Inborn errors of immunity (IEIs), also known as primary immunodeficiency diseases (PIDs) since 2017 Inborn Errors of Immunity Committee classification, comprise a heterogeneous group of genetic disorders resulting in impaired immune development and function. Malignancy is a major challenge in IEIs, particularly in those with defects in DNA repair, tumor suppression, immune surveillance, or chronic inflammatory control, highlighting the close interplay between immune dysfunction and oncogenesis. Hematologic malignancies, especially non-Hodgkin lymphomas, predominate in IEIs, though epithelial tumors also occur and present at younger ages with poorer outcomes. Both intrinsic factors - such as genomic instability and defective lymphocyte maturation - and extrinsic factors, including chronic inflammation, oncogenic viral infections, and iatrogenic exposures, contribute to cancer development. Subtypes such as ataxia-telangiectasia, Nijmegen breakage syndrome, Wiskott - Aldrich syndrome, and common variable immunodeficiency show particularly high malignancy rates. Defects in specific immune pathways, may predispose to organ-specific or virus-driven cancers. Although hematopoietic stem cell transplantation remains curative for selective IEIs, post-transplant malignancy risk persists. A deeper understanding of shared molecular pathways linking immunodeficiency and cancer is essential to refine early diagnosis, risk stratification, and targeted management in this vulnerable population.

Cancers of unknown primary (CUP) are tumors whose site of origin remains undetectable despite thorough clinical, radiologic, and histopathologic evaluations. They make up about 2% to 3% of all epithelial tumors and generally have a poor prognosis. Immunohistochemical (IHC) markers complement epidemiological and histomorphologic approaches to determine tumor type, subtype, and primary site, influencing patient prognosis, outcome, and treatment. This retrospective observational study examined patients who underwent liver biopsies for hepatic metastasis between January 2022 and January 2024. Data on age, gender, liver segment localization, tumor number and size, histomorphology, and IHC work-up were analyzed. The average age of metastatic patients was 62±12 years, with 85.5% aged 50 or older. Males slightly outnumbered females (51.1% vs. 49.9%). On average, there were 1.8 metastatic foci per case. The most common metastasizing tumors included colorectal (30.5%), pancreaticobiliary (29%), breast (8.4%), lung (6.9%), and lymphomas (4.6%). Histomorphologically, 66.4% were adenocarcinomas, followed by poorly differentiated tumors (9.2%) and neuroendocrine neoplasms (8.4%). At the time of biopsy, 33.6% had initial CUP (i-CUP), 22.9% had their primary site detected by IHC, and 10.7% had true CUP (t-CUP). On average, 9.4 IHC markers were used per case, rising to 13.8 in t-CUP cases. Significant correlations were found between histomorphologic patterns, primary site detection, and IHC marker usage ( P =0.01 and 0.02). IHC continues to enhance the diagnosis and treatment of metastatic liver tumors with its use of tumor-specific or organ-specific antibodies, including newly developed transcription factors, aiding pathologists in personalized medicine.

Genitourinary tract lymphomas are rare and comprise <5% of extranodal lymphomas. Information on prevalence in urinary and male genital tract (GU) organs is limited. A retrospective study of the B-cell lymphomas in the GU organs (kidney, prostate, bladder, testis, and ureter) between January 1, 2011, and September 16, 2021, at our institution was performed. A total of 39 specimens with lymphoma in the GU organs were identified, 51% of which were primary. The most common diagnosis within the primary subgroup was diffuse large B-cell lymphoma (60%), followed by chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, 15%) and extranodal marginal zone lymphoma (EMZL, 15%) and follicular lymphoma (5%). Kidney was the most common site (36%), followed by testes (20%), bladder (15%), and prostate (13%). All testicular lymphomas were primary. Most bladder lymphomas were secondary (83%). Most of these were either discovered incidentally or presented with organ-specific symptoms. We also identified an interesting example of primary EMZL involving both prostate and bladder and another one of proliferative glomerulonephritis with monoclonal IgG kappa immunoglobulin deposits due to primary CLL/SLL of the kidney. Our study highlights the importance of hematopathologic workup for specimens suspicious for a typical B cell infiltrates in surgical pathology practice.

Peripheral autoimmune cytopenias may complicate a fraction of lymphoproliferative disorders (LPD), particularly chronic lymphocytic leukemia, non-Hodgkin B-cell lymphomas, angioimmunoblastic T-cell lymphoma and large granular lymphocytic leukemia. The most frequent complications are autoimmune hemolytic anemia and immune thrombocytopenia, followed by pure red cell aplasia, autoimmune neutropenia and other systemic/organ specific autoimmune diseases. The latter are less frequently reported and probably underdiagnosed, and include systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, antiphospholipid syndrome and disorders of the hemostatic system. Therapy is mainly directed at the specific autoimmune complication when it arises in the context of a non-active LPD. However, autoimmune complications that are refractory to first line therapy usually require an LPD-directed treatment. Of note, several B-cell and T cell directed therapies that are used in LPD are also indicated or in trials for primary autoimmune cytopenias, underlying the overlapping pathogenic mechanisms between LPD and autoimmunity.

Continued advances in haematopoietic cell transplantation (HCT) for children with non-malignant diseases (NMDs) have led to a growing population of survivors in whom late occurring toxic effects remain a challenge. We investigated the incidence of and risk factors for post-transplant toxicities in a contemporary cohort of children and adolescents undergoing HCT for NMDs. In this retrospective cohort study, we extracted data from the Center for International Blood and Marrow Transplantation Research (CIBMTR) database to analyse timing and incidence of effects and risk factors associated with late effects of HCT for treatment of NMDs at age 21 years or younger. Late effects of interest were avascular necrosis, cataracts, congestive heart failure, myocardial infarction, diabetes, gonadal dysfunction, growth hormone deficiency, hypothyroidism, renal failure requiring dialysis, and neurological events (stroke and seizure). Cumulative incidence of each late effect was calculated at 5 years and 7 years after HCT. Risk factors were evaluated in Cox proportional hazards regression analyses. Main exposures were primary NMD, age, sex, ethnicity and race, insurance, donor and graft type, myoablative conditioning, total-body irradiation exposure, graft-versus-host disease (GVHD), and transplant year. Primary outcomes were rates, cumulative incidence probability (95% CI), and risk-factors for organ-specific late effects. Between Jan 1, 2000, and Dec 31, 2017, 7785 patients aged 21 years or younger underwent HCT. 1995 patients were ineligible or did not consent to be included. 5790 patients from 171 centres were included in the analysis. 3505 (60·5%) of 5790 patients were male and 2285 (39·5%) were female. 2106 (36·4%) patients were White, 771 (13·3%) were Hispanic, and 773 (12·7%) were Black. 1790 (30·9%) patients were non-USA residents. Median age at HCT was 5·5 years (range 0·0-21·0). 1127 (19%) of 5790 patients had one late effect, and 381 (7%) had at least two. At 7 years post-HCT, the cumulative incidence probability was 1·9 (95% CI 1·5-2·3) for cataracts, 4·9 (4·3-5·6) for diabetes, 2·6 (2·1-3·1) for gonadal dysfunction, 3·2 (2·7-3·8) for hypothyroidism, 5·0 (4·4-5·7) for growth disturbance, 8·1 (7·4-8·9) for renal failure, 1·6 (1·3-2·0) for avascular necrosis, 0·6 (0·4-0·8) for congestive heart failure, 0·2 (0·1-0·3) for myocardial infarction, and 9·4 (8·6-10·2) for neurological effects. Age 10 years or older at HCT, unrelated donor source, total-body irradiation, and GVHD were identified as risk factors for long-term effects. The findings highlight the need for, and access to, multidisciplinary and lifelong follow-up for children undergoing HCT for NMDs. As more children undergo treatment with cellular therapies for non-malignant conditions, further analyses of post-transplant data could increasingly guide treatment decisions and subsequent long-term surveillance. National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Allergy and Infectious Diseases, Health Resources and Services Administration, and Office of Naval Research.