Lymphomatoid papulosis (LyP) is a primary cutaneous CD30+ lymphoproliferative disorder characterized by a chronic and self-healing recurrent cluster of erythematous papules or nodules on the skin of the trunk and/or extremities. The disease has an indolent clinical course with spontaneous regression or waxing and waning clinical evolution. The histopathologic spectrum of LyP is vast and may show few to numerous atypical cells immersed in a mild to intense inflammatory background. The backbone for the diagnosis is the positivity for CD30, which is one of the criteria to define this group of lymphoproliferative disorders. The association of these different histological and immunophenotypical findings is used to subclassify this disease in different subtypes from A to E, associated with DUSP22/IRF4 rearrangement, and other rare forms. Although this differentiation is important to raise awareness of different differential diagnosis, it does not impact the prognosis or change the treatment, which is usually centered in symptom relief and faster regression. In this review, we aim to summarize the most updated information of the clinical, histopathological, and molecular characteristics of LyP and provide a practical assessment for the diagnostic features that could help with the main differential diagnosis.

LEARNING OBJECTIVES:After studying this article, the participant should be able to: 1. Name the 3 major subtypes of breast implant-associated (BIA) malignancies. 2. Recognize the most common presenting symptoms of BIA malignancies. 3. Identify appropriate treatment options for each BIA malignancy, including chemotherapy, radiation, and surgery. 4. Answer patient questions about recurrence and reconstruction after a diagnosis of BIA malignancy. SUMMARY:Although rare, breast implants have been associated with several malignancies, categorized into 3 major subtypes: BIA anaplastic large-cell lymphoma, B-cell lymphoma, and squamous cell carcinoma. BIA anaplastic large-cell lymphoma is the most common subtype, with more than 1700 cases reported to date. BIA squamous cell carcinoma is the most aggressive subtype. The most common presenting symptom is late seroma. Patients typically report pain and swelling. Workup should begin with an ultrasound or mammography, and any fluid collections should be aspirated and evaluated in conjunction with pathology. The authors provide an algorithm for surgical excision and adjuvant treatment based on disease stage and subtype.

Anaplastic large cell lymphoma (ALCL) cases were discussed at the 2023 Society of Hematopathology/European Association for Haematopathology workshop held on November 9-11, 2023, in Houston, Texas. This session focused on the clinical and pathologic spectrum of 3 types of ALCL: anaplastic lymphoma kinase (ALK)-positive, ALK-negative, and breast implant associated (BIA). Cases of primary cutaneous ALCL were excluded because they were included in another session. Although the diagnosis of ALCL is often straightforward, the 42 submitted cases encompassed unusual clinical presentations, morphologic variants, and atypical immunophenotypes, exemplifying potential difficulties and challenges in establishing the diagnosis of ALCL. Distinguishing ALCL from CD30-positive peripheral T-cell lymphoma, not otherwise specified, or classic Hodgkin lymphoma was discussed. In patients with a previous history of mycosis fungoides and other T-cell lymphoma/leukemia, the differential diagnosis of a CD30-positive T-cell lymphoma mimicking ALCL (mycosis fungoides transformation vs de novo ALCL) was also discussed. In patients with suspected BIA-ALCL, it is critical to properly handle the periprosthetic fluid when the disease first presents and the capsule at the time of initial capsulectomy to make a correct diagnosis and pathologic staging because a missed diagnosis may lead to disease progression. Comprehensive immunohistochemical analysis; fluorescence in situ hybridization for DUSP22, TP63, or JAK2 rearrangement; assessment of clonality of the T-cell receptor and immunoglobulin genes; and sequencing for mutations were performed as part of the workup of the submitted cases, particularly on ALK-negative ALCL cases, emphasizing the importance of ancillary testing in establishing the diagnosis.

