BackgroundActivated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).ObjectiveWe sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.MethodsWe applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.ResultsRecurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS.ConclusionAPDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

Since the publication of the Revised European-American Classification of mature lymphoid neoplasms in 1994, subsequent updates of the classification of mature lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress in the characterization of malignancies of the immune system in the last years, with many new insights provided by genomic studies, have led to the current proposal. We have followed the same process that was successfully used for the 3rd and 4th editions of the WHO classification of hematological neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional are now upgraded to definite entities. Terminology of some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification (ICC) of mature lymphoid, histiocytic, and dendritic cell tumors.

t(11;18)(q21;q21) is a specific chromosomal translocation associated with mucosa-associated lymphoid tissue (MALT) lymphoma. It fuses the amino terminal of the API2 gene to the carboxyl terminal of the MALT1 gene and generates a chimeric fusion product. Although the translocation is frequently detected in gastric and pulmonary MALT lymphoma, its incidence in MALT lymphomas from other sites is largely unknown. It also remains unknown whether the occurrence of the translocation is influenced by the nature of preceding diseases associated with MALT lymphomas. We screened for t(11; 18)(q21;q21) in 417 cases of MALT lymphoma from 8 major sites by reverse transcription-polymerase chain reaction. t(11;18)(q21;q21) was found at highest frequencies in MALT lymphomas from the lung (38%) and stomach (24%), and at moderate frequencies in those from the conjunctiva (19%) and orbit (14%). However, the translocation was found only rarely in MALT lymphomas from the salivary gland (1%) and was absent in those from the thyroid, skin, liver, and other rare sites, and in immunoproliferative small intestinal disease (IPSID). In gastric MALT lymphoma, t(11;18)(q21;q21) was significantly associated with infection by CagA-positive strains of Helicobacter pylori. As CagA-positive strains of H pylori are much more potent in induction of host inflammatory responses, including activation of neutrophils, which release highly genotoxic oxygen reactive species, we therefore examined neutrophil infiltration in recognized precursors of MALT lymphoma including H pylori-associated gastritis, lymphoepithelial sialadenitis, and Hashimoto thyroiditis. Neutrophil infiltration was prominent in H pylori-associated gastritis but not in lymphoepithelial sialadenitis and Hashimoto thyroiditis. Our results demonstrate that t(11;18)(q21; q21) occurs at markedly variable frequencies in MALT lymphoma of different sites and suggest that the occurrence of the translocation is influenced by the nature of premalignant diseases associated with MALT lymphoma. Oxidative damage might play a role in development of t(11;18)(q21; q21).

Solitary fibrous tumours ('pleural fibromas') are well-recognized in the pleura, but their rare occurrence at other sites has only become appreciated in recent years, as a consequence of which extrapleural examples often go unrecognized or misdiagnosed. Eight cases (three peritoneal, two retroperitoneal, two intrapulmonary and one mediastinal) are presented herein. All but one presented in adulthood, and three were asymptomatic chance findings. Size ranged from 0.8 to 26 cm in maximum diameter. To date, none has behaved in an aggressive fashion. Histologically, these lesions are entirely comparable to their pleural counterparts, and accurate diagnosis is largely dependent on appreciation of their potential extrapleural location. Immunohistochemistry in seven cases favoured myofibroblastic/fibroblastic differentiation, in keeping with the putative submesothelial origin of these lesions.

SummaryBackgroundCells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects.ResultsHere, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma.ConclusionsIn addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy.