Anaplastic large cell lymphoma (ALCL) is a rare subtype of non-Hodgkin lymphoma, with most cases harboring ALK gene rearrangement (ALK + ALCL); however, 20-50% of ALCLs do not have the rearrangement (ALK- ALCL) but exhibit distinct genetic alterations. In this report, we present an unusual case of systemic ALK- ALCL with NPM1::TYK2 fusion. Diagnosis of this case was challenging prior to the NGS findings. A comprehensive panel of immunohistochemical and in-situ hybridization studies was conducted. FISH assays were utilized to target the rearrangements of DUSP22 and TP63 genes. Moreover, next-generation sequencing (NGS) assays were performed to detect clonal rearrangements of IGH and TRG genes, somatic mutations, and potential fusions. The lymphoma cells in this case are negative for all hematolymphoid markers stained, except for CD30 expression and focal and weak CD43 expression. However, NGS studies detected clonal TRG rearrangement and NPM1::TYK2 rearrangement, which aid in the diagnosis of ALK- ALCL. NPM1::TYK2 rearrangement is a rare genetic alteration that has been reported in rare cases of primary cutaneous ALCL, mycosis fungoides, and lymphomatoid papulosis. To the best of our knowledge, this is the first reported instance of such rearrangement in systemic ALK- ALCL.

In the diagnostic workup of poorly differentiated tumors, T-cell receptor (TCR) clonality has long been considered as evidence of T-cell lymphoma. MET exon 14 skipping (METex14) is a mutation typically seen in lung adenocarcinoma. Herein, we present the first report of METex14 lung adenocarcinoma with isolated monoclonal TCRγ gene rearrangement. A 69-year-old woman presented to an outside hospital with pleural effusions. A pleural decortication demonstrated malignant cells positive for CD30 and CD138 but negative for BerEP4, KRT5, and EMA. An equivocal HHV8 staining was interpreted as positive, leading to the erroneous outside diagnosis of primary effusion lymphoma. Additional workup at our institution revealed a lack of HHV8 and T-cell markers but the presence of TCRγ clonality, pankeratin, and TTF1 expression. Repeat TCRγ testing on the in-house biopsy was negative for clonality. Next-generation sequencing detected METex14, confirming the diagnosis of lung adenocarcinoma. The potential diagnostic pitfall and prognostic/predictive implications are discussed.

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BACKGROUND: Previous studies have shown that at least a of intraoral eosinophilic ulcer is best classified as a CD30 + T-cell lymphoproliferative disorder (LPD), with histopathology reminiscent of lymphomatoid papulosis (LyP) of the skin. Microscopically, a mixed population of inflammatory cells, often including eosinophils and varying numbers of atypical lymphoid cells, frequently expressing CD30, is typical for LyP, whose clinicopathological spectrum includes type A, B, C, D, E, and LyP with DUSP22/IRF4 rearrangement. To date, about 27 intraoral LyP cases have been reported. Of them, 7 cases were diagnosed as LyP type C, which is frequently confused with anaplastic large cell lymphoma (ALCL) on histopathology.
METHODS: A 60-year-old male was referred for a one-month history of a tongue ulcer.
RESULTS: Microscopy showed numerous subepithelial atypical large lymphoid cells, which expressed CD4 (with partial loss of CD3, CD5, and CD7), CD8 (few cells), CD30 (about 50%, in non-diffuse pattern with size variability), TIA-1, and Ki-67 (85%), without staining for CD56, ALK, LMP1, and EBER1/2, concerning for a diagnosis of ALCL. However, after three weeks, the lesion completely healed.
CONCLUSIONS: We present here a rare case of intraoral CD30+ T-cell LPD that we believe is the oral counterpart of cutaneous LyP type C.

EBV-positive nodal T- and NK-cell lymphoma (EBV+ NT/NKCL) is a recently recognized entity in the 5th edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Notably, CD30 positivity is frequently observed in (EBV+ NT/NKCL), creating diagnostic challenges to distinguish it from ALK-negative anaplastic large cell lymphoma (ALCL). Furthermore, cases of EBV+ ALCL have been documented in the literature, predating the inclusion of EBV+ nodal cytotoxic T-cell lymphoma as a variant of peripheral T-cell lymphoma. We present a case of a 47-year-old male presenting with multiple lymphadenopathies. The histomorphologic and immunophenotypic features of the lymph node closely resemble ALK-negative ALCL, characterized by uniform CD30 expression and a subcapsular distribution of lymphoma cells. However, the lymphoma cells exhibit diffuse positivity for EBV, consistent with EBV+ NT/NKCL. A case of ALK-negative ALCL with an immunophenotype identical to the EBV-positive case is included for comparison. Given that EBV+ NT/NKCL represents an aggressive neoplasm requiring unique clinical management compared to ALK-negative ALCL, it is critical to accurately differentiate EBV+ NT/NKCL from ALK-negative ALCL with a cytotoxic T-cell immunophenotype.