Various types of lymphoma/leukemia can present with leukemic involvement by neoplastic cells with prominent nucleoli. Patients with chronic lymphocytic leukemia (CLL) most commonly can present in this fashion but other, less common types include mantle cell lymphoma, splenic marginal zone lymphoma, splenic diffuse red pulp small B-cell lymphoma, and splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN). The latter is a newly proposed category in the fifth edition of the World Health Organization classification of hematolymphoid neoplasms. This category includes most cases that were previously designated hairy cell leukemia-variant and rare cases of CD5-negative B-prolymphocytic leukemia. A case of extranodal marginal zone lymphoma (EMZL) is reported to highlight the presence of nucleolated lymphocytes in the peripheral blood and bone marrow and their impact on the differential diagnosis, particularly with SBLPN. An 80-year-old woman with a reported history of "CLL", diagnosed and treated with clinical remission, developed gastric EMZL which relapsed twice after chemotherapy. At time of last relapse, a peripheral blood smear and bone marrow aspiration and biopsy specimens were evaluated to assess the presence and extent of blood and bone marrow involvement. The pathologic findings and differential diagnosis are discussed. A complete blood count showed a leukocyte count of 7.9 × 109/L and review of the peripheral blood smear showed 32

Fibrin-associated large B-cell lymphoma (FA-LBCL) is a rare type of lymphoma usually associated with EpsteinBarr virus (EBV) infection. We report a case incidentally detected in a right ovarian mass of a 53-year-old woman. The patient presented with bloating and weight gain over 8 months. Imaging studies showed a 20.7 cm, complex right adnexal mass. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. Macroscopic examination revealed a 25 x 18.5 x 9.5 cm predominantly cystic right ovarian mass with focal solid areas. Microscopically, most of the mass was a leiomyoma with hyaline necrosis and extensive cystic degeneration. In areas, the cyst showed focally necrotic, fibrinous material associated with small aggregates of round and atypical lymphoid cells with prominent karyorrhexis and mitotic activity These large cells were confined within the cystic spaces. Immunohistochemical analysis showed that the atypical cells were positive for CD20, CD30, CD79a and MUM1/IRF4, and were negative for CD3, CD10 and BCL6, supporting B-cell lineage. In situ hybridization for Epstein-Barr virus-encoded RNA (EBER ISH) was also positive in the atypical cells supporting the diagnosis of EBV-positive fibrin-associated large B-cell lymphoma. The patient subsequently received four cycles of chemotherapy using rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP). Computed tomography (CT) scan of the neck, chest, abdomen and pelvis 5 months after the last chemotherapy cycle showed no evidence of disease. After a follow-up of 17 months, the patient is alive with no evidence of disease. This report is being used to discuss the salient features of this rare entity and its differential diagnosis.

The diagnosis of myeloid neoplasms with plasmacytoid dendritic cell (pDC) differentiation can be challenging due to immunophenotypic overlap requiring detailed characterization by flow cytometry and immunohistochemistry. We describe two patients with a history of myeloproliferative neoplasm (MPN) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN) who presented years later with leukocytosis, lymphadenopathy, splenomegaly, and cachexia, with rapid clinical deterioration and death. Lymph node biopsy specimens revealed involvement by myeloid sarcoma with prominent pDC differentiation. Furthermore, concomitant bone marrow aspiration and biopsy showed involvement by the underlying myeloid neoplasm but no parallel expansion of pDC, as seen in the lymph node specimens, suggesting that pDC differentiation is fostered in the lymph node microenvironment. These two cases could represent the "myeloid sarcoma" counterpart of the recently described acute myeloid leukemia with pDC differentiation (pDC-AML). Although patients with pDC-AML have an inferior outcome when treated with conventional therapies, the recognition of a pDC component in these neoplasms potentially expands the therapeutic options.

