Folliculocentric lymphocytic hypersensitivity reactions in CLL/SLL patients: A unique clinicopathologic entity amongst non-specific hypersensitivity reactions.

Background: Cutaneous hypersensitivity eruptions in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are a clinically and histologically heterogeneous group that can either precede, occur with, or follow the development of a hematologic malignancy. Therefore, establishing the diagnosis requires careful clinical and pathologic correlation and an understanding of the broad spectrum of presentations. Data is lacking on the correlation of skin disease with molecular/cytogenetic risk profiling of the tumor. Objectives: The aims of this study were to characterize the clinical, histological, and genetic aberrations in recurrent cutaneous hypersensitivity reactions in patients with CLL/SLL. Methods: A single site academic retrospective chart review of medical records, histopathology, molecular and cytogenetic data in CLL/SLL patients who developed biopsy-proven cutaneous hypersensitivity reactions. Results: Five hundred one new diagnoses of CLL/SLL with 73 patients requiring cutaneous biopsies for skin lesions or rashes were identified. With exclusion criteria, 20 biopsies were identified from 17 patients (mean age, 69.6 years, females = 9) with unexplained cutaneous eruptions. These were commonly pruritic, erythematous papules above the waist. Most biopsies had a prominent superficial, deep dermal eosinophilic infiltrate (85%), with a robust T-cell predominant dermal infiltrate in 40%. Five out of 17 patients (29%) had a predominately folliculocentric CD4+ T-cell infiltrate; all occurring on the head and neck. Overall, the prevalence of cutaneous hypersensitivity eruptions requiring biopsy was 3.4% (n = 17), and the prevalence of folliculocentric CD4+ T-cell infiltrate was 1% (n = 5). Conclusion: Cutaneous hypersensitivity reactions in CLL/SLL are heterogeneous; however, folliculotropic CD4+ T-cell infiltrates may be seen in a small but distinct clinical subset of patients. Commonly tested cytogenetic aberrations in CLL/SLL do not appear to be correlated with the presence of cutaneous hypersensitivity reactions.

Serologic reactivity of unidentified specificity in antenatal testing and hemolytic disease of the fetus and newborn: The BEST collaborative study.

BACKGROUND: The clinical significance of serologic reactivity of unidentified specificity (SRUS) in pregnancy is not clear based on available literature. The aim of this study is to determine if SRUS is associated with hemolytic disease of the fetus and newborn (HDFN). STUDY DESIGN AND METHODS: Retrospective data were collected from eight institutions over an 11-year study period (2010-2020), when available (5/8 sites). The outcome of the pregnancies with SRUS-no, mild, moderate, or severe HDFN-was determined. RESULTS: SRUS was demonstrated in 589 pregnancies. After excluding those with incomplete data, a total of 284 pregnancies were included in the primary HDFN outcome analysis. SRUS was detected in 124 (44%) pregnancies in isolation, and none were affected by HDFN. Of 41 pregnancies with SRUS and ABO incompatibility, 37 (90%) were unaffected, and 4 (10%) were associated with mild HDFN. Of 98 pregnancies with SRUS and concurrent identifiable antibody reactivity(s), 80 (81%) were unaffected, and 19 (19%) were associated with mild to severe HDFN. There was 1 case of mild HDFN and 1 case of severe HDFN in the 21 pregnancies with SRUS, ABO incompatibility, and concurrent identifiable antibody reactivity(s), and 19 (90%) were unaffected by HDFN. Among all patients with repeat testing, newly identified alloantibodies or other antibodies were identified in 63 of 212 (30%) patients. Although most were not clinically significant, on occasion SRUS preceded clinically significant antibody(s) associated with HDFN (3%, 5/188). CONCLUSION: The antenatal serologic finding of SRUS in isolation is not associated with HDFN but may precede clinically significant antibodies.

Histological Transformation and Clonal Relationship of Subcutaneous Marginal Zone B-Cell Lymphoma and Diffuse Large B-Cell Lymphoma.

ABSTRACT: Histological transformation (HT) is an exceptionally uncommon and poorly understood event where a low-grade or indolent B-cell lymphoma transforms into a more aggressive entity, typically diffuse large B-cell lymphoma (DLBCL). The pathogenesis is unclear; however, HT is associated with a worse prognosis. This article reports a unique case of marginal zone lymphoma (MZL) limited to skin/subcutis (confirmed with PET-CT) that subsequently developed DLBCL, followed by nodal MZL. We explored phenotypic, molecular genetic, and cytogenetic findings in subcutaneous MZL with HT to DLBCL and subsequent progression to systemic MZL. Shared clonal peaks between the tumors were demonstrated through immunoglobulin heavy chain PCR, and genomic microarray analysis revealed both unique genomic abnormalities and shared regions of copy-neutral loss of heterozygosity in all specimens. BCL-2 expression was present in the original subcutaneous MZL, lost on conversion to Primary cutaneous diffuse large B cell lymphoma (PCDLBCL)-NOS, and regained during subsequent transformation to systemic MZL. The PCDLBCL-NOS did not demonstrate FISH rearrangements for MYC, BCL2, and BCL6. Here, we describe the histologic, immunophenotypic, and cytogenetic abnormalities of the clonally related transformation of subcutaneous MZL, PCDLBCL-NOS, and eventual systemic MZL. The predominantly subcutaneous presentation of MZL may be associated with a more aggressive outcome and raises consideration for careful evaluation of patients who present with this pattern.

