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The prognosis of patients with peripheral T‐cell lymphoma (PTCL) depends on bone marrow involvement (BMI). The bone marrow (BM) tumor microenvironment in PTCL remains unclear. We performed single‐cell RNA sequencing (scRNA‐seq) on 11 fresh BM samples from patients with BMI to reveal the associations of immune landscape and genetic variations with the prognosis of PTCL patients. Compared with PTCL not otherwise specified (NOS), angioimmunoblastic T‐cell lymphoma (AITL) had a higher number of T cells, lower number of lymphocytes, and greater inflammation. Immune heterogeneity in AITL is associated with prognosis. In particular, specific T‐cell receptor (TCR) T cells are enriched in patients with good response to anti‐CD30 therapy. We observed RhoA mutation‐associated neoantigens. Chidamide‐treated patients had a higher number of CD4+ regulatory cells and a better treatment response compared with other patients. In the nonresponder group, T‐cell enrichment progressed to secondary B‐cell enrichment and subsequently diffuse large B‐cell lymphoma. Moreover, AITL patients with lymphoma‐associated hemophagocytic syndrome had more T follicular helper (Tfh) cells with copy number variations in CHR5. To our knowledge, this study is the first to reveal the single‐cell landscape of BM microenvironment heterogeneity in PTCL patients with BMI. scRNA‐seq can be used to investigate the immune heterogeneity and genetic variations in AITL associated with prognosis. Based on single‐cell RNA sequencing (scRNA‐seq), we revealed the immune landscape and genetic variation at single‐cell resolution in peripheral T‐cell lymphoma (PTCL) with different prognoses. There were more effector T cells, inflammatory response, and exhausted lymphocyte cells enriched in angioimmunoblastic T‐cell lymphoma (AITL) compared with PTCL not otherwise specified (NOS). The immune heterogeneity in AITL was associated with prognosis.

Angioimmunoblastic T‐cell lymphoma (AITL) is an age‐related malignant lymphoma, characterized by immune system‐dysregulated symptoms. Recent sequencing studies have clarified the recurrent mutations in ras homology family member A (RHOA) and in genes encoding epigenetic regulators, tet methyl cytosine dioxygenase 2 (TET2), DNA methyl transferase 3 alpha (DNMT3A) and isocitrate dehydrogenase 2, mitochondrial (IDH2), as well as those related to the T‐cell receptor signaling pathway in AITL. In this review, we focus on how this genetic information has changed the understanding of the developmental process of AITL and will in future lead to individualized therapies for AITL patients. Recent progress in next‐generation sequencing has revealed the AITL specific genomic abnormalities in epigenetic regulators and TCR signaling. In this paper, we focused on the insights on how the biological and clinical aspects are linked to the genomic features of AITL.

Adult T‐cell leukemia/lymphoma (ATLL) is a distinct type of peripheral T‐cell lymphoma (PTCL) driven by human T‐lymphotropic virus type I (HTLV‐1)–infected T cells, but diagnosis can be confounded by histological overlap with non‐ATLL PTCL. While molecular testing is the diagnostic gold standard in endemic areas, HTLV‐1/2 serology is often used as a surrogate in nonendemic settings, yet its accuracy and limitations remain unclear. We retrospectively analyzed 881 PTCL cases over 25 years at two tertiary referral hospitals in Taiwan, where HTLV‐1 is nonendemic. Serology was available in 48.2% of cases. Molecular confirmation was performed using HBZ in situ hybridization and tax quantitative polymerase chain reaction. Among the 44 seropositive PTCL patients with tissue available, 37 were diagnosed and molecularly confirmed as ATLL. Of the seven initially diagnosed as non‐ATLL PTCL, three were reclassified as ATLL, while four showed no molecular evidence, including three likely false seropositives with borderline signal‐to‐cutoff (S/CO) values in serology assay and T follicular helper cell phenotype. In seropositive PTCL, clinicopathologic interpretation without molecular testing yielded 100% positive predictive value, 93% sensitivity, and 93% accuracy, compared with 91% positive predictive value by serology alone. In addition, retrospective molecular screening in 59 PTCL without prior serologic data revealed one case of ATLL that had initially been overlooked. In conclusion, our findings support routine HTLV‐1/2 serologic testing in all newly diagnosed PTCLs. However, interpretation should be guided by clinicopathological correlation and serology index values. Borderline index results warrant molecular confirmation.

Background This study aimed to better characterize the clinicopathologic characteristics, outcomes, and prognostic factors of AITL in China. Methods We retrospectively analyzed 312 patients with AITL enrolled between January 2011 and December 2020 from five institutions in China. Results The median age was 65 years, with 92.6% advanced stage, 59.7% elevated LDH, 46.1% anemia, and 44.0% hypergammaglobulinemia. The majority of patients (84.9%) received anthracycline‐based regimens with or without etoposide, and only 6.1% underwent autologous stem cell transplantation following first remission. The 5‐year OS and PFS estimates were 43.4% and 25.0% with no significant improvement of survival between patients treated during 2011–2015 and 2016–2020, respectively. Both the International Prognostic Index (IPI) and the prognostic index for PTCL, not otherwise specified (PIT), were predictive for OS. In multivariate analysis, age >70 years, elevated LDH, and albumin level <35 g/L were independent prognostic factors for OS. Combining these three factors, a novel prognostic model (the Chinese AITL score) was constructed, which stratified patients into low‐, intermediate‐, and high‐risk groups, with 5‐year OS rates of 69.0%, 41.5%, and 23.7%, respectively. This new model was successfully validated in an independent cohort. Conclusions Patients with AITL were mainly treated with anthracycline‐based regimens, and the outcomes were still unsatisfactory in China. Our novel prognostic model may improve our ability to identify patients at different risks for alternative therapies. Patients with AITL in China are mainly treated with anthracycline‐based regimens with low rate of autologous stem cell transplantation and unsatisfactory outcomes. A novel prognostic model combining 3 factors (age 〉 70 years, elevated LDH, and albumin level 〈 35 g/L) was proposed which stratified patients into the low, intermediate, and high‐risk subgroups with differing outcomes.

Epstein‐Barr virus (EBV)‐positive B cells have been detected in 66%‐86% of patients with angioimmunoblastic T‐cell lymphoma (AITL). However, it remains controversial whether EBV status has an impact on the survival of patients with AITL. In this study, we aimed to reevaluate the impact of EBV on the clinicopathological characteristics of AITL. In particular, we focused on the impact of EBV in younger patients with AITL. In total, 270 cases of AITL were studied. Epstein‐Barr virus‐positive B cells were detected in 191 (71%) cases (EBER+ group). Among the patients who received anthracycline‐based therapy, the EBER status did not affect the overall survival (OS) or progression‐free survival (PFS). In the younger group of AITL (≤60 years), PFS was significantly worse in the EBER− group compared to the EBER+ group (P = .0013). Furthermore, the multivariate analysis identified EBER‐negative status, thrombocytopenia, and elevated serum IgA level as significant adverse prognostic factors for PFS (P < .001, P < .001, and P = .002). Based on these findings, we constructed new prognostic model for the younger group, based on three adverse factors. We classified the patients into two risk groups: low risk (no or 1 adverse factor) and high risk (2 or 3 adverse factors). This new model for younger patients with AITL showed that both OS and PFS were significantly related to the level of risk (P < .0001). In summary, this study showed that, among younger patients with AITL, an EBER+ status significantly improved prognosis compared to an EBER− status. Our new prognostic model should be applicable to younger patients with AITL. In the younger group of AITL, PFS was significantly worse in the EBER− group compared to the EBER+ group (P = .0013). Furthermore, the multivariate analysis identified EBER‐negative status, thrombocytopenia, and elevated serum IgA level as significant adverse prognostic factors for PFS (P < .001, P < .001, and P = .002).

