Archives of pathology & laboratory medicine最新文献

Context.—: Primary ovarian mucinous neoplasms represent a highly heterogeneous group of tumors. Despite being relatively common among ovarian tumors, they pose diagnostic challenges even for experienced gynecologic pathologists based on morphologic assessment, which serves as the primary means of classification and is intrinsically subject to substantial interobserver variability. Patients with low-stage disease generally have excellent outcomes, but infiltrative growth is associated with increased risk and high-stage disease is typically both aggressive and resistant to traditional therapy.

Objective.—: To review diagnostic criteria for classification of mucinous tumors, highlight recent updates on grading and ancillary testing, and discuss ongoing challenges of classification as they relate to clinical management.

Data sources.—: Published peer-reviewed literature and personal experience of the authors.

Conclusions.—: Primary ovarian mucinous neoplasms are frequently encountered in routine gynecologic pathology practice; however, their classification remains problematic. Much of the difficulty surrounding their diagnosis stems from their incredible spatial heterogeneity, which is confounded by frequent discordance between gross and histologic findings. One is faced with an even greater challenge during intraoperative assessment, because it drastically alters surgical management in real time, with limited sampling. The recent adoption of growth pattern-based grading may ultimately serve as a means of simplifying the approach to these elusive tumors for patients who present with low-stage disease. For those presenting with high-stage disease, ancillary testing to guide individualized therapy remains largely rooted in pan-tumor strategies, and study of potential biomarker-based approaches is ongoing.

Context.—: Recent clinical trials have identified significant benefits of human epidermal growth factor receptor 2 (HER2)-targeting antibody conjugates in invasive breast carcinomas with HER2-low and HER2-ultralow expression, challenging the conventional binary HER2 status.

Objective.—: To examine the clinicopathologic features and genomic profile of HER2-low and HER2-ultralow invasive breast carcinomas.

Design.—: Two hundred thirteen cases were identified with HER2 immunohistochemistry (IHC) reported as 0, 1+, and 2+/in situ hybridization-negative with Oncotype DX results from 2017-2022. One hundred seventy-eight cases with hematoxylin-eosin and HER2 slides available were independently scored by 5 pathologists blinded to the reported HER2 results as HER2 0, 0-1, 1+, 2+, using light microscopy. For each HER2 IHC score, patient age, tumor characteristics, and HER2 mRNA expression scores were compared. Additionally, each hormone receptor IHC score was compared to its respective mRNA expression scores.

Results.—: The overall interobserver agreement of HER2 IHC scoring was substantial, with a κ value of 0.689 (0.658-0.710; P < .001). There was no statistically significant difference in age and tumor characteristics by HER2 IHC scores. HER2 IHC scores were significantly associated with median HER2 mRNA expression scores (P < .001). However, for all 3 biomarkers, significant overlaps in mRNA expression scores existed between the different IHC scores.

Conclusions.—: In our study, there were no significant differences in clinicopathologic features among HER2 IHC scores. In addition, there was considerable overlap in HER2 and hormone receptor mRNA scores across different IHC categories, limiting their utility as predictors of HER2 and hormone receptor IHC scores.

Context.—: In the absence of conventional testing media, thyroid cytology smear slides may be used for molecular analysis of nodules with indeterminate cytology results.

Objective.—: To present solutions for overcoming challenges of ThyroSeq testing using smear slides and report findings from tested nodules.

Design.—: We developed software to parse unstructured ThyroSeq reports for actionable data extraction. To ensure compliance with sample retention requirements, substitute specimen records were created by digitizing smear slides before they were exhausted for molecular analysis. We streamlined the test send-out process and recorded the clinical, molecular, and pathologic findings of the cases in our cohort.

Results.—: We submitted 61 thyroid fine-needle aspiration specimens from 59 cases for ThyroSeq testing. All 61 specimens were adequate for DNA analysis, and only 1 was insufficient for RNA analysis. In 8 cases, the smear slide was the only viable sample for molecular testing. A total of 21 specimens (34.4%) had a positive ThyroSeq result. Gene mutations were the most common findings, with 16 mutations detected in 13 "positive" specimens. Additionally, copy number alterations, gene expression alterations, and gene fusions were identified.

Conclusions.—: This study presents our approach to extending the utility of thyroid cytology smear slides by enabling molecular analysis, particularly when routine sample types are unavailable. High adequacy rates and successful detection of molecular alterations highlight the potential of smear slides in molecular testing, reducing the need for repeated procedures and streamlining care. Effective communication between clinical and cytology teams remains essential to manage the additional workload.

Context.—: Accurate measurement of breast cancer metastatic deposits in sentinel lymph nodes (SLNs) can be challenging despite the presence of guidelines.

Objective.—: To assess interobserver variability in measuring metastatic breast carcinoma involving axillary SLNs.

Design.—: A survey of 10 microscopic images of lymph nodes involved by metastatic carcinoma was electronically shared with a large group of practicing pathologists. Images were all taken at ×1 or ×10 magnification from AE1/3-stained slides. Three options were included on how to measure metastatic foci (a, b, c) without providing the size. A fourth option for uncertain responses was included (not sure/other, d).

Results.—: A total of 88 pathologists completed the survey. We observed significant variability regarding how metastatic deposits are measured. Cases with extracapsular extension were prone to more variability (cases 5, 9, 10) with a significant number of the responders demonstrating uncertainty or excluding the extracapsular extension from the metastatic size.

Conclusions.—: Our results underscore the inherent difficulty and thus the interobserver variability that exist when measuring and classifying small metastatic tumor deposits in SLNs, even when definitive guidelines have already been established.

Context.—: Though numerous quality assurance (QA) measures are in place for the practice of gynecologic cytopathology, many of them are not clearly defined and may be variably used by laboratories worldwide.

Objective.—: To assess current practice patterns regarding the implementation of selected gynecologic cytology QA metrics to help develop guidance for laboratories.

Design.—: A supplemental questionnaire was mailed to laboratories participating in the 2022 College of American Pathologists (CAP) Gynecologic Cytopathology (PAP Education) Program requesting data regarding their QA measures in gynecologic cytology.

Results.—: A total of 562 laboratories responded to the supplemental questionnaire; responses from 511 laboratories were analyzed further. Of 492 laboratories, most considered Papanicolaou (Pap) tests from patients with untreated abnormal cytology in the previous year (386; 78.5%) or with an abnormal gynecologic biopsy finding (concurrent or within the past year) (331; 67.3%) as high-risk for negative rescreening. Many laboratories (436 of 511; 85.3%) required pathologist review of Pap tests for indications other than reactive/abnormal cells (eg, endometrial cells in women 45 years of age and older). For assessing cytologists' performance, 88.5% (399 of 451) of respondents recorded the discrepancy rate between cytologist's and pathologist's interpretations. For monitoring pathologists' performance, most laboratories (243 of 389; 62.5%) evaluated cases with significant cytologic-histologic discrepancy.

Conclusions.—: The CAP survey provided a detailed assessment of current QA practices regarding gynecologic cytology, which can aid laboratories in making decisions related to enhancement of QA in their setting. As the guidelines and tools for cervical cancer screening evolve, QA metrics will need to be accordingly refined.

Context.—: The first version of the Template for Reporting Results of Biomarker Testing of Specimens From Patients With Carcinoma of Gynecologic Origin (hereafter referred to as the Gynecologic Biomarker Protocol) was released by the College of American Pathologists (CAP) in 2022. Minor updates included clarification of the content of p53 status and explanatory notes for human epidermal growth factor receptor 2 (HER2) and mismatch repair testing in 2023. Recent developments in biomarker testing have prompted a major update to this protocol, published in December 2024.

Objective.—: To assess prognostic and/or therapeutic markers since the release of the 2023 Gynecologic Biomarker Protocol and to update testing recommendations in gynecologic carcinomas, with expanded explanatory notes and illustrative examples provided in this article.

Design.—: The CAP Cancer Committee assembled a panel of experts subspecialized in gynecologic pathology to augment the existing biomarkers, add new biomarkers, expand test reporting, and revise explanatory notes based on available evidence and clinical practice guidelines such as those of the American Society of Clinical Oncology/CAP, National Comprehensive Cancer Network, and Society for Immunotherapy of Cancer.

Results.—: The changes to the Gynecologic Biomarker Protocol include updates to hormone receptors and addition of subclonal loss of mismatch repair proteins, subclonal abnormal p53 expression, programmed death ligand-1 (PD-L1) testing, and folate receptor alpha testing, as well as updates to HER2 testing and all explanatory notes.

Conclusions.—: The updated CAP Gynecologic Biomarker Protocol provides improved structure and clarity in the reporting of prognostic and/or therapeutic biomarkers and comprehensive explanatory notes that aid in understanding the rationale for testing, interpretive guidance, and common testing pitfalls, based on the current standard of care.

Context.—: The phase 3 study Quizartinib With Standard of Care Chemotherapy and as Continuation Therapy in Patients With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia (AML) (QuANTUM-First; NCT02668653) demonstrated improved overall survival (OS) in newly diagnosed patients with FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication-positive AML treated with the FLT3 inhibitor quizartinib over placebo, leading to the approval of quizartinib in this population.

Objective.—: To describe the bridging study between the Navigate clinical trial assay (CTA) used for patient selection in QuANTUM-First and the LeukoStrat CDx [companion diagnostic] FLT3 Mutation Assay, necessary to establish concordance between these 2 assays to support the QuANTUM-First supplemental premarket application for the CDx.

Design.—: Assay agreement was established if lower bounds of the 95% CI for both positive and negative percentage agreement were 90% or greater. Treatment efficacy was evaluated to assess if OS in the intent-to-treat (ITT) CDx+ population (CTA+, CDx+) and the QuANTUM-First ITT were comparable.

Results.—: The lower bounds of the 95% CI were greater than 90% for positive percentage agreement (94.7%) and negative percentage agreement (100%) based on results from 1029 patients, demonstrating agreement between CTA and CDx. The OS benefit provided by quizartinib in the ITT CDx+ population in the bridging study, with a median OS of 29.4 months for quizartinib versus 14.8 months for placebo (hazard ratio, 0.794; 2-sided stratified log-rank P = .06), was comparable with the OS benefit in the QuANTUM-First ITT.

Conclusions.—: The LeukoStrat CDx FLT3 Mutation Assay aids in selecting newly diagnosed patients with FLT3 internal tandem duplication-positive AML for quizartinib therapy.

Context.—: Patients with melanoma can develop second tumors representing either metastases or new primary melanoma. This distinction has profound implications for management. Although clinicopathologic features are often sufficient, molecular assays can support the presence or absence of clonal relatedness in challenging cases. However, the potential for false-positive and false-negative results in this context is not well described.

Objective.—: To evaluate clinical molecular assays used to determine whether melanoma tumors represent primary-metastasis pairs or unrelated tumors.

Design.—: We identified clinical cases at our institution in which paired melanocytic tumors were analyzed for clonal relatedness by molecular assays. Results were compared against data sets and/or controls to establish the likelihood that paired tumors were clonally related.

Results.—: In total, 12 pairs were evaluated by single-nucleotide polymorphism (SNP) array, targeted next-generation sequencing (NGS), or both. SNP array predicted relatedness in 5 of 9 cases and unrelatedness in 4 cases. In SNP comparisons, whole-chromosomal and arm-level changes were often nonspecific (coincidentally similar between unrelated tumors). Targeted NGS predicted relatedness in 2 of 4 cases and unrelatedness in 1 case, and was equivocal/noncontributory in 1 case. For targeted NGS, nonspecific (coincidentally similar) results were related to recurrent oncogenic drivers or pairs lacking detected oncogene mutations.

Conclusions.—: The genome-wide analysis provided by SNP array was optimal for assessment of clonality. Targeted NGS can be informative but may be equivocal in some cases. The choice of assay may rely upon considerations including the amount of DNA, likelihood of distinctive mutations, and need for therapeutic target identification.

Context.—:

Objective.—: To report the isolation and significance of C kroppenstedtii, features of patients with GLM, pathologic findings and mechanism, bacteriologic workup, and optimal treatment.

Design.—: Analysis of the cases with C kroppenstedtii at The University of Texas MD Anderson Cancer Center from 2016 to March 2024 for mechanistic insights.

Results.—: During a period of 8 years, isolates of C kroppenstedtii were obtained from 10 women and 7 men. All of the women, with an average age of 34 years (range, 18-61 years), presented with chronic or subacute mastitis, and were subsequently diagnosed with GLM. The men, with an average age of 66 years, had neoplastic diagnoses with the bacterium being commensal in 6 cases. Thus, C kroppenstedtii shows a predilection to infect the female breast (P < .001). Predisposing risks for GLM included childbirth in 8 women and nipple inversion in 2 women. Histopathology revealed xanthogranulomatous inflammation and Gram-positive bacilli within fat droplets or extracellularly. From GLM aspirates or tissue, the liquid culture media and/or anaerobic incubation yielded 9 of 10 isolates. Up to 14 tested strains were susceptible to vancomycin, linezolid, rifampin, and gentamicin. Nine women received extensive antimicrobial therapy.

Conclusions.—: