Clinicopathological diagnosis of Lennert lymphoma: a case report and review of the literature.

BACKGROUND: Lennert lymphoma (LL) is a variant of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), also known as a lymphoepithelioid variant of PTCL. Because of the rarity and lack of clear-cut diagnostic criteria, LL is susceptible tomisdiagnosis. Although previously diagnosed with LL might be reclassified and evaluated with the advent of of molecular and/or genetic findings, cytomorphology and immunohistochemistry are still the key to give rise to correct diagnosis. CASE PRESENTATION: We report a case of a patient who was diagnosed as LL based on cytomorphology and immunohistochemistry. Routine stain (Hematoxlin and Eosin-H&E) revealed tumor cells were mainly small to medium-sized CD4(+) T cells, the CD8 +/TIA-1 + cytotoxic cells were less minority, no expressions of follicle helper T cell markers (CD10, BCL6, PD1, CXCL13, ICOS) or CD21(+) hyperplastic FDC network, or proliferation of high edndothelial venules were noted; however, numerous epithelioid histiocytes are noted in the background and scattered EBV(+) cells were also present. The patient was achieved complete remission after six courses of chemotherapy with cyclophosphamide, epirubicin, vincristine, etoposide, and prednisone regimen. She was followed for 5 years without recurrence or progression. CONCLUSIONS: Classic LL is not difficult to diagnose by cytomorphology and immunohistochemistry, and the mutation profiles can be helpful to distinguish LL from other lymphomas.

Intestinal Perforation in a Case of Peripheral T Cell Lymphoma after Initiation of Chemotherapy.

Non-Hodgkin's lymphoma (NHL) is the most common type of Gastrointestinal (GI) lymphoma with known complications such as bleeding, obstruction and perforation. In this article we present a 59-year-old male patient diagnosed with Peripheral T cell Lymphoma - Not Otherwise Specified (PTCL-NOS) with GI involvement was started on chemotherapy. On day 2 post completion of first cycle of chemotherapy, patient had presented to the emergency department with sudden onset abdominal pain and distension. On evaluation, he was diagnosed with multiple perforations in the small bowel. Patient underwent exploration with primary repair of few perforations and ileal resection with double barrel ileostomy. Chemotherapy plays an important role in the management of NHL. One well-known NHL consequence, intestinal perforation, can happen at the time of initial presentation or after starting chemotherapy. Surgeons should be aware of possibility of such complications and high-risk factors for perforation. At present, there is no role for elective surgery in GI lymphoma and is mainly reserved for complications like uncontrolled bleeding, obstruction or perforation.

Long-term successful use of belinostat in a patient with relapsed-refractory angioimmunoblastic lymphoma who has previously been heavily treated.

ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL) is one of the sub-types of peripheral T-cell lymphomas (PTCLs) that are remarkably refractory and has the potential to have a poor prognosis. The treatment process includes a wide range of treatment modalities, from anthracycline-based regimens that have been used for years to novel agents, such as histone deacetylase inhibitor romidepsin and belinostat. Increased treatment response rates and prolonged survival have been reported in studies with belinostat. Similarly, in this case report, we wanted to share a patient of an advanced age and with a high IPI score, whom we had treated in many treatment lines and maintained a long-term treatment response by administering belinostat.

TP53 and KMT2D mutations associated with worse prognosis in peripheral T-cell lymphomas.

There are limited studies on mutation profiling for Peripheral T-cell lymphomas (PTCL) in the Chinese population. We retrospectively analyzed the clinical and genetic landscape of 66 newly diagnosed Chinese patients. Targeted next-generation sequencing (NGS) was performed for tissues from these patients. At least one mutation was detected in 60 (90.9%) patients, with a median number of 3 (0-7) mutations, and 32 (48.5%) cases detected with more than 4 mutations. The genes with higher mutation frequencies were TET2, RHOA, DNMT3A, IDH2, TP53, STAT3, and KMT2D respectively. When mutant genes are classified by functional group, the most prevalent mutations are related to epigenetics and signal transduction. IPI ≥2, PIT ≥2, and failure to achieve partial remission (PR) were factors for inferior progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed TP53 was an adverse factor for PFS (HR, 3.523; 95% CI, 1.262-9.835; p = 0.016), and KMT2D was an adverse factor for OS (HR, 10.097; 95% CI, 1.000-101.953; p = 0.048). Mutation profiling could help differentiate distinct types of PTCL and serve as a useful tool for determining treatment options and prognoses.

Single-cell landscape reveals the immune heterogeneity of bone marrow involvement in peripheral T-cell lymphoma.

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.

Myositis as a prominent manifestation of primary skeletal muscle peripheral T-cell lymphoma: a case report and literature review.

The patient presented to the clinic with painful muscle swelling in the right lower extremity, which improved with immunosuppressive therapy. Initially, the condition was diagnosed as polymyositis but recurred soon after. After imaging and biopsy, the final diagnosis was primary skeletal muscle peripheral T-cell lymphoma, not otherwise specified (PSM-PTCL, NOS). In this report, we discuss the challenges in diagnosing and treating this aggressive malignancy and review the literature on PSM-PTCL, NOS. Key Points • To date, there are few reports of PSM-PTCL, NOS, and our case is the tenth. • It is crucial to consider PSM-PTCL, NOS, when presenting with localized muscle edema and unexplained pain. • Histopathological examination is likely the most effective method for diagnosing this rare disease.

Immunophenotypic classification regarding prognosis in peripheral T cell lymphoma, NOS, and nodal T follicular helper T cell lymphoma, angioimmunoblastic-type.

This study aimed to determine the clinicopathological predictive factors of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), and nodal T-follicular helper cell lymphoma, angioimmunoblastic-type (nTFH, AI-type). In this single-centered, retrospective study, medical records of 59 patients who were diagnosed with PTCL, NOS, or nTFH, AI-type from March 2007 to September 2022 were reviewed. The clinicopathological variables, including immunohistochemistry(IHC) subgroups, distinguishing TBX21 from the GATA3 subgroups were analyzed. Overall, 28 patients (75.7%) in the TBX21 group were PTCL, NOS. There were 9 (24.3%) patients in the GATA3 group. In univariable analyses, lymphoma subtype, age, and performance status were associated with progression-free survival (PFS), and overall survival (OS). In multivariable analyses, lymphoma subtype, and performance status were related to PFS and OS (P = 0.012, P < 0.001, P = 0.006, and P < 0.001, respectively). The GATA3 subgroup tended to have a worse prognosis in univariable analyses; however, it became more insignificant in multivariable when lymphoma subtype and performance status were adjusted (P = 0.065, P = 0.180, P = 0.972, and P = 0.265, respectively). The double-positive group showed variable prognoses of better PFS and worse OS. PD-1 and PD-L1 were associated with the EBV in situ hybridization (P = 0.027, and P = 0.005), and PD-1 was associated with CD30 expression (P = 0.043). This study demonstrated the potential of IHC classification to predict prognosis for PTCL, NOS, as well as nTFH AI-type, although further validation is necessary. Treatments targeting CD30, PD-1, and PD-L1 appear promising for lymphoma treatment.

A new mode for the diagnosis of angioimmunoblastic T-cell lymphoma.

In order to explore a new mode for the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), 31 cases of AITL and 28 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) were used as the study subjects. Identifying T follicular helper (TFH) cells with CD4, CD10, Bcl-6, and PD-1, identifying proliferative B cells with CD20 and EZH2, identifying proliferative follicular dendritic cells (FDCs) with CD21 and CD23, and analyzing the value of TFH/B/FDC proliferation and immunolocalization in the diagnosis of AITL. (1) Outside the inherent lymphoid follicles, simultaneous proliferation of TFH/B/FDC (a new diagnostic mode) were observed in AITL [83.87%; 26/31], with their immunolocalizations in the same site [83.87%; 26/31], while this phenomenon was not observed in 28 cases of PTCL-NOS (P<0.05). (2) The sensitivity and specificity of using this new mode to diagnose AITL were both high (83.87%, 100%), which was superior to CD2 (100%, 0%), CD3 (100%, 0%), CD4 (100%, 32.14%), CD5 (100%, 25%), CD10 (61.9%, 100%), Bcl-6 (42.86%, 100%), PD-1 (83.87%, 96.43%), and its Youden Index (0.84) was the highest. The areas under the curve (AUC) of CD10, Bcl-6, PD-1, and new mode to diagnosis AITL were 0.81, 0.71, 0.90, and 0.92, respectively, while the new mode had the highest AUC. The simultaneous proliferation of TFH/B/FDC cells outside the inherent lymphoid follicles can be used to assist in the diagnosis of AITL, and the simultaneous spatiotemporal proliferation of TFH/B/FDC cells is a specific immunomorphology of AITL.

HDAC Inhibition Increases CXCL12 Secretion to Recruit Natural Killer Cells in Peripheral T-cell Lymphoma.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous and aggressive disease with a poor prognosis. Histone deacetylase (HDAC) inhibitors have shown inhibitory effects on PTCL. A better understanding of the therapeutic mechanism underlying the effects of HDAC inhibitors could help improve treatment strategies. Herein, we found that high expression of HDAC3 is associated with poor prognosis in PTCL. HDAC3 inhibition suppressed lymphoma growth in immunocompetent mice but not in immunodeficient mice. HDAC3 deletion delayed the progression of lymphoma, reduced the lymphoma burden in the thymus, spleen, and lymph nodes, and prolonged the survival of mice bearing N-methyl-N-nitrosourea-induced lymphoma. Furthermore, inhibiting HDAC3 promoted the infiltration and enhanced the function of natural killer (NK) cells. Mechanistically, HDAC3 mediated ATF3 deacetylation, enhancing its transcriptional inhibitory activity. Targeting HDAC3 enhanced CXCL12 secretion through an ATF3-dependent pathway to stimulate NK-cell recruitment and activation. Finally, HDAC3 suppression improved the response of PTCL to conventional chemotherapy. Collectively, this study provides insights into the mechanism by which HDAC3 regulates ATF3 activity and CXCL12 secretion, leading to immune infiltration and lymphoma suppression. Combining HDAC3 inhibitors with chemotherapy may be a promising strategy for treating PTCL. Significance: Targeting HDAC3 suppresses progression of T-cell lymphoma by activating ATF3 to induce secretion of CXCL12 and promote infiltration of NK cells, providing an immunostimulatory approach for treating T-cell lymphoma patients.

Peripheral T-cell lymphomas expressing CD30 and CD15 expand the spectrum of anaplastic large cell lymphoma, ALK-negative.

Peripheral T-cell lymphomas (PTCL) are morphologically and biologically heterogeneous and a subset expresses CD30, including anaplastic large cell lymphomas (ALCL) and a minority of PTCL, not otherwise specified (PTCL, NOS). ALCL with ALK translocations (ALCL, ALK+) are readily identified by routine diagnostic methods, but differentiating ALCL without ALK translocation (ALCL, ALK-) and PTCL, NOS expressing CD30 (PTCL CD30+) can be challenging. Furthermore, rare PTCL co-express CD30 and CD15 (PTCL CD30+CD15+); some resemble ALCL, ALK- while others resemble classic Hodgkin lymphoma. To explore the relationship between PTCL CD30+CD15+ and ALCL, ALK-, we analysed 19 cases of PTCL with CD30 expression, previously diagnosed as ALCL, ALK- (nine cases) and PTCL CD30+CD15+ (10 cases) for DUSP22/IRF4 rearrangements, coding RNA expression and selected transcriptome analysis using the NanoString nCounter gene expression analysis platform. Unsupervised clustering showed no clear segregation between ALCL, ALK- and PTCL CD30+CD15+. Three cases previously classified as PTCL CD30+CD15+ showed DUSP22/IRF4 rearrangements, favouring a diagnosis of ALCL, ALK-. Our results suggest that cases previously designated PTCL CD30+CD15+, likely fall within the spectrum of ALCL, ALK-; additionally, a subset of ALCL, ALK- with DUSP22/IRF4 rearrangement expresses CD15, consistent with previous reports and expands the immunophenotypic spectrum of this lymphoma subgroup.

