Case Of Anaplastic Large Cell Lymphoma Research Articles

Podcast on Emerging Treatment Options for Pediatric Patients with ALK-Positive Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumors.

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.

The Difficulties and Ease of Diagnosing Anaplastic Large Cell Lymphomas on Cytology.

Anaplastic large cell lymphoma (ALCL), a unique non-Hodgkin lymphoma (NHL), is a CD30-positive neoplasm of T-cell lineage. Its distinctive yet variable cytomorphology makes diagnosing fine needle aspiration cytology (FNAC) challenging. This study was undertaken to study the cytomorphology and the utility of immunocytochemical (ICC) stains on cytology in ALCL and to discuss their morphological differential diagnosis. The present study was conducted in the Department of Pathology of a tertiary care center. A retrospective review was done from January 2017 to July 2022, and all histopathologically and immunohistochemically (IHC) diagnosed cases of ALCL were taken and correlated with the cytological diagnosis. Twenty-one cases of histopathology examination and IHC-proven cases of ALCL were retrieved from the departmental archives and reviewed. The ages ranged from 3 to 80 years (median age 28 years). Commonly noted cytomorphologic features included singly dispersed large pleomorphic cells, hallmark cells, and Reed-Sternberg-like cells. CD15, CD30, epithelial membrane antigen, and anaplastic lymphoma kinase-1 were some of the ICC stains used in this study. All 21 cases had cytology correlation. Fourteen cases had concordant cyto-histological correlation. Seven cases of histopathologically proven ALCL were reported as Hodgkin lymphoma (HL) in three, ALCL/anaplastic diffuse large B-cell lymphoma, HL/ALCL, poorly differentiated carcinoma, and NHL in one case each on cytology. ALCL has a reasonably distinct cytomorphologic appearance and ICC staining pattern, and a careful interpretation of both helps arrive at a reliable FNAC diagnosis.

Challenges in utilizing ALK expression to distinguish primary cutaneous from systemic anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a CD30+ peripheral T-cell lymphoma with a clinical spectrum including cutaneous and systemic presentations. While primary cutaneous ALCL (pcALCL) has a favorable prognosis, systemic ALCL (sALCL) has poorer survival outcomes. Expression of anaplastic lymphoma kinase (ALK) by malignant cells has been suggested to distinguish sALCL from pcALCL. However, there have been documented cases of ALK-positive ALCL confined to the skin. The present study reviewed characteristics of published cutaneous ALK-positive ALCL cases to distinguish between these two entities. In 23 identified adults with ALK-positive pcALCL, 26% developed systemic involvement and 74% had skin-limited disease. In 14 pediatric patients, 36% had both cutaneous and systemic involvement and 64% had cutaneous disease only. This analysis revealed that pcALCL and sALCL could not reliably be distinguished by ALK expression or nuclear vs. cytoplasmic localization. Localized treatment with frequent monitoring may be sufficient in ALK-positive pcALCL until there is evidence of progression. Physicians should be aware of the overall spectrum of ALCL, including cutaneous limited disease, systemic disease, disease with NPM-ALK translocation, disease with ALK positivity and disease with skin recurrence.

TIGIT is Frequently Expressed in the Tumor Microenvironment of Select Lymphomas: Implications for Targeted Therapy.

Immune checkpoint inhibitors against Programmed Cell Death Protein 1/Programmed Cell (PD-1/PD-L1) and CTLA-4/B7 axes have had limited success in hematologic malignancies, requiring the need to explore alternative targets such as T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 to improve durable clinical responses. We undertook this study to investigate the expression profile of TIGIT such that the potential efficacy of TIGIT blockade could be mapped among lymphoma subtypes. We validated an immunohistochemical assay for TIGIT and evaluated its expression in lymphoma and tumor microenvironment (TME) cells in 661 lymphoma/leukemia biopsies. Multiplex immunofluorescence was used for correlation with normal TME cell subsets. Tumor or TME TIGIT-positivity was defined as moderate to strong membrane staining in at least 10% of tumor or TME cells, respectively. TME TIGIT expression was correlated with overall survival and progression-free survival and comparison with PD-L1 expression. In most cases, lymphoma cells were TIGIT-negative except for angioimmunoblastic and peripheral T-cell lymphomas, which showed 91% and 47% positivity, respectively. A high proportion of small B-cell lymphoma and anaplastic large cell lymphoma cases had TIGIT-positive TME cells. Chronic lymphocytic leukemia/small lymphocytic lymphoma patients with TIGIT-negative TME cells showed significantly shorter overall survival ( P =0.04). No other statistically significant differences were found. When TIGIT was expressed in TME cells, there were a comparable number of TIGIT-positive only and dual TIGIT/PD-L1 positive cases except for more TIGIT-positive only cases in CLL/SLL. TIGIT expression shows distinctive profiles among lymphoma subtypes. Chronic lymphocytic leukemia/small lymphocytic lymphoma and anaplastic large cell lymphoma demonstrated high TME TIGIT expression compared with PD-L1, with a high proportion of dual TIGIT and PD-L1-positivity. Our results are likely to contribute to the design and correlative study of therapeutic response in clinical trials targeting TIGIT alone or in combination with PD1/PDL1.