ABO antibody titer performance characteristics and correlates between two automated platforms.

BACKGROUND: AABB standards require a policy for assessing transfusing ABO-incompatible plasma. After a fatal hemolytic event with incompatible plasma, our institution instituted platelet donor population titer method for ABO antibodies on the PK7300, with high-titer being defined as having isohemagglutinin titers greater than 256. We recently switched titering platforms to the Neo Iris and we seek to determine the equivalent isohemagglutinin high-titer cutoff on the Neo Iris as compared to the PK7300. METHODS: We measured the titers on 299 apheresis platelet donors and compared its performance characteristics at various cutoffs to the PK7300 reference standard. Discrepant results were manually diluted and retested on the Neo Galileo. Furthermore, since the Neo Iris is able to determine isotype and antigen specific titers, we also characterized these features in our donor population. RESULTS: IgM titer of 128 on the Neo Iris has better accuracy compared to the titer of 64 (94 % vs 93.6 %). Eleven of sixteen discordant results were in agreement with Neo Iris. Blood group O had the highest IgG antibody titers for both anti-A and anti-B (p = 8.4E-17 and 4.3E-09, respectively). Additionally, group O donors exhibited lower anti-A2 than anti-A1 IgG titers. DISCUSSION: The Neo Iris titer cut-off of 128 had the best overall accuracy and correlation with a 256 cut-off on our laboratory developed test on the PK7300 platform. Additionally, we found that group O donors had the highest titer antibodies, with typically higher IgG titers than IgM, and generally multiple dilution levels greater than other blood types.

Platelet Component False Positive Detection Rate in Aerobic and Anaerobic Primary Culture: A Systematic Review and Meta-Analysis.

Septic reactions from platelet transfusions are one of the leading causes of transfusion-associated mortality. The FDA guidance for platelet bacterial risk control includes bacterial culture using both aerobic and anaerobic bottles. Several studies have reported false positive rates (FPR) of culture, but these data have not been summarized or influencing factors analyzed. A systematic review and meta-analysis was performed according to published guidelines to assess the false positive rate and influencing factors. Eighteen studies were included for analysis. The combined aerobic/anaerobic FPR was 2.4 events per thousand (EPT) with a prediction interval of 0.5 to 5.7, while the aerobic FPR rate was 1.0 EPT (prediction interval: 0.2-2.2) and the anaerobic rate was 1.8 EPT. Estimates were based on a total of almost 5 million units tested. The rate of false positives due to instrument error was between 0.5-1.7 EPT, while it was between 0.3-1.0 EPT for sampling contamination based on whether only aerobic, anaerobic, or aerobic/anaerobic cultures were performed. The FPR is approximately 2 to 5 times higher than the literature reported true positive rate of 0.5 EPT.

The incremental benefit of anaerobic culture for controlling bacterial risk in platelets: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Septic transfusion reactions are a principal cause of transfusion-related mortality. The frequency of detectable bacterial contamination is greater in platelets compared to other blood components because platelets are stored at room temperature. Most strategies outlined in the September 2019 FDA guidance require both aerobic culture (AC) and anaerobic culture (AnC) testing. We performed a systematic review and meta-analysis in an effort to provide the best available estimate of the effectiveness of AnC. MATERIALS AND METHODS: Our analysis was performed according to published guidelines. Broad and context-specific meta-analyses of bacterial detection rates in platelets by AnC were performed to assess the practical effectiveness of AnC as a risk control measure. RESULTS: Seven studies with a total of 1 767 014 tested platelet components were included for analysis. With exclusion of positives due to Cutibacterium/Propionibacterium species and redundancy due to AC results, AnC detected 0·06 contamination events per thousand (EPT) components tested, twofold lower than the AC (0·12 EPT). CONCLUSION: Excluding Cutibacterium/Propionibacterium species, AnC detects occasional bacterial contamination events that are not detected by AC (~1 in 17 000 platelet components).

Whole blood for postpartum hemorrhage: early experience at two institutions.

BACKGROUND: Death from postpartum hemorrhage (PPH) remains a significant preventable problem worldwide. Cold-stored, low-titer, type-O whole blood (LTOWB) is increasingly being used for resuscitation of injured patients, but it is uncommon in PPH patients, and it is unclear what its role may be in this population. STUDY DESIGN AND METHODS: Brief report of the early experience of WB use for PPH in two institutions, one university hospital and one private hospital. RESULTS: Different approaches have been implemented at the two institutions, one designed for emergency release, uncrossmatched transfusion of LTOWB as part of a massive transfusion protocol (MTP) and one for high-risk obstetric patients with known placental abnormalities. A total of 7 PPH patients have received a total of 17 units of LTOWB between the two institutions. No severe adverse transfusion reactions were observed clinically in either institution and the clinical outcomes were favorable in all cases. CONCLUSION: In our early experience, LTOWB can be implemented for two different PPH clinical scenarios. Larger studies are needed to compare outcomes between LTOWB and traditional component resuscitation strategies.

