Context.—
The International Collaboration on Cancer Reporting is a not-for-profit organization whose goal is to develop evidence-based, internationally agreed standardized data sets for each anatomic site to be used throughout the world.
Objective.—
To update the changes in the 2nd edition of the data set suite, including carcinomas of the hypopharynx, larynx and trachea, major salivary glands, nasal cavity and paranasal sinuses, oropharynx and nasopharynx, and oral cavity, and ear and temporal bone tumors, malignant odontogenic tumors, mucosal melanomas of the head and neck, and nodal excisions and neck dissection specimens.
Design.—
International consensus by expert data set authoring committees, especially authors of the World Health Organization head and neck tumor classification.
Results.—
The unique features have been updated based on current research and developments in histologic classification and standardized reporting guidelines. Separation between core and noncore elements is based on data meaningful to prognosis and stratification. The changes are in conjunction with publication of the 5th edition of the World Health Organization head and neck tumor classification.
Conclusions.—
Increased harmonization of reporting and benchmarking improves patient outcomes and international collaborative research.
Context.—
Optical genome mapping (OGM) represents a promising cytogenomic technology that detects structural variants, including fusions, rearrangements, copy number variants, and loss of heterozygosity, in a single assay. Unlike karyotyping, fluorescence in situ hybridization, or chromosomal microarray, OGM leverages long-molecule imaging to map the whole genome with high resolution. This positions OGM as a novel tool for constitutional and somatic/cancer genomics. However, its current and planned utilization in clinical and research settings remains unknown, necessitating further investigation.
Objective.—
To investigate the current utilization of OGM in clinical and research laboratories, assess its applications, and evaluate future utilization strategies.
Design.—
In 2024, a supplemental questionnaire was incorporated into 6 College of American Pathologists proficiency testing programs to evaluate OGM’s utilization.
Results.—
Of 921 returned questionnaires, 712 were analyzed after duplicates were removed. Sixty-seven (9.4%) currently offered OGM testing: 5.2% (37) for research only, 1.8% (13) for only clinical use, and 2.4% (17) for both. Future adoption plans showed 7.6% (53 of 700 laboratories) and 7.9% (55 of 700 laboratories) aiming to implement OGM clinically within 12 and 24 months, respectively. The most common applications included hematologic malignancies and constitutional/germline postnatal disorders, followed by prenatal testing. International laboratories demonstrated statistically higher utilization rates than domestic laboratories (P = .001).
Conclusions.—
This first survey on OGM clinical utilization reveals its status as a niche technology, with 67 laboratories currently using it. Its primary clinical applications are in constitutional/germline analysis and hematologic malignancies. Although international laboratories led in 2024, 108 laboratories (domestic and international) plan clinical adoption within 24 months, signaling OGM’s potential for broader integration.
Context.—
Cancers in children show incidence distributions by age that cannot be explained by mathematical models designed to understand carcinogenesis in adults. Unlike carcinomas that tend to increase in incidence with age, pediatric cancers demonstrate unique phases of increasing incidence with a peak age of incidence followed by declining incidence. To date, mathematical models of this phenomenon are limited to statistical representations describing the frequency of oncogenic second genetic alterations in genetically susceptible individuals.
Objective.—
To develop a mathematical description of pediatric cancer incidence, we created an algebraic model based on the concept that a limited cell population is available to become Ewing sarcoma.
Design.—
Our algebraic models for the incidence of Ewing sarcoma express incidence as a function of both the risk of oncogenic genetic events and the number of available cells capable of becoming Ewing sarcoma.
Results.—
Our models allow predictions about changes in the abundance of available cells capable of undergoing oncogenesis. This concept can explain the anatomic distribution and incidence by age of Ewing sarcoma. We believe that this concept also explains how the same genetic alterations can be seen in diverse cancer types.
Conclusions.—
Verification of our models for Ewing sarcoma with experimental data can predict how the risk of oncogenic events for pediatric cancers changes with age. Our algebraic model is a novel articulation of the biological concepts that drive pediatric oncogenesis and can be applied to the observed age distributions of nearly all pediatric cancer types.
Context.—
Immune checkpoint inhibitors (ICIs) can trigger severe cutaneous adverse reactions that mimic Stevens-Johnson syndrome/toxic epidermal necrolysis. Reports describe a wide spectrum of cutaneous reactions, including epidermal necrosis, raising questions about whether this represents a distinct clinicopathologic entity.
Objective.—
To review the literature on ICI-related epidermal necrosis (ICIREN), examining terminology, histopathologic features, clinical course, pathophysiology, the pathologist’s role in diagnosis, and implications for management.
Data Sources.—
A systematic literature search of PubMed and relevant conference proceedings was conducted. Key sources include case series, retrospective reviews, and mechanistic studies detailing ICIREN.
Conclusions.—
ICIs have transformed cancer therapy but are associated with a spectrum of immune-related adverse events, notably cutaneous toxicities. Among the most severe is ICIREN, a reaction that can clinically resemble Stevens-Johnson syndrome and toxic epidermal necrolysis but may follow a distinct, more indolent course. Emerging terminology, including progressive immunotherapy-related mucocutaneous eruption, reflects growing recognition that not all cases fit the paradigm of classic drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. ICIREN often presents with delayed onset, variable progression, limited mucosal involvement, and distinct histopathologic features such as lichenoid interface dermatitis and adnexal involvement. Understanding these differences is crucial, as early recognition and management may allow patients to safely continue ICI therapy. The underlying pathogenesis involves checkpoint blockade–driven T-cell activation with potential amplification by additional drug exposures. This review aims to equip pathologists and clinicians with a structured approach to the diagnosis, reporting, and multidisciplinary management of ICIREN, emphasizing the need for clinicopathologic correlation to optimize patient outcomes.