Anaplastic Large Cell Lymphoma With Intraocular or Ocular Adnexal Involvement: A Case Report and Systematic Review.

To review the existing literature on patients with anaplastic large cell lymphoma (ALCL) affecting the globe and/or ocular adnexa, and to present a report documenting the clinical course of a patient with ALCL that involved their globe and ocular adnexa. PubMed, Scopus, and Google scholar were systematically searched for all cases of ALCL involving intraocular or adnexal ocular structures from inception to May 2023. Moreover, a new reported case added to the cases found in searches. The review identified 1680 studies, with 8 meeting inclusion criteria. A total of 9 patients were included with a mean age of 29.7 years (median: 30.0, range: 1.3-48). Primary ALCL was present in 5/9 (55.6%) patients. The most common ophthalmic manifestations included periorbital swelling (5/8), chemosis (5.8), and decreased vision (5/7). Misdiagnoses were initially made in 3 patients, and the lag time to correct diagnosis from 3 weeks to 3 months. CD30 expression was positive in all cases, and 6/9 patients were positive for anaplastic lymphoma kinase, resulting in 6/9 patients being diagnosed with anaplastic lymphoma kinase-positive ALCL. In terms of management modalities, chemotherapy was administered in 8/9 patients, while radiation therapy was utilized in 4/9 patients, and 2 underwent autologous stem cell transplantation. Five (55.6%) patients succumbed to ALCL while 4 (44.4%) were alive and disease-free at the last follow-up. The median times from the initial presentation of ALCL to death, ophthalmic presentation to death, and diagnosis to death were 4.12 months (range: 1.1-168.0), 2.62 months (range: 1.1-144), and 4.00 months (range: 0.10-168), respectively. The median follow-up duration was 21.0 months (range: 1.1-168.0). ALCL involving the globe and ocular adnexa is a rare and highly malignant tumor that can mimic benign clinical conditions. Early biopsy and aggressive treatment with chemotherapy regimens such as CHOP and radiation therapy may be useful.

Plasma small‐extracellular vesicles enriched in miR‐122‐5p promote disease aggressiveness in pediatric anaplastic large‐cell lymphoma

Plasma small‐extracellular vesicles enriched in miR‐122‐5p promote disease aggressiveness in pediatric anaplastic large‐cell lymphoma

THE UNFORTUNATE PERFECT STORM - SEPTIC SHOCK DUE TO CHRONIC IMMUNOSUPPRESIVE MEDICAL THERAPY AND MEDICATION-INDUCED LYMPHOMA

Pharmacological treatment of Crohn's Disease (CD) involves immunomodulators such as adalimumab, a tumor necrosis factor (TNF) inhibitor and azathioprine, a purine analogue. These medications have risks associated with severe illness from infectious etiologies as well as lymphoma development. This is due to the immunosuppressive effect of the medications as well as a chronic inflammatory state(1). Anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma (NHL). We present a rare case of sepsis and ALCL in a patient on immunomodulator therapy.

