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This review article summarizes key changes in the 5th edition of the World Health Organization (WHO) 'blue book' on tumors of the female genital tract (FGT) released in 2020. (1) [...], Context.--The World Health Organization Classification of Tumours: Female Genital Tract Tumors, 5th edition, published in September 2020, comes 6 years after the 4th edition, and reflects the monumental leaps made in knowledge about the biology of gynecological tumors. Major changes include revised criteria for the assignment of the site of origin of ovarian and fallopian tube tumors, a revision in the classification of squamous and glandular lesions of the lower genital tract based on human papillomavirus association, and an entire chapter devoted to genetic tumor syndromes. This article highlights the changes in the 5th edition relative to the 4th edition, with a focus on areas of value to routine clinical practice. Objective.--To provide a comprehensive update on the World Health Organization classification of gynecological tumors, highlighting in particular updated diagnostic criteria and terminology. Data Sources.--The 4th and 5th editions of the World Health Organization Classification of Tumours. Conclusions.--The World Health Organization has made several changes in the 5th edition of the update on female genital tumors. Awareness of the changes is needed for pathologists' translation into contemporary practice. doi: 10.5858/arpa.2022-0166-RA

The diagnosis of a lymphoid malignancy requires the establishment of monoclonality of a lymphocyte population through morphologic assessment and laboratory testing, such as flow cytometry, immunohistochemistry, and cytogenetic analysis. (1) [...], * Context.--The significance of positive immunoglobulin (IG) or T-cell receptor (TCR) gene rearrangement studies in the context of otherwise normal ancillary findings is unknown. Objective.--To examine long-term hematologic outcomes of individuals with positive gene rearrangement studies with otherwise unremarkable blood or bone marrow studies in parallel. Design.--Data from patients who underwent IG or TCR gene rearrangement testing at the authors' affiliated Veterans Affairs Hospital January 1, 2013 to July 6, 2018 were extracted from medical records. Date of testing, specimen source, and morphologic, flow cytometric, immunohistochemical, and cytogenetic characterization of the tissue source were recorded. Gene rearrangement results were categorized as test positive/phenotype positive (T+/P+), test positive/phenotype negative (T+/P-), test negative/phenotype negative (T-/P-), or test negative/ phenotype positive (T-/P+) based on comparison to other studies and/or final diagnosis. Patient records were reviewed for subsequent diagnosis of hematologic malignancy for patients with positive gene rearrangements but no other evidence for a disease process. Results.--A total of 136 patients with 203 gene rearrangement studies were analyzed. For TCR studies, there were 2 T+/P- and 1 T-/P+ results in 47 peripheral blood assays, as well as 7 T+/P- and 1 T-/P+ results in 54 bone marrow assays. Regarding IG studies, 3 T+/P- and 12 T-/P+ results in 99 bone marrow studies were identified. None of the 12 patients with T+/P- TCR or IG gene rearrangement studies later developed a lymphoproliferative disorder. Conclusions.--Positive IG/TCR gene rearrangement studies in the context of otherwise negative bone marrow or peripheral blood findings are not predictive of lymphoproliferative disorders. doi: 10.5858/arpa.2019-0663-OA