Background T follicular helper (Tfh) cell lymphomas, including their most prevalent form, angioimmunoblastic T‐cell lymphoma, frequently present with clinical symptoms, such as fever and rash, accompanied by substantial immune cell infiltration within the tumor microenvironment. These features often obscure the distinction between Tfh lymphoma and other autoimmune or inflammatory conditions. Notably, the p.Gly17Val RHOA (G17V) mutation is commonly associated with Tfh lymphomas, including angioimmunoblastic T‐cell lymphoma, suggesting that testing for the G17V mutation may serve as a valuable diagnostic tool. However, it remains unclear which patients would benefit the most from G17V mutation testing. Methods In this study, we retrospectively reviewed the medical records of 224 patients tested for the G17V mutation as part of routine clinical practice. Results We detected G17V in 17 patients. Among Tfh lymphoma cases, the sensitivity and specificity of the G17V test were 0.533 and 0.955, respectively. We further explored the association between G17V positivity and the clinical features of patients undergoing testing for the first time (n = 186). The G17V mutation was more frequent in patients presenting with lymphadenopathy in combination with fever or skin rash and elevated soluble interleukin‐2 receptor levels (p = 0.002). The median time from G17V test submission to results was 11.6 d shorter than that for pathological diagnosis (p = 0.0009). Conclusions Given the noninvasive nature of the G17V test, its rapid administration to appropriate patients is expected to enable faster and more efficient diagnosis of Tfh lymphomas compared with conventional methods. Tfh lymphomas, including angioimmunoblastic T‐cell lymphoma, often present with symptoms resembling autoimmune conditions. The p.Gly17Val RHOA (G17V) mutation is commonly found in these lymphomas and can aid diagnosis, offering faster results, especially in patients with specific clinical features like lymphadenopathy, fever, and skin rash.

Background Angioimmunoblastic T‐cell lymphoma (AITL) is one of the most frequent peripheral T‐cell lymphomas (PTCL) in western countries. Skin involvement is common and may reveal the malignancy. Despite its frequency, skin involvement in AITL has been poorly described. Objectives We aimed to analyze the cutaneous expression of PTCL of TFH origin and its prognostic impact. Methods We conducted a multicenter retrospective cohort study by retrieving histopathological reports including the mention ‘AITL’ or ‘PTCL with T‐follicular helper phenotype’ (PTCL‐TFH) from five French tertiary hospital centers. Results From 2000 to 2022, we reviewed 382 histopathological records and identified 52 AITL cases and 5 PTCL‐TFH cases with cutaneous involvement. Thirty‐two (56%) patients were males with a mean age of 63 years. Fifty‐six (98%) patients presented with lymphadenopathy, 32 (56%) splenomegaly and 17 (30%) hepatomegaly. B signs were present in 34 (60%) patients. Skin lesions were present on the lower limbs in 44 (77%) patients, trunk in 38 (67%) patients, upper limbs in 35 (61%) and head in 27 (47%). Macules and papules were the most frequent lesions found in 47 (82%) patients, followed by nodules in 10 (17%) patients, erythemato‐squamous plaques in 10 (17%) patients, purpura in 9 (16%), urticaria in 9 (16%) and blisters in 5 (9%) patients. Erythroderma affected seven patients (12%). A skin biopsy was taken in 50 patients and revealed a specific lymphomatous infiltrate in 36 cases. A dominant skin T‐cell clone was detected in 13 out of 17 (76%) patients. Among the 14 patients with a nonspecific dermatitis, various histopathological patterns were observed including interface dermatitis, psoriasiform dermatitis, vasculitis, bullous dermatitis, granulomatous dermatitis and thrombotic vasculopathy. After a median follow‐up of 24 months (range, 0–121 months), median overall survival was 121 months (95% CI, 25.2–NA). At last follow‐up, 33 patients (58%) were alive, 20 (35%) were in complete remission and 7 (12%) were in partial remission; 30 (53%) patients experienced at least one relapse, including nodal relapses in 24 (80%) cases and cutaneous relapses in 12 (40%). Conclusions This study revealed the deep heterogeneity of skin presentations in AITL. Atypical skin presentations were common and included blistering, purpuric and psoriasiform eruptions.

Angioimmunoblastic T‐cell lymphoma (AITL) is a subtype of nodal peripheral T‐cell lymphoma (PTCL). Somatic RHOA mutations, most frequently found at the hotspot site c.50G > T, p.Gly17Val (G17V RHOA mutation) are a genetic hallmark of AITL. Detection of the G17V RHOA mutations assists prompt and appropriate diagnosis of AITL. However, an optimal detection method for the G17V RHOA mutation remains to be elucidated. We compared the sensitivity and concordance of next‐generation sequencing (NGS), droplet digital PCR (ddPCR) and peptide nucleic acid‐locked nucleic acid (PNA‐LNA) clamp method for detecting the G17V RHOA mutation. G17V RHOA mutations were identified in 27 of 67 (40.3%) PTCL samples using NGS. ddPCR and PNA‐LNA clamp method both detected G17V mutations in 4 samples in addition to those detected with NGS (31 of 67, 46.3%). Additionally, variant allele frequencies with ddPCR and those with NGS showed high concordance (P < .001). Three other RHOA mutations involving the p.Gly17 position (c.[49G > T;50G > T], p.Gly17Leu in PTCL198; c.[50G > T;51A > C], p.Gly17Val in PTCL216; and c.50G > A, p.Gly17Glu in PTCL223) were detected using NGS. These sequence changes could not appropriately be detected using the ddPCR assay and the PNA‐LNA clamp method although both indicated that the samples might have mutations. In total, 34 out of 67 PTCL samples (50.7%) had RHOA mutations at the p.Gly17 position. In conclusion, our results suggested that a combination of ddPCR/PNA‐LNA clamp methods and NGS are best method to assist the diagnosis of AITL by detecting RHOA mutations at the p.Gly17 position. Angioimmunoblastic T‐cell lymphoma (AITL) is a distinct subtype of nodal peripheral T‐cell lymphoma (PTCL). Somatic RHOA mutations, (most frequently c.G50T, p.G17V RHOA mutation) are a genetic hallmark of AITL. Our results showed that a combination of NGS, ddPCR and PNA‐LNA clamp methods increased the detection rate of RHOA mutations at the p.G17 position.

Angioimmunoblastic T‐cell lymphoma (AITL) is a type of peripheral T‐cell tumour that belongs to the group of non‐Hodgkin's lymphomas. Pulmonary lesions can be found in 7%–10% of AITL cases. Imaging findings of the lungs varied; however, immunoblastic infiltration in the lungs is rare. Our patient was a 73‐year‐old man who received repeated chemotherapy for AITL. Fourth‐line therapy using romidepsin controlled the illness, but the patient was hospitalized for dyspnoea and an infiltrative shadow. We performed bronchoalveolar lavage (BAL), and the culture was positive for Haemophilus influenzae. The patient was initially discharged with antibiotic therapy, but hospitalized again. Antibiotics were ineffective and the patient required mechanical ventilation. BAL was performed again, after which fluid cytology revealed immunoblast‐like atypical cells. Therefore, the patient was diagnosed with pulmonary infiltration due to AITL. Steroid therapy proved ineffective, and the patient died. BAL was used to effectively diagnose pulmonary AITL infiltration. To our knowledge, we report here the first case of angioimmunoblastic T‐cell lymphoma in which pulmonary involvement was detected using bronchoalveolar lavage.

Abstract Objectives Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma derived from T-follicular helper cells. For pathologists, diagnosing AITL may be challenging due to its wide clinical and histopathologic spectrum, which can mimic a variety of reactive and neoplastic processes. Methods We summarize and discuss the clinicopathologic features of AITL, emphasizing diagnostic tools available to the practicing pathologist. Common diagnostic dilemmas are discussed. Results AITL exhibits various histologic patterns and is often associated with a prominent microenvironment that can obscure the neoplastic cells. Atypical B-cell proliferations, which can take a number of forms, are common in AITL, and clonal B-cell expansion can be seen. The atypical B cells can closely resemble Hodgkin/Reed-Sternberg cells, leading to misdiagnosis as classic Hodgkin lymphoma. Molecular studies have revealed recurrent genetic alterations, which can aid in differential diagnosis, particularly in problematic cases. Conclusions Given the complex diagnostic challenges in AITL, an integrated approach, incorporating clinical, morphologic, immunophenotypic, and molecular findings, is helpful to reach an accurate diagnosis.