THE UNFORTUNATE PERFECT STORM - SEPTIC SHOCK DUE TO CHRONIC IMMUNOSUPPRESIVE MEDICAL THERAPY AND MEDICATION-INDUCED LYMPHOMA

Abstract INTRODUCTION Pharmacological treatment of Crohn's Disease (CD) involves immunomodulators such as adalimumab, a tumor necrosis factor (TNF) inhibitor and azathioprine, a purine analogue. These medications have risks associated with severe illness from infectious etiologies as well as lymphoma development. This is due to the immunosuppressive effect of the medications as well as a chronic inflammatory state(1). Anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma (NHL). We present a rare case of sepsis and ALCL in a patient on immunomodulator therapy. CASE DESCRIPTION A 31-year-old G1P0 female at 19 weeks gestation with history of Crohn’s disease presents with abdominal pain. Her medications are adalimumab and azathioprine which were started one year ago due to poorly controlled CD resulting in anal fistulas. She was recently treated for right thigh folliculitis. This progressed to abdominal pain and right inguinal lymphadenopathy. She met SIRS criteria on presentation and was admitted to the intensive care unit for respiratory failure requiring intubation. Despite broad-spectrum antibiotics for pneumonia, she remained febrile with an increasing leukocytosis. Blood, lower respiratory, and fungal cultures, acid-fast staining, viral cultures and smears, and urine tests were negative for a source of infection. Commuted tomography (CT) of the abdomen and pelvis was significant for extensive retroperitoneal lymphadenopathy but found no infectious source. An excisional biopsy of the right groin lymph node was a preliminary read as Hodgkin's lymphoma (HL), but the initial immunohistochemical stain was consistent with NHL. Her immunomodulator therapy was stopped due to sepsis and her risk of lymphoma. She subsequently developed septic shock, acute renal failure requiring continuous renal replacement therapy, atrial fibrillation with rapid ventricular response, and suffered a spontaneous vaginal delivery of a 20-week stillborn baby. A final diagnosis of ALCL was confirmed by pathology. The molecular studies were significant for positivity for CD45, CD30, EMA, CD2, CD4, CD25, ALK1, granzyme B, perforin, and TIA1. She was started on brentuximab, cyclophosphamide, and prednisone. DISCUSSION ALCL is a rare subtype of NHL that accounts for roughly one percent of all NHL (3). The development of lymphomas occurs when the TNF alpha subunit binds to the cell surface. This inhibits both the apoptosis pathway and cytokine-mediated inhibition of CD30+ lymphoma cells resulting in cell proliferation (4). There is limited documentation of adalimumab or azathioprine associated ALCL and this association should be studied further. The patient suffered from severe consequences of her immunosuppression from her chronic immunomodulator therapy and immunosuppression from her malignancy resulting in septic shock with multiorgan failure. Right inguinal lymph node biopsy showing atypical large lymphoid infiltrate, background small lymphocytes, plasma cells, and histiocytes. The large atypical cells are characterized by large irregular nuclei with occasional bilobed nuclei and horseshoe-shaped nuclei, multiple small nucleoli, and abundant amphophilic cytoplasm.

The spectrum of intestinal mature T- and NK-cell neoplasms in a tertiary center in Taiwan with a high frequency of perforation.

Primary intestinal T-cell lymphomas (PITLs) comprise enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), extranodal NK/T-cell lymphoma (ENKTL), anaplastic large cell lymphoma (ALCL), and intestinal T cell lymphoma, NOS (ITCL-NOS). MEITL is composed of monomorphic medium cells expressing CD8 and CD56, with a cytotoxic phenotype. We retrospectively analyzed 77 cases of intestinal T-cell lymphomas, 71 primary and six secondary, at a tertiary center in Taiwan from 2001 to 2021. Perforation occurred in 57 (74%) patients, including 56 (73%) at presentation and one after chemotherapy. The primary cases included MEITL (68%), ENKTL (14%), ITCL-NOS (13%), ALCL (4%), and EATL (1%). The perforation rate was 90%, 70%, and 22% in MEITL, ENKTL, and ITCL-NOS cases, respectively (p<0.0001, Fisher's exact test). Most (75%; n=36) MEITL cases were typical; while seven (15%) had atypical morphology and five (10%) exhibited atypical immunophenotype. The tumor cells of ITCL-NOS were pleomorphic, with various expression of CD8 or CD56. All METIL, ITCL-NOS and ALCL cases were negative for EBER; while all ENKTL cases, either primary or secondary, were positive for cytotoxic granules and EBER. The prognosis of PITL was poor, with a medium survival of 7.0, 3.3, and 3.7 months among patients with MEITL, ENKTL, and ITCL-NOS, respectively. Of the six secondary cases, the primary tumors orginated from nasal ENKTL (n=5) and cutaneous PTCL-NOS (n=1). We showed a wide spectrum of intestinal T-cell lymphomas in Taiwan, with MEITL as the most common PITL, a high rate of perforation, and a wider morphological and immunophenotypic spectrum.