DISEASE OVERVIEW:Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an aggressive B-cell lymphoma associated with EBV infection included in the WHO classification of lymphoid neoplasms since 2016. Although historically associated to poor prognosis, outcomes seem to have improved in the era of chemoimmunotherapy. DIAGNOSIS:The diagnosis is established through meticulous pathological evaluation. Detection of EBV-encoded RNA (EBER) is the standard diagnostic method. The ICC 2022 specifies EBV+ DLBCL, NOS as occurring when >80% of malignant cells express EBER, whereas the WHO-HAEM5 emphasizes that the majority of tumor cells should be EBER positive without setting a defined threshold. The differential diagnosis includes plasmablastic lymphoma, DLBCL associated with chronic inflammation, primary effusion lymphoma, among others. RISK-STRATIFICATION:The International Prognostic Index (IPI) and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD-1/PD-L1 are emerging as potential adverse but targetable biomarkers. MANAGEMENT:Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV-negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV-negative DLBCL in the era of chemoimmunotherapy. Therefore, inclusion of patients in clinical trials when available is recommended. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.

Cytogenomic characterization is crucial for the classification and risk stratification of acute myeloid leukemia (AML), thereby facilitating therapeutic decision-making. We examined the clinical utility of optical genome mapping (OGM) in 159 AML patients (103 newly diagnosed and 56 refractory/relapsed), all of whom also underwent chromosomal banding analysis (CBA), fluorescence in situ hybridization, and targeted next-generation sequencing. OGM detected nearly all clinically relevant cytogenetic abnormalities that SCG identified with >99% sensitivity, provided the clonal burden was above 20%. OGM identified additional cytogenomic aberrations and/or provided information on fusion genes in 77 (48%) patients, including eight patients with normal karyotypes and four with failed karyotyping. The most common additional alterations identified by OGM included chromoanagenesis (n = 23), KMT2A partial tandem duplication (n = 11), rearrangements involving MECOM (n = 7), NUP98 (n = 2), KMT2A (n = 2), JAK2 (n = 2), and other gene fusions in 17 patients, with 10 showing novel fusion gene partners. OGM also pinpointed fusion genes in 17 (11%) patients where chromosomal rearrangements were concurrently detected by OGM and CBA. Overall, 24 (15%) aberrations were identified exclusively by OGM and had the potential to alter AML classification, risk stratification, and/or clinical trial eligibility. OGM emerges as a powerful tool for identifying fusion genes and detecting subtle or cryptic cytogenomic aberrations that may otherwise remain undetectable by CBA.

This review focuses on mature T cells, natural killer (NK) cells, and stroma-derived neoplasms in the fifth edition of the World Health Organization classification of hematolymphoid tumors, including changes from the revised fourth edition. Overall, information has expanded, primarily due to advancements in genomic understanding. The updated classification adopts a hierarchical format. The updated classification relies on a multidisciplinary approach, incorporating insights from a diverse group of pathologists, clinicians, and geneticists. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, Epstein-Barr virus-positive nodal T- and NK-cell lymphoma, and several stroma-derived neoplasms of lymphoid tissues have been newly introduced or included. The review also provides guidance on how the fifth edition of the World Health Organization classification of hematolymphoid tumors can be applied in routine clinical practice. (c) 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

BACKGROUND:In the absence of high-quality evidence, there is a need for guidelines and multidisciplinary consensus recommendations on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL). The purpose of this expert consensus conference was to evaluate the existing evidence regarding the diagnosis and management of BIA-ALCL caused by textured implants. This article aims to provide evidence-based recommendations regarding the management and prevention of BIA-ALCL. METHODS:A comprehensive search was conducted in the MEDLINE, Cochrane Library, and Embase databases, and supplemented by manual searches of relevant English-language articles and "related articles" sections. Studies focusing on breast surgery and lymphoma associated with breast implants were included for analysis. Meta-analyses were performed and reviewed by experts selected by the American Association of Plastic Surgeons using a Delphi consensus method. RESULTS:A total of 840 articles published between January of 2011 and January of 2023 were initially identified and screened. The full text of 188 articles was assessed. An additional 43 articles were excluded for focus, and 145 articles were included in the synthesis of results, with 105 of them being case reports or case series. The analysis encompassed a comprehensive examination of the selected articles to determine the incidence, risk factors, clinical presentation, diagnostic approaches, and treatment modalities related to BIA-ALCL. CONCLUSIONS:Plastic surgeons should be aware of the elevated risks by implant surface type, implement appropriate patient surveillance, and follow the recommendations outlined in this statement to ensure patient safety and optimize outcomes. Ongoing research on the pathogenesis, genetic drivers, and preventative and prophylactic measures for BIA-ALCL is crucial for improving patient care. CLINICAL QUESTION/LEVEL OF EVIDENCE:Risk, V.

Background: Anaplastic large cell lymphomas (ALCLs) represent a heterogeneous group of T-cell lymphomas that currently are classified by the presence or absence of ALK tyrosine kinase (TK) fusion genes (ALK+ or ALK−) and clinical presentation (systemic, cutaneous, or breast implant-associated). Two overarching molecular types of ALCL recently were discovered, defined by the presence (Type I) or absence (Type II) of a gene expression signature highly enriched for JAK-STAT3 activation. Fusions involving non-ALK TK genes occur in some ALK− cases, but the fusion landscape of ALCL remains incompletely characterized. Methods: Expert consensus pathology review was conducted in the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). RNAseq was performed and fusions were identified using FusionCatcher. Here, we focused on recurrent in-frame coding fusions. Previously unreported fusions were validated by RT-PCR. Type I/II was assigned using a previously validated gene expression-based model. Genes with adjusted (adj) P<0.05 were considered differentially expressed. Overall survival (OS) was assessed for systemic ALCL, when available. Results: We evaluated 379 ALCLs (229M/150F; mean age, 56 y). Of 199 candidate fusions (excluding reciprocal events), 28 were recurrent and passed quality metrics. At least 1 of these 28 fusions was present in 150 cases (40%). ALK fusions were present in 106 ALK+ ALCLs (all Type I; P<0.0001). Of these, NPM1::ALK was seen in 68/106 (64%). Alternate partners (X::ALK) included ATIC (N=24) and CTLC, COL1A2, MSN, MYH9, RNF213, SATB1, TFH, TPM3, and TRAF1 (1-3 cases each). X::ALK was associated with older age (mean, 52 y) than NPM1::ALK (32 y; P<0.0001) and showed relative overexpression of 49 genes, including multiple activators of small GTPases such as CGNL1 (FC, 5.6; Padj=2.4×10-6), SRGAP1, ALS2, DOCK1, and NCKAP1. ALK expression was similar in cases with NPM1::ALK and X::ALK and there was no significant difference in OS. Non-ALK TK fusions were seen in 17/273 ALK− cases (6%), including TYK2 (N=9); JAK2 (N=6); and ROS1 (N=2). All were Type I ALCLs (P<0.0001). ALK− cases with non-ALK TK fusions overexpressed 38 genes compared to ALK− cases without TK fusions, including cytokines involved in the IL17 signaling pathway such as CXCL6 (FC, 12.5; Padj=4.2×10-3), CXCL1, and CSF3. We then assessed the relationship between ALK− cases with non-ALK TK fusions and ALK+ cases by separately comparing each subset to ALK− cases without TK fusions. FC values for ALK− cases with non-ALK TK fusions were significantly correlated with FC values for ALK+ ALCLs over the set of expressed genes (R=0.54; P<0.0001). At a median follow-up of 32 months, 0/4 systemic ALCL patients with non-ALK TK fusions had died, while 30% of those with ALK− ALCL without TK fusions had died, but this was not statistically significant (P=0.26). The other 13 ALK− cases with non-ALK TK fusions were either localized ALCLs or did not have outcome data available. Of 20 TP63 fusions, 17 (85%) were TBL1XR1::TP63 and 3 were X::TP63. As previously reported, TP63 fusions were associated with poor OS (median OS, 10 months; not reached for other ALK− ALCLs; P=0.007). Four ALCLs had a novel NCL::UBTF fusion involving genes encoding the nucleolar proteins nucleolin and nucleolar (upstream binding) transcription factor-1. Four cases each had PARG::BMS1 and TNK1::GPS2 (the latter seen only in Type I ALCLs). Conclusions: This large consortium-based analysis of coding fusions further elucidates the molecular distinction between Type I and Type II ALCLs. Both ALK and non-ALK TK fusions were seen exclusively in Type I ALCLs, which we have shown previously are enriched for JAK-STAT3 pathway genes and correlate strongly with pSTAT3Y705 positivity by immunohistochemistry. These fusions were not identified in Type II ALCLs, which previous data suggest are associated with epigenetic alterations. ALK+ ALCLs with NPM1::ALK and X::ALK showed differences in gene expression, suggesting biological differences. Furthermore, ALCLs with non-ALK TK fusions shared gene expression features with ALK+ ALCL. Clinical fusion detection could enhance molecular classification of Type I and Type II ALCLs and may guide precision therapy.

