Natural history of clonal haematopoiesis seen in real-world haematology settings.

Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real-world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non-sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real-world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non-sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high-risk CH in non-sole DTA (vs. sole DTA) patients and in progressors (vs. non-progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00-52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non-progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post-CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN.

Assessing Residents' Frozen Section Skills for Endometrial Cancer.

Intraoperative frozen section (IFS) on endometrial cancer is an invaluable skill for pathologists-in-training to master. Within limited time constraints, pathologists are expected to determine tumor type, grade, and depth of myometrial invasion. During their training, pathology residents gradually gain experience in handling the majority of cases. However, significant errors can still be seen among senior level trainees. We aimed to improve training effectiveness by evaluating our trainees' performance, identifying common errors, and recommending focused curriculum. Twenty-two residents [postgraduate year (PGY)-1-PGY-4] performed 260 IFS during a 4-yr period. We compared their independent IFS diagnoses with final diagnoses. Overall resident IFS accuracy was 73%. Accuracy for tumor type and depth of myometrial invasion was 80% and 93%, respectively. Two thirds of errors were due to sampling with the rest because of interpretation. Major deficiencies lay in recognizing high-risk histologic types (serous, clear cell, sarcoma) and unconventional myometrial invasion patterns (MELF, adenoma malignum, and adenomyosis-like). Resident IFS errors would theoretically result in suboptimal staging for 32 (12%) patients and unnecessary staging for 1 (0.4%). Overall IFS performance improved as training level increased (76% accuracy for PGY-1 accompanied by PGY-5; 59% for PGY-2; 74% for PGY-3; and 86% for PGY-4). We recommend a dedicated curriculum targeting these difficult yet clinically important entities through review literature and a collection of classic cases demonstrating the diverse morphology variations. Implementing such focused training would greatly improve our trainees' competence on IFS, preparing them to handle a wide variety of cases and situations in future practice.

Frameshift Mutations in Leukemia-Associated Genes Correlate With Superior Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant for De Novo Acute Myeloid Leukemia.

Background: Allogeneic stem cell transplant (allo-SCT) is a mainstay of treatment for acute myeloid leukemia (AML). Its success depends largely on response of donor T lymphocytes against leukemia cells, known as graft-vs-leukemia (GvL) effect. A key potential driver of GvL is immune response to mutation-derived neoantigens. Previous studies in solid tumors have demonstrated enhanced immunogenicity of frameshift (FS)-derived peptides vs. those from non-synonymous single nucleotide variants (SNVs). We therefore hypothesized that AML cases bearing FS mutations in leukemia-associated genes would be more immunogenic than those with only other types of mutations (non-FS), and thus benefit more from allo-SCT via more robust GvL. Methods: We identified AML patients who had undergone allo-SCT between 2010 and 2022 and had next-generation sequencing data available on diagnostic specimens using a 42-gene hot spot panel. We compared the impact of tumor mutations present at diagnosis on overall survival and relapse-free survival based on FS versus non-FS status. Results: Ninety-five AML allo-SCT patients were identified. We observed superior relapse-free survival (P = 0.038, hazard ratio (HR): 0.24) and borderline superior overall survival (P = 0.058, HR: 0.55) post-transplant in de novo AML patients, who had at least one FS mutation (other than NPM1) in one of the 42 assessed genes versus those with only non-FS mutations. Conclusions: Our findings suggest that FS-mutated AML cases may benefit more from allo-SCT than those with only non-FS mutations, possibly due to increased generation of immunogenic neoepitopes. If validated in an expanded study, incorporation of somatic FS mutation status in AML could improve patient selection algorithms for bone marrow transplant and thereby lead to superior outcomes.

Recurrent Giant Cell Tumor of Bone with New Pulmonary Metastases 9 Years After En Bloc Distal Radius Resection: A Case Report.

CASE: A 31-year-old man with a history of giant cell tumor of bone (GCTB) in the distal radius presents to clinic 9 years after en bloc distal radius resection. He was found to have a new soft tissue mass consistent with GCTB and new pulmonary metastases. Ultimately, he underwent excision of his soft tissue recurrence and partial lobectomy for his lung metastases. CONCLUSION: This case highlights the importance of having a high level of suspicion for local recurrence or metastasis, even years after wide resection and negative margins.

Prognostic heterogeneity and clonal dynamics within distinct subgroups of myelodysplastic syndrome and acute myeloid leukemia with TP53 disruptions.

TP53 aberrations constitute the highest risk subset of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The International Consensus Classification questions the blast threshold between MDS and AML. In this study, we assess the distinction between MDS and AML for 76 patients with TP53 aberrations. We observed no significant differences between MDS and AML regarding TP53 genomics. Median overall survival (OS) was 223 days for the entire group, but prognostic discrimination within subgroups showed the most inferior OS (46 days) for AML with multihit allelic state plus TP53 variant allele frequency (VAF) > 50%. In multivariate analysis, unadjusted Cox models revealed the following variables as independent risk factors for mortality: AML (vs. MDS) (hazard ratio [HR]: 2.50, confidence interval [CI]: 1.4-4.4, p = 0.001), complex karyotype (HR: 3.00, CI: 1.4-6.1, p = 0.003), multihit status (HR: 2.30, CI 1.3-4.2, p = 0.005), and absence of hematopoietic cell transplant (HCT) (HR: 3.90, CI: 1.8-8.9, p = 0.0009). Clonal dynamic modeling showed a significant reduction in TP53 VAF with front-line hypomethylating agents. These findings clarify the impact of specific covariates on outcomes of TP53-aberrant myeloid neoplasms, irrespective of the diagnosis of MDS versus AML, and may influence HCT decisions.

Langerin staining identifies most littoral cell angiomas but not most other splenic angiomatous lesions.

Although littoral cell angiomas (LCAs) are phenotypically well characterized, the antibodies used to support the diagnosis identify many other cells in the normal spleen, and some may be found in other angiomatous lesions. Based on a langerin/CD207+ LCA index case, langerin and other selected immunohistochemical staining was performed on 10 LCAs, 20 other splenic angiomatous lesions, and 7 reactive lymph nodes to further investigate the role of langerin as a diagnostic tool. Ninety percent (9/10) of LCAs were langerin positive, whereas only 1 (5%) of 20 other splenic vascular lesions was partially positive (P < .00001). All LCAs were CD1a-, CD68+, CD34-, and CD8-; 20% were S100+, 70% CD21+, and 90% cyclin D1+. Ultrastructural studies of one LCA did not show Birbeck-type granules in definite lining cells. Sinus lining cells in 7 of 7 reactive lymph nodes showed partial langerin positivity, and 4 of 4 showed partial cyclin D1 positivity. In conclusion, langerin staining is an easily interpreted and highly sensitive and specific (sensitivity [0.90], specificity [0.95]) ancillary study to help distinguish LCA from other vascular tumors of the spleen. Whether this represents cross-reactivity or true CD207 expression is uncertain, as other immunohistochemical and ultrastructural studies do not support a Langerhans cell origin. The cyclin D1 staining seen in most LCA would be consistent with their expression of other selected vascular and histiocytic markers. The similar staining pattern in some lymph node sinus lining cells suggests a possible similar cell of origin, although LCA of lymph nodes is not described.