Too Sensitive or Just Right?

To compare the performance of the rabbit monoclonal antihuman CD246 antibody (D5F3 clone) with the established ALK1 clone for immunohistochemical assessment of anaplastic large cell lymphoma (ALCL). Archival cases of ALCL (n = 27) were assessed immunohistochemically by use of ALK1 and D5F3 clones under standard Clinical Laboratory Improvement Amendments-compliant conditions. The intensity of cytoplasmic staining (0 = none; 1 = faint; 2 = moderate; 3+ = strong) and proportion of neoplastic cells (0%, <5%, 5%-50%, >50%) were evaluated and compared with clinical ALK break-apart fluorescence in situ hybridization (FISH) assays. Nine ALCL specimens were positive for ALK expression by ALK1 staining (33%; 1 = 1+; 0 = 2+; 8 = 3+), while 14 were positive by D5F3 staining (48%; 3 = 1+; 1 = 2+; 10 = 3+). Across the cohort, D5F3 staining showed a significantly greater proportion of cells staining positive (P = .02) and greater intensity (P = .03). Of 3 cases positive for D5F3 only with FISH results, none showed rearrangements, although 1 showed copy number gains at the ALK locus in a subset of cells. Overall, D5F3 showed greater stain intensity and proportion staining than ALK1 in ALK-positive ALCL cases, which is especially helpful in limited samples. Caution and consideration of orthogonal ALK testing types is recommended, especially for cases with weak or focal staining.

IRF8 as a Novel Marker to Differentiate Between CD30-Positive Large Cell Lymphomas.

Interferon regulatory factor 8 (IRF8) is a new biomarker shown to be positive in monocytic leukemias as well as in B cells. As a transcription factor, it plays a critical role in pre-B-cell differentiation and induction of tolerance pathways, among other functions. Given the frequent diagnostic dilemma in CD30-positive large cell lymphomas that could resemble both Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL), we sought to determine whether IRF8 can be useful in distinguishing between these neoplasms that require different treatment strategies. In this retrospective study, 74 cases of classic Hodgkin lymphoma (CHL) and 7 cases of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) on a tissue microarray (TMA), as well as 15 individual cases of ALK-negative ALCL and 4 cases of ALK-positive ALCL, were stained for IRF8. Paired box 5 (PAX5) immunostaining of the TMA was also performed and compared alongside since that marker is occasionally the only marker to help clinically differentiate between T- and B-cell lymphomas with anaplastic/Hodgkin-like cytology. None (0%) of the ALCLs were positive for IRF8 while all (100%) of the NLPHLs and 85% of the CHLs were positive for IRF8. Six (8%) cases of CHL were PAX5 negative but IRF8 positive. Conversely, seven (10%) cases of CHL were PAX5 positive but IRF8 negative. Four (6%) cases of CHL were negative for both PAX5 and IRF8. There is significant morphologic and immunophenotypic (CD30 positive and CD45 and CD20 negative) overlap between CHL and ALCL. Since many ALCLs show downregulation of lineage-specific T-cell markers or are "null cell" type, only PAX5 has been a reliable marker to differentiate between borderline cases. This is further confounded by positivity of PAX5 in some ALCLs due to amplification of PAX5. On the basis of recent discoveries of IRF8 function as well as performance as an immunostain, we tested this marker in human lymphoma samples and found that it aids in the discrimination between these tumors.

Erythematous, telangiectatic nodule within the melomental fold

Erythematous, telangiectatic nodule within the melomental fold

Small cell/lymphohistiocytic morphology is associated with peripheral blood involvement, CD8 positivity and retained T-cell antigens, but not outcome in adults with ALK+ anaplastic large cell lymphoma

Several morphologic variants of ALK+ anaplastic large cell lymphoma (ALCL) are recognized. The small cell (SC) and lymphohistiocytic (LH) variants are reported to be associated with poorer outcome in children with ALK + ALCL. In this study of 102 adults with ALK + ALCL, there were 18 (18%) cases of SC and/or LH variants. Patients with SC/LH ALK + ALCL more often had peripheral blood involvement than patients with non-SC/LH neoplasms (60% vs 0%, p = 0.02). There were no other significant differences in clinical features between patients with SC/LH versus non-SC/LH ALK + ALCL. Compared with non-SC/LH cases of ALK + ALCL, neoplasms with SC/LH features were more often positive for CD2 (92% vs. 36%, p = 0.0007), CD3 (81% vs. 15%, p = 0.0001), CD7 (80% vs. 37%, p = 0.03), and CD8 (54% vs. 7%, p = 0.0006). There were no other significant differences in the immunophenotype between SC/LH and non-SC/LH ALK + ALCL cases. The initial chemotherapy regimens and the response rates were similar between patients with ALK + ALCL with SC/LH patterns versus those with non-SC/LH patterns. After a median follow-up of 30.8 months (range, 0.3–208 months), patients with high (>3) International Prognostic Index (IPI) scores had significantly shorter overall survival than patients with low (<3) IPI scores (p = 0.003). However, there was no significant difference in overall or progression-free survival between patients with SC/LH versus non-SC/LH ALK + ALCL (p = 0.99 and p = 0.94, respectively). We conclude that, in adults with ALK + ALCL, SC and LH variants are associated with peripheral blood involvement and a CD8 + immunophenotype with retention of T-cell markers (CD2, CD3, and CD7). However, in contrast with children with ALK + ALCL, SC and LH variants appear to have no impact on prognosis in adults with ALK + ALCL.

The Leukemic Phase of ALK-Negative Anaplastic Large Cell Lymphoma Is Associated with CD7 Positivity, Complex Karyotype, TP53 Deletion, and a Poor Prognosis

Simple SummaryAnaplastic large cell lymphoma (ALCL) is a systemic peripheral T-cell neoplasm characterized by strong and uniform CD30 expression and, usually, the aberrant loss of one or more T-cell antigens. ALCL is further classified into anaplastic lymphoma kinase (ALK)-positive and ALK-negative types. ALCL rarely involves the peripheral blood. The reported leukemic phase ALCL cases are almost all pediatric patients with ALK-positive ALCL, which are frequently associated with the small cell morphology, t(2;5)(p23;q35), and a poorer prognosis. Leukemic phase ALK-negative ALCL is extremely rare, with approximately ten cases reported in the literature to date, mostly as single case reports. Here we report on nine patients with leukemic ALK-negative ALCL—the largest case series to date—and we compare these cases with 39 non-leukemic cases of ALK-negative ALCL. We show that the patients with leukemic ALK-negative ALCL have a greater frequency of absolute lymphocytosis, thrombocytopenia, bone marrow involvement, CD7 positivity, complex karyotype, TP53 deletion, and a dismal outcome. These data suggest that leukemic phase ALK-negative ALCL is associated with a number of poor prognostic factors and affected patients may need more aggressive treatment.Patients with anaplastic large cell lymphoma (ALCL) rarely develop a leukemic phase of the disease. The reported leukemic ALCL cases are almost all ALK-positive, which are frequently associated with small cell morphology, t(2;5)(p23;q35), and a poorer prognosis. Rare leukemic ALK-negative ALCL cases have been reported. In the present study, we investigated the clinical and pathologic features and outcomes of nine patients with leukemic ALK-negative ALCL and compared these features with 39 patients without leukemic disease. Compared with the non-leukemic ALK-negative ALCL group, patients with leukemic disease more often had absolute lymphocytosis (50% vs. 0%, p = 0.008), thrombocytopenia (60% vs. 11%, p = 0.03), bone marrow involvement (50% vs. 14%, p = 0.04), and CD7 positivity (71% vs. 19%, p = 0.02). Four of five (80%) patients with leukemic ALK-negative ALCL had a complex karyotype, which was significantly higher than that of the patients in the non-leukemic group. A fluorescence in situ hybridization for TP53 was performed on six leukemic ALK-negative ALCL cases and all (100%) had TP53 deletion. There were no significant differences in the other clinicopathologic features, treatment, and complete remission rates between patients in the leukemic versus non-leukemic group (all p > 0.05). The median follow-up of this cohort was 18 months with a range of 0.3–140 months. Eight of nine (90%) patients with leukemic ALK-negative ALCL died, and their overall survival was significantly shorter than that of the patients with non-leukemic disease (median 15.5 vs. 60 months, p = 0.001). In conclusion, we show that the leukemic phase of ALK-negative ALCL is associated with high-risk biologic features and, in particular, a complex karyotype and TP53 deletion. Compared with the non-leukemic ALK-negative ALCL patients, the patients with a leukemic phase of disease have poorer survival and may require more aggressive treatment.