Pyroptotic macrophages promote proliferation and chemotherapy resistance of peripheral T-cell lymphoma via TLR4 signaling pathway.

Peripheral T-cell lymphoma (PTCL) is a highly aggressive type of non-Hodgkin's lymphoma with a poor prognosis. Pyroptosis is a newly discovered procedural cell death mode, which has been implicated to occur in both tumor cells and immune cells. However, the occurrence and effect of pyroptosis on PTCL remain unclear. Here, we found that pyroptosis occurred in interstitial macrophages of PTCL rather than in tumor cells. In clinical specimens, macrophage pyroptosis was associated with a poor prognosis of PTCL. In vitro experiments and gene sequencing results showed that pyroptotic macrophages could upregulate the expression of TLR4 through secreting inflammatory cytokines IL-18. Upregulated TLR4 activated its downstream NF-κB anti-apoptotic signaling pathway, thus leading to malignant proliferation and chemotherapy resistance of tumor cells. Moreover, the expression of factors such as XIAP in the NF-κB anti-apoptotic pathway was downregulated after the knockdown of TLR4, and the malignant promotion effect of pyroptotic macrophages on PTCL cells was also reversed. Our findings revealed the mechanism of pyroptotic macrophages promoting the malignant biological behavior of PTCL and elucidated the key role of TLR4 in this process. In-depth analysis of this mechanism will contribute to understanding the regulatory effect of PTCL by the tumor microenvironment and providing new ideas for the clinical treatment of PTCL.

Peripheral T cell lymphoma initially presenting in lung biopsies: A diagnostic challenge.

BACKGROUND: Primary or secondary pulmonary involvement by peripheral T cell lymphoma (PTCL) is rare and difficult to diagnose particularly via lung biopsies. METHODS: 22 cases of PTCL diagnosed initially in lung biopsies between January 2006 and November 2020 were retrospectively reviewed followed at Nanjing Drum Tower Hospital and the First Affiliated Hospital of Zhengzhou University, respectively, including clinical manifestations, baseline biochemical indexes, images, histological findings and other available ancillary studies such as immunostaining, Epstein-Barr virus encoded RNA (EBER) in situ hybridization and T-cell receptor rearrangement analysis upon diagnosis. RESULTS: The median age of these patients was 59 years old (range: 29-82 years) at diagnosis. The majority of them complained of fever, cough and fatigue. Computed tomography scans mainly revealed multiple ill-defined nodules/masses of various sizes and densities with or without air bronchogram. Microscopically, most lesions showed lymphoid cells with clear cytoplasm and irregular nuclear contours diffusely infiltrating alveolar septa or alveolar spaces in an inflammatory background. Several cases had a predominance of small neoplastic cells (n = 4) with atypical, irregular nuclei. One case showed a diffuse monotonous pattern of growth. Angioinvasion and necrosis were not uncommon findings. The neoplastic cells in all cases were positive for one or more T-cell markers, and negative for B-cell-lineage antigens and EBER. 19 out of 22 patients had complete follow-up information, and 17 patients were dead at the last follow-up. CONCLUSIONS: Pulmonary involvement by PTCL is rare with dismal outcome. Aggressive clinical course and several clinicopathologic clues, albeit unspecific, may alert the pathologists of the possibilities of pulmonary PTCLs.

Low T3 syndrome as a predictor of poor prognosis in peripheral T-cell lymphomas

Purpose The purpose of the study was to evaluate the prognostic value of low T3 syndrome in peripheral T-cell lymphomas (PTCLs). Methods One hundred and seventy-four patients of newly diagnosed PTCLs were enrolled in the study. We performed statistical analysis based on the clinical data collected. Results Thirty-Six (20.69%) patients had low T3 syndrome at first admission. Results suggested that the patients with higher score of ECOG PS, International Prognostic Index (IPI) and Prognostic Index for T-cell lymphoma (PIT), bone marrow involvement and lower level of albumin tended to develop low T3 syndrome. The median progression-free survival (PFS) and overall survival (OS) were 10 months and 36 months, respectively, for all patients. Pre-existing low T3 syndrome was in correlation with worse PFS and OS. Patients with low T3 syndrome showed worse PFS (4 months vs 13 months, P = 0.0001) and OS (7 months vs 83 months, P < 0.0001) than patients without low T3 syndrome. IPI and PIT, respectively, combined with low T3 syndrome improved the ability to predict OS and PFS of PTCLs. Conclusions The study indicated that low T3 syndrome may be a good candidate for predicting prognosis of peripheral T-cell lymphomas (AU)

NOT OTHERWISE SPECIFIED T-CELL LYMPHOMA: OUTCOMES OF A SINGLE CENTER STUDY.

BACKGROUND: The peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is the most common subtype of peripheral T-cell lymphoma (PTCL). It constitutes approximately 25% of all PTCLs and accounts for more than 15% of all lymphomas. The results of the first Ukrainian prospective study of patients with PTCL-NOS are presented in the article. The aim of the study was to analyze the morbidity of PTCL patients and the treatment performed, to evaluate overall survival and progression-free survival, and to determine the factors that predict the treatment response. PATIENTS AND METHODS: An analysis was performed on the data of 31 patients diagnosed with peripheral PTCL-NOS from February 2018 to the present. T-cell lymphoid neoplasms were diagnosed according to the 2016 WHO classification. The treatment regimens were in alignment with ESMO and NCCN guidelines. More than 90% of patients were prescribed anthracycline-based regimens (CHOP; CHOEP - cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone). An initial treatment was performed with CHOP-based regimens in 38.70% (n = 12) of patients, with the addition of etoposide in 58.06% of patients (n = 18). RESULTS: The response was assessed according to the response criteria for malignant lymphoma (Cheson, 2008, 2014). The overall response to therapy was 58.06% (n = 18), with complete responses in 29.03% of patients and partial responses in 29.03% of patients. The stabilization of the disease occurred in 3.44%, while the disease progression in 41.37% of patients. The 12-month and 24-month survival rates were 75.44% and 50.81%, respectively. The 12-month and 24-month progression-free survivals were 47.68% and 33.1%, respectively. Ki-67 overexpression (> 65%) was a negative prognostic factor. CONCLUSIONS: The results of the treatment of PTCL obtained in a Ukrainian population study are similar to those in other European studies, all of which remain unsatisfactory. Further research is required to develop a new strategy for examination and therapy to improve treatment outcomes. The emphasis should be placed on the pragmatic clinical trials comparing the efficacy of first-line treatment in PTCL patients with both favorable and unfavorable clinical factors.

Clonal haematopoiesis: A common progenitor for cytotoxic peripheral T-cell lymphoma and angioimmunoblastic T-cell lymphoma.

Recent studies have shown that follicular helper T-cell lymphoma of angioimmunoblastic type (AITL), the most common nodal peripheral T-cell lymphoma (PTCL), frequently arises in a background of clonal haematopoiesis (CH), a preneoplastic condition affecting up to 40% of elderly individuals. Data on a potential CH association are limited for other PTCL. We report a unique patient who sequentially developed both cytotoxic PTCL, not otherwise specified and AITL with distinct T-cell receptor rearrangements but shared somatic mutations originating from the same CH clone, thus providing convincing evidence that CH can give rise to T-cell neoplasms of different lineage.

Case of angioimmunoblastic T-cell lymphoma presenting as peripheral and bone marrow plasmacytosis: A diagnostic conundrum.

ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL), a subtype of peripheral T-cell lymphoma (PTCL), is associated with unique clinical, morphological, and immunohistochemical features. The peripheral circulation might show presence of an occasional reactive plasma cell but significant plasmacytosis masquerading as plasma cell leukemia is rare. We report a case of AITL in a 42-year-old male, who presented with two-month history of generalized lymphadenopathy. On investigations, he had hypergammaglobulinemia and plasmacytosis in the peripheral blood and bone marrow masquerading as plasma cell leukemia. Immunohistochemistry and serum protein electrophoresis revealed polyclonal nature of plasma cells. Diagnosis of AITL was made on cervical lymph node biopsy. This case highlights the diagnostic challenge faced due to heterogeneity in the clinical presentation and pathological findings and to alert the clinician so that timely accurate diagnosis can be made to initiate the treatment.