patients with AITL, 42 had a cutaneous presentation. In situ hybridizations positive for EBV were noted in 19 of 42 patients with cutaneous AITL. EBV positivity was more common in papular and nodular skin lesions than other cutaneous morphologies, such as nonspecific rash or purpuric patches. An EBV-positive in situ hybridization was associated with a pattern of dense, superficial and deep infiltrates of pleomorphic, large-sized, atypical lymphocytes. EBV positivity in skin lesions was an independent negative prognostic factor in patients with AITL. LIMITATIONS: Retrospective study at a single institution. CONCLUSION: EBV-positive cutaneous AITL is associated with distinctive clinicopathologic features.

The curious origins of angioimmunoblastic T-cell lymphoma.

PURPOSE OF REVIEW: Once an obscure disease, recent studies have transformed our understanding of angioimmunoblastic T-cell lymphoma (AITL). In this review, we summarize new major advances in the genetics and biology of AITL. RECENT FINDINGS: Genome wide sequencing studies have dissected the repertoire of the genetic alterations driving AITL uncovering a highly recurrent Gly17Val somatic mutation in the small GTPase RHOA and major role for mutations in epigenetic regulators, such as TET2, DNMT3A and IDH2, and signaling factors (e.g., FYN and CD28). These findings support a multistep model of follicular T helper cell transformation in AITL and pinpoint novel candidates for the development of targeted therapies in this disease. SUMMARY: AITL originates from follicular T helper cells and is characterized by the presence of RHOA G17V mutation together with genetic alterations in TET2, DNMT3A, and IDH2. Research efforts now focus on the elucidation of the specific roles and interplay of these genetic alterations in the pathogenesis of AITL.

Observation versus neck dissection for positron-emission tomography-negative lymphadenopathy after chemoradiotherapy.

OBJECTIVES/HYPOTHESIS: To analyze outcomes among patients with residual positron-emission tomography (PET)-negative lymphadenopathy after chemoradiotherapy for head and neck cancer based on whether or not they underwent neck dissection. STUDY DESIGN: Retrospective review. METHODS: Fifty-five patients with stage III/IV squamous cell carcinoma of the head and neck were identified with residual PET-negative lymphadenopathy based on standardized uptake value of <3. All patients had been treated with chemoradiotherapy to a median dose of 70 Gy (range, 60-4 Gy). RESULTS: With a median follow-up of 30 months (range, 6-67 months), the 3-year overall survival (85% vs. 81%, P = .57), progression-free survival (88% vs. 88%, P = .42), and local-regional control (96% vs. 100%, P = .68), did not differ between patients treated by neck dissection or observation. CONCLUSIONS: Omission of neck dissection appears to be reasonable for patients with residual lymphadenopathy but negative PET after chemoradiotherapy for head and neck cancer. LEVEL OF EVIDENCE: 4.

Angioimmunoblastic T cell lymphoma: an unusual presentation of posttransplant lymphoproliferative disorder in a pediatric patient.

Posttransplant lymphoproliferative disorders (PTLD) are a potentially life-threatening complication of immunosuppression in transplant recipients. The majority of cases are Epstein-Barr virus-associated lesions of B cell origin. T cell PTLD is rare, particularly in pediatric patients. We present an unusual case of monomorphic T cell PTLD with features of angioimmunoblastic T cell lymphoma in an 8-year-old heart transplant patient, presenting with cranial nerve palsy.

Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice.

Angioimmunoblastic T-cell lymphoma (AITL) is the second most common peripheral T-cell lymphoma with unusual clinical and pathologic features and a poor prognosis despite intensive chemotherapy. Recent studies have suggested AITL derives from follicular helper T (T(FH)) cells, but the causative molecular pathways remain largely unknown. Here we show that approximately 50% of mice heterozygous for the "san" allele of Roquin develop tumors accompanied by hypergammaglobulinemia by 6 months of age. Affected lymph nodes displayed the histologic features diagnostic of AITL, except for the presence of expanded FDC networks. Accumulation of T(FH) cells preceded tumor development, and clonal rearrangements in the TCR-ß genes were present in most tumors. Furthermore, T(FH) cells exhibited increased clonality compared with non-T(FH) cells from the same lymph nodes, even in the absence of tumors. Genetic manipulations that prevent T(FH) development, such as deletion of ICOS, CD28, and SAP, partially or completely abrogated tumor development, confirming a T(FH)-derived origin. Roquin(san/+) mice emerge as a useful model to investigate the molecular pathogenesis of AITL and for preclinical testing of therapies aimed at targeting dysregulated T(FH) cells or their consequences.

[Angioimmunoblastic T-cell lymphoma with marked polyclonal plasmacytosis in peripheral blood and bone marrow mimicking plasma cell leukemia].

A 70-year-old man was admitted to our hospital with fever, generalized lymphadenopathy and hypoxia in October 2009. Blood examination demonstrated leukocytosis, anemia, thrombocytopenia and hyper γ-globulinemia. Peripheral blood and bone marrow smear showed marked plasma cell proliferation mimicking plasma cell leukemia. However, flow cytometric analysis showed that plasma cells were of polyclonal origin and M-protein was not detected by immunofixation of serum protein. Elevations of soluble interleukin 2 receptor and serum IL-6 were observed. A heavy Epstein-Barr viral load was detected in serum by real-time PCR. Biopsy was obtained from the right inguinal lymph node. The pathological diagnosis was angioimmunoblastic T-cell lymphoma (AITL) and rearrangement of the T-cell receptor Cß1 gene was detected. The patient was treated with CHOP therapy, and all clinical manifestations, including fever, lymphadenopathy, anemia, thrombocytopenia, hyper γ-globulinemia, plasmacytosis and hypoxia, were improved. Only a few reported cases have demonstrated AITL with marked polyclonal plasmacytosis. Although pathological mechanisms of plasmacytosis in AITL patients have not been fully elucidated, it is suggested that IL-6 and IL-10 were involved in its pathogenesis in the present case.

[Angioimmunoblastic T-cell lymphoma complicated by recurrent drug-induced agranulocytosis].

A 73-year-old man was hospitalized with fever, erythema, generalized superficial lymphadenopathy and marked neutropenia in July 2007. Hematologic examination demonstrated a white blood cell count of 1,400/microl with 0% neutrophils, and 18% abnormal lymphocytes. A bone marrow aspirate showed marked myeloid hypoplasia. A diagnosis of drug-induced agranulocytosis was made. Although neutrophil counts immediately returned to normal levels in response to filgrastim, fever, skin rash and systemic lymphadenopathy were all persistent. He also developed autoimmune hemolytic anemia and a second episode of agranulocytosis. The causative agent of the both episodes of agranulocytosis appeared to be acetaminophen. The histologic picture of a biopsied lymph node showed diffuse infiltration of polymorphous lymphoid cells with clear cytoplasm and proliferation of arborizing capillary vessels. Based on the histologic findings, PCR, and immunohistologic analyses, he was diagnosed with angioimmunoblastic T cell lymphoma (AILT) in leukemic state. The response of the lymphoma to conventional chemotherapy (CHOP and ESHAP) was poor. We next performed an immunomodulatory therapy using cyclosporine A to suppress cytokine production by neoplastic T cells. The treatment resulted in a partial remission of AILT including disappearance of circulating lymphoma cells. To our knowledge, this is the first published report of AILT complicated by drug-induced agranulocytosis.

Histological diversity of reactive and atypical proliferative lymph node lesions in systemic lupus erythematosus patients.

Localized or generalized lymphadenopathy, which may be associated with systemic symptoms such as fever, is frequently found in patients with systemic lupus erythematosus (SLE). Histologically, the lymph node lesion is characterized by varying degrees of coagulative necrosis with hematoxylin bodies or reactive follicular hyperplasia. The former histology is unique to SLE, but is rarely seen in biopsied specimens. In this review, we describe a histologic variation of SLE lymphadenopathy based on the findings of our own cases, and discuss several problems related to the differential diagnosis of various benign and malignant lymphoproliferative disorders (LPDs). Among 33 cases we encountered, 17 (51%) cases exhibited atypical LPDs: (i) reactive follicular hyperplasia with giant follicles (RFHGFs), 3 cases; (ii) histologic findings of Castleman's disease (CD), 5 cases ; (iii) atypical paracortical hyperplasia with lymphoid follicles (APHLFs), 7 cases; and (iv) atypical lymphoplasmacytic and immunoblastic proliferation (ALPIBP), 2 cases. This finding indicates that atypical LPDs frequently appear in SLE. Moreover, the majority of patients with atypical LPDs exhibited follicular hyperplasia (RFHGF, 3 cases; histologic findings of CD, 5 cases; and APHLF, 7 cases). Previously, follicular hyperplasia was usually considered a non-specific change and therefore has received little attention in the literature. However, the present review indicates that reactive follicular hyperplasia in lymph nodes from SLE occasionally poses serious problems in the differential diagnosis of various benign and malignant LPDs. The presence of numerous copies of Epstein-Barr virus was determined by in situ hybridization studies in only two (8%) of the 26 cases examined. As previously suggested, the absence of EBV, as determined by ISH studies, in the majority of LPDs associated with SLE indicates that EBV is not related to the lymphoproliferative process, and suggests that the underlying cause of the patient's lymphadenopathy may reside in the immune deficit of SLE in the majority of reactive and atypical LPDs associated with SLE.

Sustained remission from angioimmunoblastic T-cell lymphoma induced by alemtuzumab.

BACKGROUND: A 73-year-old woman presented with acute lower back pain, fever, chills and arthralgias. She had previously had a positive protein derivative test with a negative chest X-ray; her medical history was also remarkable for a mitral valve prolapse. Initial symptoms resolved spontaneously without therapy, but fever recurred with associated arthralgias, myalgias, diffuse and worsening lymphadenopathy, splenomegaly, and bilateral pulmonary infiltrates. INVESTIGATIONS: Physical examination, blood and urine cultures, MRI of the spine, echocardiogram, extensive serologies, serum and urine protein electrophoresis, immunofixation electrophoresis, bone-marrow aspiration and biopsy with flow cytometry, cytogenetics, and gene rearrangement studies, CT scan of the chest, abdomen and pelvis, whole-body PET, and lymph-node biopsy for histological examination, immunohistochemistry, and gene rearrangement studies. DIAGNOSIS: Angioimmunoblastic T-cell lymphoma. MANAGEMENT: Steroids (prednisone, methylprednisolone), levofloxacin, isoniazid with pyridoxine, ciclosporin A, methotrexate, alemtuzumab, broad-spectrum antibiotics, Pneumocystis carinii prophylaxis, vancomycin, and clindamycin.

[Angioimmunoblastic T-cell lymphoma occurring four months after autologous peripheral blood stem cell transplantation with high-dose chemotherapy for follicular lymphoma].

A 62-year-old Japanese woman was diagnosed as having follicular lymphoma (FL, grade 3, CS IIIA, IPI high-intermediate risk) in May 1998. After eight courses of CHOP therapy, she achieved a complete remission (CR). In November 1998, her FL relapsed, and she achieved a second CR after two courses of MINE therapy. High-dose etoposide was used for autologous peripheral stem cell mobilization. In May 1999, she underwent high-dose chemotherapy with autologous peripheral blood stem cell transplantation (auto-PBSCT). Four months after the auto-PBSCT, bilateral cervical lymphadenopathy developed. Histopathological findings from a biopsied cervical lymph node showed angioimmunoblastic T-cell lymphoma (AILT). The patient was treated with modified CVP therapy, and she is alive with no evidence of lymphoma five years after auto-PBSCT. Clinical and histopathological findings showed that the FL and AILT in this case were not concomitant. It is thought that in this case, the AILT developed as a post-transplant lymphoproliferative disorder after auto-PBSCT for the FL.

Linfadenopatía angioinmunoblástica: fisiopatología, citogenética, histología y tratamiento / Angioimmunoblastic lymphadenopathy: physiopathology, cytogenetic, histology and treatment

La linfadenopatía angioinmunoblástica, a pesar de ser clínicamente similar a la enfermedad de Hodking, es una entidad hiperinmune distinta, aparentemente de linfocitos B. Es una enfermedad caracterizada por síntomas constitucionales y linfadenopatía. El diagnóstico se establece mediante biopsia del ganglio linfático, con la cual se observan alteraciones en la morfología del mismo, ausencia de centros germinativos, arborización de vénulas poscapilares y un infiltrado polimorfo que incluye inmunoblastos. Los hallazgos de laboratorio incluyen, anemia hemolítica autoinmune e hipergammaglobulinemia policlonal

Angioimmunoblastic lymphadenopathy with dysproteinemia: emphasis on pathogenesis and treatment.

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a rare lymphoproliferative disorder characterized by diffuse lymphadenopathy, fever, hepatosplenomegaly, hemolytic anemia, and polyclonal hypergammaglobulinemia. Morphologically, the involved lymph nodes demonstrate complete effacement of the normal architecture, prominent neovascularization and infiltration by immunoblasts and plasma cells. Other terms that have been used to describe this entity include diffuse plasmacytic sarcomatosis, immunoblastic lymphadenopathy, lymphogranulomatosis X, and immunologic aberrations in idiopathic reticulosis. Initially, AILD was thought to be a disease of B-cell origin that represented reactive immune response to unknown stimulus and high potential for malignant transformation. It is now evident that AILD in 80% of cases follows an aggressive course with short median survival, especially, if complete response with chemotherapy is not achieved. Immunologic and molecular studies have demonstrated that the majority of AILD cases are T-cell clonal disorders. Despite the numerous reports on the role of Epstein-Barr virus in this disorder, it is unknown whether the presence of this virus is associated with the immune defect that accompanies AILD, or whether it is a pathogenetic factor. In contrast to non-Hodgkin's lymphomas, a stage is not usually assigned to the patient since the disease is systemic in nature, subsequently, parameters such as extent of disease and tumor bulk used to identify high-risk patients with non-Hodgkin's lymphomas, do not appear to correlate with disease activity or prognosis in AILD. Treatment of AILD has been unsatisfactory, with approximately 25% of patients achieving complete and sustained remission when combined chemotherapy agents are used. This article is devoted to a discussion of the different manifestations, suggested pathogenesis, and treatment of AILD.

Angioimmunoblastic lymphadenopathy with disproteinemia arising in a patient with rheumatoid arthritis.

Angioimmunoblastic lymphadenopathy with disproteinemia (AILD) is a systemic lymphoproliferative disorder characterized by constitutional symptoms such as generalized lymphadenopathy, hepatosplenomegaly and skin rash. In this article, we report on a patient with seronegative Rheumatoid Arthritis of 18 years duration who recently developed AILD.