Epstein–Barr-virus-positive large B-cell lymphoma associated with breast implants: an analysis of eight patients suggesting a possible pathogenetic relationship

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein–Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting.

Central nervous system ALK-negative anaplastic large cell lymphoma with IRF4/DUSP22 rearrangement

Anaplastic large cell lymphomas (ALCL) are mature T-cell neoplasms, approximately half of which harbor rearrangements of the ALK gene that confer a good prognosis. Recent studies have demonstrated that a significant proportion of ALK-negative ALCLs demonstrate rearrangements of the IRF4/DUSP22 locus that also are typically associated with a favorable prognosis. ALCL with primary involvement of the central nervous system (CNS) is extremely rare. We report what may be the first case of ALK-negative ALCL with IRF4/DUSP22 rearrangement involving the brain in a 55-year-old man. Magnetic resonance imaging demonstrated signal abnormalities in the periventricular region, corpus callosum and cingulate gyrus. Biopsy revealed a diffuse parenchymal and angiocentric infiltrate of CD30-positive cells that showed IRF4/DUSP22 rearrangement by fluorescence in situ hybridization. We also review the clinical and pathologic features of primary CNS ALK-negative ALCLs in the literature and highlight the need for awareness of this entity to optimize appropriate management.

HHV-6 in the Lymphoma Microenvironment: Both Chicken and Egg?

HHV-6 in the Lymphoma Microenvironment: Both Chicken and Egg?

Risk of Anaplastic Large Cell Lymphoma After Post-Mastectomy Implant-Reconstruction for Breast Cancer

Approximately one in eight women in the United States is diagnosed with breast cancer and eligible for mastectomy with implant reconstruction. Although it has been suggested that patients with breast cancer or those who are at high risk for breast cancer may have an increased risk of anaplastic large cell lymphoma (ALCL) after breast implantation, no studies have explored the association in this population. Our objective was to determine the relative and absolute risks of breast ALCL after post-mastectomy implant reconstruction for breast cancer compared with the general population.This population-based study obtained incidence data on breast ALCL in the general population from the Surveillance, Epidemiology, and End Results (SEER) program from 2000 - 2017. Patients who underwent post-mastectomy implant reconstruction for primary breast cancer from 2000 - 2016 were identified and followed through 2017. Because breast implant-associated ALCL has been documented as early as 2 months after implantation, patients with less than two months of follow-up were excluded. Observed-to-expected ratios for breast ALCL were derived from multiple primary - standardized incidence ratios in the study population versus the general U.S. population after adjusting for age, sex, race, anatomical site, and year of diagnosis. For external validation, we compared the number of cases of breast ALCL diagnosed in SEER with the estimated number of FDA-reported cases over a similar time period.The incidence rate of breast ALCL in the general U.S. female population was 0.08 - 0.12 per 1,000,000 persons per year and was rising. 52,882 women were identified that received post-mastectomy implant reconstruction for primary breast cancer and were followed for a median of 69 months, including 10,979 patients with follow-up time greater than or equal to 10 years (range 2 - 215 months). After adjusting for demographical characteristics of the cohort, the expected incidence rate of breast ALCL was 0.25 - 0.34 per 1,000,000 persons per year versus an observed rate of 5.8 - 8.7 per 1,000,000 persons per year (standardized incidence ratio 23.4 [95% confidence interval 2.8 - 84.7]). These findings corresponded well with FDA-reported cases; 353 SEER versus 333 FDA cases, respectively.Although breast cancer patients who receive post-mastectomy implant reconstruction are at increased risk of breast ALCL, the absolute risk remains extremely low. Furthermore, the risk does not appear to be increased compared to patients that receive implantation (for cosmesis or reconstruction) in previously reported literature.

Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL).

Simple SummaryAnaplastic large cell lymphoma (ALCL) is a lymphoid malignancy considered to be derived from T cells. Currently, two types of systemic ALCL are distinguished: anaplastic lymphoma kinase (ALK)-positive and ALK-negative ALCL. Although ALK+ and ALK− ALCL differ at the genomic and molecular levels, various key biological and molecular features are highly similar between both entities. We have developed the concept that both ALCL entities share a common principle of pathogenesis. In support of this concept, we here describe a common deregulation of CD74, which is usually not expressed in T cells, in ALCL. Ligation of CD74 induces cell death of ALCL cells in various conditions, and an anti-CD74-directed antibody-drug conjugate efficiently kills ALCL cell lines. Furthermore, we reveal expression of the proto-oncogene and known CD74 interaction partner MET in a fraction of ALCL cases. These data give insights into ALCL pathogenesis and might help to develop new treatment strategies for ALCL.In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL. Key pathogenic events in ALK-negative (ALK−) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK+ and ALK− ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK+ ALCL or of CD95 death-receptor signaling in ALK− ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity.

CDC37 As a Novel Target for the Treatment of NPM1-ALK Expressing Anaplastic Large Cell Lymphomas

Anaplastic large cell lymphoma (ALCL) is an aggressive CD30+ T-cell lymphoma that accounts for 2-8% and 10-15% of non-Hodgkin lymphomas in adults and children, respectively. The currently used standard therapy for anaplastic lymphoma kinase (ALK, a member of the insulin receptor superfamily) positive ALCL has limited effectiveness, resulting in a substantial percentage of cases with poor outcomes, either failing to enter remission or relapse within a few months after starting treatment. Thus, there is a clear unmet clinical need for developing novel, effective and safer therapeutic strategies for ALCL. Nucleophosmin 1 (NPM1) is a nucleolar phosphoprotein, which functions as a molecular chaperone for proteins and nucleic acids. Approximately 50% of ALCL cases are positive for the NPM1-ALK fusion chimera generated by the t(2;5) chromosomal translocation. The oligomerization domain of NPM1 in the fusion protein NPM1-ALK mediates the ligand-independent dimerization of chimeric protein, which results in constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for the oncogenicity. As NPM1-ALK is an established heat shock protein 90 (HSP90) client protein, we hypothesized that disruption of the interaction between master chaperone HSP90 and co-chaperone Cdc37 would be a viable druggable target. Celastrol is a natural compound extracted from the root bark of Chinese medicinal plant Tripterygium wilfordi. Anticancer properties of celastrol are attributed to its action on the interaction of HSP90 and its co-chaperone Cdc37. Hsp90 is an ATP-dependent master molecular chaperone. Cdc37 is a Hsp90 co-chaperone and disruption of Hsp90-Cdc37 interaction will result in the degradation of Hsp90 client proteins. Celastrol disrupts the interaction of Hsp90 and Cdc37 through inhibition of Hsp90 ATPase activity without blockage of ATP binding site as observed with Hsp90 inhibitors. We used NPM1-ALK endogenously expressing Karpas299, SUDHL-1 and ectopically expressing Ba/F3-FG-NPM1-ALK cell lines in our study. Treatment with celastrol (0.1-1 µM) significantly induced apoptosis dose dependently in ALCL cells. Apoptosis was associated with activated caspase 3 and poly (ADP-ribose) polymerase cleavage. We also observed upregulation of proapoptotic protein BAD and downregulation of antiapoptotic proteins survivin and MCL1. Celastrol treatment inhibited NPM1-ALK mediated signaling and downstream signaling effectors STAT3, AKT, and ERK1/2 by degradation of the NPM1-ALK fusion protein. Cell survival was evaluated by clonogenic survival assay and results were clearly indicative that the clonogenic survival is diminished in celastrol treated samples compared to controls. Our immunoprecipitation studies clearly demonstrated that celastrol treatment disrupted the interaction between Hsp90 and Cdc37 and induced degradation of the NPM1-ALK fusion protein. Altogether, targeting Cdc37 using celastrol is a novel therapeutic approach to induce apoptosis in ALCL cells expressing NPM1-ALK and warrants developing future therapeutic intervention strategies. DisclosuresGanguly:Amgen: Other: Advisory Board; Seattle Genetics: Speakers Bureau.