Bone marrow findings in metastatic melanoma, including role of BRAF immunohistochemistry.

INTRODUCTION: We describe peripheral blood smear, bone marrow morphology, histopathology, immunohistochemistry, including BRAF V600E, and molecular testing results of patients with metastatic melanoma to the bone marrow. METHODS: We performed a retrospective review for patients with metastatic melanoma to the bone marrow at our institution. Bone marrow morphology, histology, immunophenotyping, and cytogenetic/molecular genetic testing were reviewed, and BRAF V600E immunohistochemistry was performed. Results were compared to the literature. RESULTS: We identified four patients with metastatic melanoma to the bone marrow presenting with at least one cytopenia. Two of the four patients had leukoerythroblastosis, with three patients having atypical cells on bone marrow aspirate/touch preparation, and all patients had aggregates of atypical cells on biopsy. Immunohistochemistry for S100, Melan A, and HMB45 confirmed the diagnosis in all patients, and BRAF V600E immunohistochemistry was detected in two of four patients, which correlated with molecular testing findings. Review of the literature found 27 total patients, with normocytic anemia and leukoerythroblastosis as common peripheral blood smear findings. CONCLUSIONS: Features including cytopenias (typically anemia), leukoerythroblastosis, and morphology of cohesive, large atypical cells in aspirate and biopsy, and immunohistochemical expression for S100, Melan A, and HMB45 were present in patients with metastatic melanoma. BRAF V600E immunohistochemistry is useful as a surrogate marker of molecular results. Regardless of clinical history, at the time of the bone marrow biopsies, hematologic malignancies are in the main differential diagnosis and very rarely included metastatic melanoma, likely due to the under-recognized metastatic potential of melanoma to the bone marrow.

Cribriform-Morular Variant of Papillary Thyroid Carcinoma With Poorly Differentiated Features: A Case Report With Immunohistochemical and Molecular Genetic Analysis.

Cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) is usually an inherited malignancy and may be a presenting indicator of familial adenomatous polyposis syndrome although it may occasionally be sporadic. Known CMVPTC mutations include adenomatous polyposis coli ( APC) and ß-catenin ( CTNNB1) genes. Despite its malignant classification, CMVPTC is considered to be a well-differentiated thyroid tumor with a generally good behavior. In contrast, poorly differentiated thyroid carcinoma is an aggressive tumor. We report a case of CMVPTC with poorly differentiated features in a young female without phenotypic features of familial adenomatous polyposis but with known germline alterations of the APC gene. High throughput sequencing showed germline chromosome 5q deletion encompassing the APC gene in all components with additional unique genetic alterations in the somatic components. A single nucleotide substitution (c.1548+1G>A, NM_000038.5) located one base pair downstream of exon 12 of the APC gene was identified in the CMVPTC component, and a pathogenic frameshift deletion in exon 14 of APC (c.3642del, p.Ser1214Argfs*51, NM_000038.5) was identified in the poorly differentiated thyroid carcinoma component. No other cancer-associated genes were identified by our techniques. Our case represents a rare phenomenon of poorly differentiated features in association with CMVPTC. To our knowledge, ours is the only such report of poorly differentiated features arising in association with an inherited CMVPTC.

A Rare Case of ALK-Positive Large B-Cell Lymphoma with CD33 Expression.

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a very rare and aggressive subtype of diffuse large B-cell lymphoma characterized by ALK rearrangement. Immunophenotypically, the tumor cells are typically negative for common B-cell markers, T-cell markers, and CD30; however, they express markers of terminally differentiated B cells/plasma cells such as CD38, CD138, and MUM-1/IRF4. The diagnosis of ALK+ LBCL can be challenging, and often a large panel of immunostains is required to exclude other hematopoietic and nonhematopoietic neoplasms. To date, approximately 130-140 cases have been reported, but here we report the first known case of ALK+ LBCL with unusual CD33 expression.

Quality Improvement After Multiple Fatal Transfusion-Transmitted Bacterial Infections.

OBJECTIVES: Transfusion-transmitted bacterial infection (TTBI) from platelet components is likely underrecognized and can be fatal. Twenty-four-hour prospective culture was felt to be insufficiently preventive after multiple TTBIs occurred and strategies to improve safety were sought. METHODS: Two fatal and one severe TTBIs occurred from a split-apheresis platelet donation contaminated with Klebsiella pneumoniae. Improvement opportunities were identified and corrective and preventive action (CAPA) followed. RESULTS: To mitigate bacterial contamination and improve detection sensitivity, additional prospective culture 48 hours postcollection was implemented. Since implementation, secondary cultures have caught two true positives (0.01%) missed by 24-hour culture. Bacterial testing at issue and pathogen reduction were later implemented as an added layer of safety. CONCLUSION: While rare, TTBI is a prominent cause of morbidity and mortality from contaminated platelets. The approach to CAPA presented here may lower the risk of future transfusion-transmitted infections but must be weighed against potential added costs.