Enhancer of zeste homolog 2 (EZH2) expression is found in about 40% of mantle cell lymphoma (MCL) patients, which is associated with aggressive histology, high Ki-67 proliferation rate, p53 mutant pattern and inferior overall survival (OS). We conducted 11 -gene ( ATM, BIRC3, CCND1, KMT2C, KMT2D, NOTCH1, NOTCH2, RB1, TP53, TRAF2 and UBR5 ) next generation sequencing panel to shed more light on MCL with EZH2 expression (EZH2+ MCL). EZH2+ MCL more frequently harbor TP53 mutation compared to EZH2(-) MCL (41.2% vs. 19.1%, respectively, p = 0.045). TP53 mutation and EZH2 expression demonstrated overlapping features including aggressive histology, high Ki-67 proliferation rate and p53 mutant pattern by immunohistochemistry. Comparative analysis disclosed that EZH2 expression correlates with high Ki-67 proliferation rate irrespective of TP53 mutation. Aggressive histology is associated with EZH2 expression or TP53 mutation, possibly via independent mechanisms. p53 mutant pattern is due to TP53 mutation. MCL patients with EZH2 expression or TP53 mutation show inferior outcome and when both are present, patients have dismal outcome.

Granulomatous Mycosis Fungoides (GMF) is a rare form of mycosis fungoides (MF) characterized by a granulomatous infiltrate associated with the neoplastic lymphoid population and is considered to have a worse prognosis compared with regular MF. The upregulation of the T helper (Th) axis, especially Th17, plays an important role in the pathogenesis of several inflammatory/infectious granulomatous cutaneous diseases, but its role in GMF is still not elucidated to date. In this study, we evaluated the immunohistochemical expression of Th1 (Tbet), Th2 (GATA-3), Th17 (RORγT), T regulatory (Foxp3), and immune checkpoint (IC) (PD-1 and PD-L1) markers in a cohort of patients with GMF and MF with large cell transformation (MFLCT). Skin biopsies from 49 patients (28 GMF and 21 MFLCT) were studied. Patients with GMF were associated with early clinical stage (p = 0.036) and lower levels of lactate dehydrogenase (p = 0.042). An increased percentage of cells positive for Tbet (p = 0.017), RORγT (p = 0.001), and PD-L1 (p = 0.011) was also observed among the GMF specimens, while a stronger PD-1 intensity was detected in cases of MFLCT. In this cohort, LCT, RORγT < 10%, Foxp3 < 10%, age, and advanced stage were associated with worse overall survival (OS) in univariate analysis. GMF demonstrated Th1 (cellular response) and Th17 (autoimmunity) phenotype, seen in early MF and granulomatous processes, respectively, which may be related to the histopathological appearance and biological behavior of GMF. Further studies involving larger series of cases and more sensitive techniques are warranted.

Background Peripheral T-cell lymphomas (PTCLs) are a diverse group of aggressive non-Hodgkin lymphomas characterized by a high relapse rate and poor prognosis in the relapsed/refractory (r/r) setting. Despite advances in treatment, there remains a critical need for new therapeutic strategies. This study investigates the combination of Pembrolizumab, an immune checkpoint inhibitor, and Romidepsin, a histone deacetylase inhibitor, based on the hypothesis that PTCLs harbor mutations in epigenetic modifier genes that may impair immunogenicity and promote immune escape. The combination aims to synergistically prime the immune system, potentially enhancing anti-tumor responses. Here, we present updated results from our phase I/II study (NCT03278782), including survival analysis and integrated spatial and genomic data, to correlate the efficacy of this novel therapeutic approach in r/r PTCL patients. Methods We enrolled 38 patients (pts) between February 2018 and April 2022. Treatment consisted of Pembrolizumab (200 mg, day 1) and Romidepsin (14 mg/m², days 1 and 8) in 21-day cycles, with a maximum of 35 cycles. The primary endpoint was overall response (OR: CR+PR) using Lugano Revised Response Criteria, with secondary endpoints of progression-free survival (PFS), overall survival (OS), and exploratory studies. Correlative studies were performed in 26 pt samples to delineate components of the tumor microenvironment (TME) contributing to primary or acquired resistance to immune checkpoint blockade. These included CODEX analysis of 122 phenotypes using 33 different markers, whole exome sequencing (WES), RNA-seq, targeted next-generation sequencing (NGS), and whole slide image (WSI) analysis. Survival analysis was conducted using R and Python with a p-value threshold of ≤0.05. Results Patient characteristics (n=38) included: median age 67, 57.9% male, 86.8% >60 years, 68.4% with elevated LDH, 63.2% at Stage III/IV. Common ≥grade 3 adverse events were infections (n=11) and thrombocytopenia (n=10). Three patients discontinued due to immune-related adverse events (iRAEs), while two continued after steroid treatment. Response rates varied by PTCL subtype, with best responses for the TfH/AITL subtype showing CR 57.1%, PR 28.6%, ORR 85.7%. At a median follow-up of 40 months (Mo), median OS was 21.32 months (TfH vs. PTCL: 65 vs. 16.6 Mo, p=0.024). OS rates were: 1-year 67.9%, 2-year 48.7%, 3-year 36.7%. Median PFS was 3.6 Mo (TfH vs. PTCL-NOS: NR vs. 1.23 Mo, p=0.013), with PFS rates: 1-year 42.1%, 2-year 36.8%, 3-year 34.0%. CODEX analysis revealed higher levels of cytotoxic T cells (CD3+CD8+), macrophages (CD68+), and proliferating B cell subset (CD20+Ki67+) in responders. Non-responders showed higher levels of CD4+PD1+ T cells, suggesting T cell exhaustion. Spatial analysis showed CTLs were generally closest to Tregs across most lymphoma subtypes, with subtype-specific variations in cellular distances and clustering coefficients. RNA-seq analysis of 10 samples revealed distinct clustering of responders and non-responders in PCA and heatmap analyses of the top 500, 800, and 1000 variable genes. NGS showed heterogeneity in genetic alterations with top genes including TET2, DNMT3A, RHOA, IDH2, PLCG1, CD28, FYN, and STAT3. Finally, WSI analysis (n=27) using machine learning and deep learning techniques identified patch clusters that correlated with outcomes. Conclusions The combination of Romidepsin and Pembrolizumab leads to high response rates and prolonged remissions in r/r TCL, particularly in the TFH subtype. The exploratory analysis revealed a clear separation of responders and non-responders based on WES, CODEX and spatial analysis. WES and RNA-seq show significant genetic and transcriptomic heterogeneity among the samples, with some patterns potentially associated with treatment response. CODEX displayed a more diverse and active immune profile in responders, including higher levels of cytotoxic T cells, B cells, and macrophages, with subtype-specific variations in the TME. Through single-cell analysis, we were able to simultaneously detect various biomarkers in neoplastic cells and the immune microenvironment while considering spatial relationships. Further integration of biomarker for treatment response and resistance mechanisms will be presented at the annual meeting.