Perumal Kalaiyarasi JayachandranAnaplastic large cell lymphoma (ALCL) is the second most common type of peripheral T cell lymphoma and an aggressive mature T cell lymphoma. About 50 to 70% of systemic ALCLs are anaplastic lymphoma kinase positive (ALK +), the proportion even higher in the pediatric population. The 5-year survival after chemotherapy is around 70 to 80%. But there is a subgroup of ALK+ ALCL patients who are refractory to chemotherapy. Brentuximab vedotin is an approved agent for such patients. The activity of ALK inhibitors in ALK+ non-small cell lung cancer is well known and has been approved for use. The efficacy and safety of ALK inhibitors in ALK + ALCL are largely under-reported. Here we have reported our experience in the use of ALK inhibitors in relapsed refractory ALK+ ALCL.

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UNASSIGNED: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored.
UNASSIGNED: On the basis of the non-Hodgkin\'s lymphoma Berlin-Frankfurt-Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL).
UNASSIGNED: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% [95% Confidence Interval (CI), 69.0%-83.9%] and 92.3% (95% CI,86.1%-95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5%-95.5%, and 67.9% (95% CI, 55.4%-77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6%-19.0%), 65.7% (95% CI, 47.6%-78.9%), 55.7% (95% CI, 26.2%-77.5%), and 70.7% (95% CI, 48.6%-84.6%), respectively. At the end of follow-up, one of the 5 patients who received maintenance therapy with VBL relapsed, and seven patients receiving ALK inhibitor maintenance therapy did not experience relapse.
UNASSIGNED: This study has confirmed the poor prognostic of MDD (+) ，high risk site and SC/LH ,but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305).

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an emerging disorder that has gained global attention throughout the past era. The present meta-analysis was performed to retrieve the risk of BIA-ALCL from population-based epidemiological studies. Factors associated with BIA-ALCL were evaluated to identify patients at higher risk of BIA-ALCL.
METHODS: A systematic literature search was executed throughout 12 databases. All epidemiological studies encompassing patients with breast implants either for aesthetic or reconstructive purposes and reported the risk of BIA-ALCL were included. Studies reported the risk factors of BIA-ALCL were included.
RESULTS: The present meta-analysis included 17 articles, encompassing 525,475 patients with breast implants. There were 254 patients with BIA-ALCL with a mean duration to the diagnosis of BIA-ALCL of 13.16 years (95% CI 11.7-14.6, P < 0.001). There were 44 patients with textured breast implants and two with smooth implants. Patients with breast implants were 28.86 times more at high risk of BI-ALCL (95% CI 3.123-266.681). The risk ranged from 0 to 1 per 1000 cases with breast implants, with a similar risk among patients seeking aesthetic and reconstructive surgeries. The risk was 0 to 1 case per 1000 cases among patients with textured breast implants. There was a significant association between the history of breast cancer and BIA-ALCL (P = 0.0016).
CONCLUSIONS: This meta-analysis confirmed the association between breast implants and ALCL. There was a similar risk of BIA-ALCL among patients with aesthetic or reconstructive surgeries. Patients with a history of breast cancer were at higher risk of BIA-ALCL.
METHODS: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT) are rare cancers observed predominantly in children and young adults. ALCL accounts for 10-15% of all pediatric non-Hodgkin lymphomas and is commonly diagnosed at an advanced stage of disease. In children, 84-91% of cases of ALCL harbor an anaplastic lymphoma kinase (ALK) gene translocation. IMT is a rare mesenchymal neoplasm that also tends to occur in children and adolescents. Approximately 50-70% of IMT cases involve rearrangements in the ALK gene. A combination of chemotherapeutic drugs is typically used for children with ALK-positive ALCL, and the only known curative therapy for ALK-positive IMT is complete surgical resection. Crizotinib, a first-generation ALK inhibitor, was approved in the USA in 2021 for pediatric patients and young adults with relapsed or refractory ALK-positive ALCL; however, its safety and efficacy have not been established in older adults. In 2022, crizotinib was approved for adult and pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT. This podcast provides an overview of ALK-positive ALCL and IMT. We discuss the current treatment landscape, the role of ALK tyrosine kinase inhibitors, and areas of future research.