Electronic consult (e-consult) systems have emerged as a potential solution to increasing demands within health care systems. E-consults are an electronic method for primary providers to request input from specialty [...], * Context.--A novel electronic consult (e-consult) system for a pathology and laboratory medicine service (PlMS) was implemented in 2015 at a high-complexity Veterans Administration health care facility. Consults were previously made through direct provider communication without documentation in the medical record. Objective.--To evaluate the utilization trends of the laboratory e-consult system at the Department of Veterans Affairs Connecticut facility during the first 2 years since inception. Design.--E-consultation involves pathology and laboratory medicine resident review followed by attending pathologist review and cosignature. E-consults to the pathology and laboratory medicine service from 2015 to 2017 were reviewed to record type of consult, requesting department, patient location, and turnaround time. Results.--The pathology and laboratory medicine service received 351 e-consults from 2015 to 2017. The volume varied by subsection: hematology and coagulation (215 of 351; 61%), chemistry (109 of 351; 31%), blood bank (19 of 351; 6%), and microbiology/virology (8 of 351; 2%). Hematology and coagulation consults were entirely for peripheral blood smear review (215 of 215; 100%). Chemistry consults were placed for toxicology/ drugs of abuse (81 of 109; 74%), test utilization (17 of 109; 16%), or nontoxicology (11 of 109; 10%). Three services placed the majority of consults: primary care (279 of 351; 80%), hematology/oncology (39 of 351; 11%), and psychiatry (27 of 351; 8%). The median turnaround time for completion of e-consults was 1.2 days. Since e-consult implementation, the mean number of consults increased from 8.6/mo in 2015 to 18.1/mo in 2017, peaking in the last quarter of analysis in 2017 with a mean of 25.3 consults/mo. Conclusions.--This novel e-consult system improved accessibility to and documentation of answers to laboratory questions and increased the visibility of the pathology and laboratory medicine service. Future goals include development of outcomes-based measures to better assess the clinical impact of e-consults. (Arch Pathol Lab Med. 2021;145:75-81; doi: 10.5858/arpa.2019-0267-OA)

Objectives Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is historically associated with Helicobacter pylori (HP) infections in more than 80% of patients. However, the incidence of HP-negative MALT lymphoma has been increasing. The clinicopathologic features have not been well studied, and optimal management strategies remain unclear. Methods The pathology database was searched for primary gastric MALT lymphomas diagnosed from 2000 to 2017. The clinical data and the slides were reviewed. The cases were divided for analysis into those with a background of chronic gastritis with HP, chronic gastritis without HP, and without either a background of chronic gastritis or HP. Results Of 70 gastric MALT lymphoma cases identified, 26 (37% of total) had chronic gastritis and were positive for HP histologically (n = 23) or were HP positive by additional laboratory testing (n = 3). The remaining 44 (63% of total) cases were HP negative by histology. Within the HP-negative cases, 5 (11% of HP-negative cases) showed histologic gastritis while 39 (89% of HP-negative cases) did not have sufficient evidence of gastritis through review of slides (n = 18) or based on available pathology reports (n = 21). The HP-negative cases without gastritis had higher propensities to show a mass lesion on endoscopy compared with HP-positive cases (37.5% vs 11.1%, P =.02) at the initial diagnosis. The immunophenotype and rate of positive B-cell gene rearrangement were not significantly different between the 2 groups. While all HP-positive patients received antibiotics for HP eradication, treatment in the HP-negative group varied among antibiotics, radiation, rituximab, or chemotherapy. Among HP-negative patients with available follow-up, 13 (39%) showed disease recurrence, similar to the recurrence rate in HP-positive patients; however, no individual from either group has died of the disease thus far. Conclusions The incidence of HP-negative MALT lymphoma is increasing, and in our practice, it is currently more common than HP-associated MALT lymphomas. The pathophysiology of HP-negative MALT lymphoma without chronic gastritis remains unclear. Follow-up data in our study suggest that the prognosis of these cases is excellent despite varied management modalities. [ABSTRACT FROM AUTHOR]

The proliferation of new molecular technologies in recent years has greatly advanced our knowledge of the genetics that underlie hematologic cancers. Particularly, with the advent and wide‐implementation of next‐generation sequencing (NGS), a host of somatic (and some germline) gene mutations have been identified as significant in the classification, prognostication, and treatment of the spectrum of myeloid neoplasms. These driver and disease modifier mutations now play a prominent role in the updated international diagnostic guidelines of acute myeloid leukemia (AML), myelodysplastic syndromes/neoplasms (MDS), and myeloproliferative neoplasms (MPN). As high‐throughput technologies such as NGS increasingly become standard in the genetic evaluation of myeloid disorders, it is critical that clinicians understand the clinical relevance of these mutations in order to further personalize patient care. In this review we discuss some of the most essential somatic and cytogenetic findings. [ABSTRACT FROM AUTHOR]

Objectives This study compares the effectiveness of an interactive e-learning module with a traditional text-based method for teaching peripheral blood smear analysis. Methods Pathology trainees at Accreditation Council for Graduate Medical Education residency programs were asked to participate. Participants completed a multiple-choice test on peripheral blood smear findings. Trainees were randomized into completing an e-learning module or a PDF reading exercise with the same educational content. Respondents rated their experience and completed a postintervention test composed of the same questions. Results In total, 28 participants completed the study; 21 improved their score in the posttest (mean, 21.6 correct answers) compared with the pretest (19.8; P <.001). This improvement was seen in both the PDF (n = 19) and interactive (n = 9) groups, with no difference in performance between the 2 groups. Trainees with less clinical hematopathology experience showed a trend of having the largest performance improvement. Most participants completed the exercise within 1 hour, rated the exercise as easy to navigate, were engaged, and reported learning new information about peripheral blood smear analysis. All participants indicated that they would likely complete a similar exercise in the future. Conclusions This study suggests that e-learning is an effective tool for hematopathology education and equivalent to traditional narrative-based methods. This module could easily be incorporated into a curriculum. [ABSTRACT FROM AUTHOR]

Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p =.009 and p =.007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p =.007 and p =.008, respectively). AML harbored a higher average number of gene mutations (p =.002) including more frequent PTPN11 mutations (p <.001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p <.001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p =.037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation. First study comparing genetic profiles of MS and AML with a common disease-defining lesion. NPM1Mut MS may be genetically distinct from NPM1Mut AML. NPM1Mut MS may have inferior overall survival compared to NPM1Mut AML. [ABSTRACT FROM AUTHOR]

Introduction: Recent data suggest basophils can adopt an atypical appearance in myeloid disorders including myeloproliferative neoplasms (MPNs) and myeloproliferative/myelodysplastic disease. We hypothesized that automated analysers may not accurately quantitate basophils in myeloid neoplasms based on scatter properties. This study examined basophil counts and properties in myeloid disorders by automated cell analyser, manual differential, and flow cytometry. Methods: Patients with myeloid neoplasms and control patients with no myeloid disorder diagnosis at a tertiary care centre were identified. Basophil percentage was compared for automated analyser counts (Sysmex XN9000), manual differential, and flow cytometry. Basophil scatter properties in MPNs were examined using flow cytometry. Results: Thirty‐one patients with myeloid neoplasms were included: 58% were male, mean age was 70.2 (±20.7) years, 32% had a diagnosis of chronic myeloid leukaemia with the remaining patients divided among various other forms of myeloid disease (including: essential thrombocythemia, polycythemia vera, unclassifiable MPN, myelodysplastic syndromes). For these patients, mean basophil percentage by automated analyser was significantly lower than manual differential (2.7 ± 2.9 vs. 7.1 ± 4.6, respectively, p < 0.001). No significant difference was found between automated versus manual differential for basophils in control subjects (p = 0.373). For myeloid neoplasm patients, mean basophil percentage was not significantly different between manual differential and flow cytometry (p = 0.116); mean basophil percentage by automated analyser was significantly lower than flow cytometry (2.7 ± 2.9 vs. 5.3 ± 3.7, respectively, p = 0.003). Conclusion: Automated analysers underestimate basophil counts in patients with myeloid neoplasms. Manual differential and flow cytometry are recommended for more accurate quantitation and characterization of aberrant basophils. [ABSTRACT FROM AUTHOR]

Objectives Clinical experts recommend against testing for lupus anticoagulant (LAC) during anticoagulation. Methods We quantitated the risk of a single-positive dilute Russell viper venom time (dRVVT) result or partial thromboplastin time–based phospholipid neutralization (PN) result on anticoagulation. Results Any anticoagulation led to a fourfold greater likelihood of single-positive results, primarily by rivaroxaban (odds ratio [OR] = 8.6) and warfarin (OR = 6.6), resulting in a positive dRVVT test with a normal PN test. Heparin and apixaban were twofold more likely to show single-positive results, but enoxaparin did not show significant single positivity. Conclusions Our results quantitatively support experts' avoidance of LAC testing during anticoagulation. [ABSTRACT FROM AUTHOR]

CEBPA- mutant acute myeloid leukemia (AML) encompasses clinically and biologically distinct subtypes of AML in both adults and children. CEBPA- mutant AML may occur with monoallelic (moCEBPA) or biallelic (biCEBPA) mutations, which can be somatic or germline, with each entity impacting prognosis in unique ways. BiCEBPA AML is broadly associated with a favorable prognosis, but differences in the type and loca- tion of CEBPA mutations as well as the presence of additional leukemogenic mutations can lead to heterogeneity in survival. Concurrent FLT3- ITD mutations have a well- documented negative effect on survival in adult biCEBPA AML, whereas support for a negative prognostic effect of mutations in TET2, DNMT3A, WT1, CSF3R, ASXL1, and KIT is mixed. NPM1 and GATA2 mutations may have a positive prognostic impact. MoCEBPA AML has similar survival outcomes compared to AML with wild-type CEBPA, and risk stratification is determined by other cytogenetic and molecular findings. Germline CEBPA mutations may lead to familial biCEBPA AML after acquisition of second somatic CEBPA mutation, with variable penetrance and age. BiCEBPA AML in children is likely a favorable- risk diagnosis as it is in adults, but the role of a single CEBPA mutation and the impact of concurrent leukemogenic mutations are not clear in this population. Laboratory evaluation of the CEBPA gene includes PCR- based fragment- length analysis, Sanger sequencing, and next- generation sequencing. Phenotypic analysis using multiparameter flow cytometry can also provide additional data in evaluating CEBPA, helping to assess for the likelihood of mutation presence. [ABSTRACT FROM AUTHOR]

Objective Acute promyelocytic leukemia (APL) with variant RARA translocation, eg, t(11;17), is not sensitive to all-trans retinoic acid and requires distinct chemotherapy. However, there are some leukemic entities that may mimic aspects of the clinical and/or laboratory picture of APL and cause confusion because of karyotype nomenclature. Therefore, recognition of such entities may be of therapeutic and prognostic significance. Methods We present 2 cases of acute myeloid leukemia (AML) with t(11;17) that were clinically concerning for APL based primarily on clinical presentation but were ultimately diagnosed as AML with monocytic differentiation. Results Both leukemias harbored KMT2A translocations, one located near but not involving RARA and the other with SEPT9. Conclusion In leukemias that clinically and/or immunophenotypically mimic APL, identification of specific gene translocations can lead to the correct diagnosis and may carry therapeutic/prognostic implications. [ABSTRACT FROM AUTHOR]

Second, it is notable that at the time of relapse, Sanger sequencing identified this patient's germline mutation but not the acquired mutation, whereas NGS detected the acquired mutation but not the germline mutation. Germline I CEBPA i analysis of individuals with biallelic I CEBPA i -mutated AML can help to decide if germline testing of unaffected relatives is indicated and is particularly important when sibling donors are being considered for alloHCT. As discussed by Ram and colleagues, the apparent incomplete penetrance of the germline mutation c.442G>T may be related to its location downstream of the p30 start codon outside of gene N-terminus where most germline mutations are found [[9]]. [Extracted from the article]

Background: Allogeneic platelet (PLT) infusion is a strategy to raise Factor V (FV) levels in patients with congenital FV deficiency. However, since FV is labile in vitro, we hypothesized that FV activity could be low in PLT units. Study Design and Methods: FV activity was tested using a prothrombin time‐based platform in the supernatant and platelet lysate (PL) of apheresis PLT units (16 units stored in PLT additive solution with acetate and phosphate [PAS‐C] and 10 units stored in plasma only), on post‐collection days 3‐6. Statistical analysis was performed using Student's t test (P <.05). Results: FV activity was severely diminished in PAS‐C PLTs (N = 16) supernatant (3.70% ± 1.02%) and PL (3.26% ± 1.02%). FV activity in plasma‐only PLTs (N = 10) was lower in both supernatant (44.55% ± 6.46%) and lysate (39.67% ± 6.33%) relative to normal plasma levels, but both were significantly higher (P <.0001) compared to PAS‐C PLTs. In a separate set of experiments, FV activity in PAS‐C PLTs examined serially over storage time (N = 3 for these experiments) showed that FV levels were reduced by day 3 and not significantly different by day 5 of storage (Day 3 supernatant 5.03% ± 1.41%; Day 5 supernatant: 3.10% ± 0.57%; P =.2; Day 3 lysate: 3.89% ± 1.03%; Day 5 lysate: 2.61% ± 0.41%; P =.4). Conclusion: Plasma should be considered over PLTs as first‐line therapy for non‐complex FV deficiency‐associated hemorrhage. If PLTs are considered for transfusion, plasma‐only PLT units should be preferentially utilized, as PAS‐C PLT have near‐absent FV activity. [ABSTRACT FROM AUTHOR]

Case Presentation: A 50-year-old woman presented with 3 months of cough, dyspnea, and fatigue. She also reported new fevers, night sweats, and a rash on her face and torso. On presentation she was tachycardic and tachypneic, with oxygen saturation of 81% on 2 L/min of oxygen. She was in mild respiratory distress. Results of the physical examination were remarkable for tender left cervical and axillary adenopathy and bibasilar pulmonary crackles. She had an acneiform rash on her face, chest, and back, consisting of multiple nonblanching erythematous or violaceous macules and papules (Fig 1) and had conjunctival edema. Admission laboratory test results were significant for a WBC count of 56,000, of which 79.5% were lymphocytes. Hemoglobin and platelet levels were normal. She was admitted for further management. [ABSTRACT FROM AUTHOR]

Mutations in the tumor suppressor gene TP53 are detected in 5–10% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes. TP53 mutations have been associated with complex karyotypes, therapy-related malignancies, lower response rates to cytotoxic chemotherapy, and an overall adverse prognosis. In this single-center retrospective study, we analyzed the clinicopathologic characteristics and outcomes of 83 patients with TP53-mutated myeloid malignancies treated at Yale Cancer Center between 9/2015 and 5/2019. Complex karyotypes (n = 75; 90%) and therapy-related malignancies (n = 32; 39%) were common. Median overall survival (OS) was 7.6 months. Intensive chemotherapy did not improve OS compared to lower-intensity treatment for AML patients. Patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT) had a significantly longer median OS, despite relatively limited follow-up. In conclusion, our data confirm the limited efficacy of intensive chemotherapy approaches for TP53-mutated patients with myeloid neoplasms and suggest that a minority of patients achieve long-term survival with alloHSCT. [ABSTRACT FROM AUTHOR]

Objectives: Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms that are often difficult to diagnose due to their pathologic and clinical heterogeneity. The key features of MDS are peripheral blood cytopenias, ineffective hematopoiesis manifesting as morphologic dysplasia, and clonal genetic abnormalities. The most difficult diagnostic dilemmas often arise in low-grade MDS cases (lacking excess blasts), which can be difficult to distinguish from other causes of cytopenia. This distinction requires the integration of information from the peripheral blood (both CBC parameters and morphology), bone marrow morphology, genetic studies, and interrogation of the clinical record to exclude secondary causes.Methods: We discuss the approach to the diagnosis of low-grade MDS (cases lacking increased blasts), including a diagnostic algorithm and two illustrative cases.Results: The appropriate use of ancillary studies is important to support or dispute the likelihood of low-grade MDS in conjunction with the findings of morphologic dysplasia. Interpreting the results of cytogenetics and next-generation sequencing can be challenging and must incorporate the emerging knowledge of clonal hematopoiesis of indeterminate potential.Conclusions: The role of pathologists in integrating data from multiple sources in the diagnosis of low-grade MDS is evolving and becoming increasingly complex; in this challenging diagnostic setting, it is important to feel comfortable with uncertainty and maintain a conservative approach. [ABSTRACT FROM AUTHOR]