Context.—
Treatments are available for common forms of systemic amyloidosis that show promise for extending and improving the quality of life for patients. Early diagnosis and accurate identification of amyloid fibril type are crucial for successful treatment, but the diagnosis and workup of amyloidosis, is inconsistent among pathologists and laboratories. Thus, the goal of this guideline is to offer recommendations for proper testing and workup for amyloidosis to optimize patient care.
Objective.—
To establish evidence-based recommendations for appropriate laboratory testing to detect amyloidosis and identify the specific amyloidogenic protein.
Design.—
The College of American Pathologists convened a panel of experts to develop recommendations following the standards established by the National Academy of Medicine for developing trustworthy clinical practice guidelines. The panel conducted a systematic literature review addressing 6 key questions. Using the Grading of Recommendations Assessment, Development and Evaluation framework, recommendations were created based on the available evidence, certainty of that evidence, and key judgments as defined in the framework.
Results.—
Four conditional recommendations and 3 good practice statements were established to provide guidance for proper testing and workup of amyloidosis.
Conclusions.—
This guideline summarizes the available evidence on the diagnosis and workup of systemic amyloidosis in tissue samples, including the challenges and limitations of common approaches and techniques. Recommendations for pathologists and laboratories receiving these samples are provided.
Context.—
Clinical laboratories are increasingly implementing pharmacogenomic (PGx) testing. Although PGx is similar to genetic testing for other indications, there are unique aspects that laboratories should consider.
Objective.—
To aid clinical laboratories that are implementing clinical PGx testing by describing characteristics of PGx test design and validation, as well as approaches to reporting. Resources that are useful for clinical laboratories performing PGx testing will be highlighted.
Design.—
The College of American Pathologists formed a workgroup composed of laboratorians with expertise in clinical PGx testing. The workgroup included representatives from the Association for Molecular Pathology and the American College of Medical Genetics and Genomics. The workgroup reviewed pertinent literature, as well as experience from proficiency testing and from members’ laboratories.
Results.—
The workgroup recommends that laboratories implementing PGx consider the following concepts: testing platform, test design (ie, selection of pharmacogenes and variants/alleles), use of reference materials during test development and as controls during clinical runs, star allele and standard nomenclature systems, translations from genotype to predicted phenotype, and considerations for result reporting including making medication recommendations. The workgroup provides considerations when using report vendors, emphasizing the clinical laboratory’s role and responsibility when implementing such reporting tools from vendors.
Conclusions.—
Clinical laboratories should be familiar with the fundamentals of PGx, ensure that PGx testing meets the applicable regulatory requirements for all aspects of the clinical laboratory testing process, and follow recommendations for standardization of nomenclature and reporting.
Context.—
Succinate dehydrogenase–deficient renal cell carcinoma (RCC) is a newly classified subtype of RCC in the World Health Organization classification of urinary and male genital tumours. However, systemic reports on this tumor are limited.
Objective.—
To give new insights into the clinicopathologic and molecular features of succinate dehydrogenase complex iron sulfur subunit B (SDHB)–deficient RCC.
Design.—
Data from 5 SDHB-deficient RCC patients diagnosed at our hospital between 2016 and 2022 were collected and studied through light microscopy, immunohistochemistry (IHC), ultrastructural analysis, and Sanger sequencing.
Results.—
The median age of patients was 34 years; 2 were male and 3 female. Grossly, the tumors were well defined, with an average diameter of 7 cm. Histologically, the cells were arranged in diverse patterns: solid, nested, glandular, or tubular with scattered cysts containing eosinophilic, wispy, or bubbly appearances. One patient’s tumor exhibited an obvious papillary structure with focal aggregation of foam cells, and 3 tumors displayed focal micropapillary structures. Two patients presented with high-grade International Society of Urologic Pathology 3 nuclei. The tumor cells in all cases lacked SDHB expression by IHC stain. In addition, the average value of the combined positive score of programmed death ligand-1 (PD-L1, SP263) in all patients was 18. Electron microscopy revealed significant mitochondrial abnormalities. Genetic testing confirmed SDHB germline mutations in all tumors. One patient’s tumor presented a novel, previously unreported mutation: c.697_700del in exon 7. Follow-up revealed metastasis in 1 patient, leading to mortality.
Conclusions.—
Our findings broaden the morphologic spectrum and highlight a new point mutation in the SDHB gene, providing a genetic change spectrum for this tumor entity.
Context.—
The Nottingham grading system, developed by Elston and Ellis, is the recommended method for grading invasive breast carcinoma. A previous study demonstrated the mean concordance for 35 breast pathologists in classifying 58 images as glandular (acinar)/tubule formation (G/TF) based on the World Health Organization definition was only 64%.
Objective.—
To determine if an expanded description of G/TF according to the original definition and current use of the Nottingham grading system would improve recognition of G/TF among breast pathologists and pathologists in training.
Design.—
Fifty-eight images with one structure circled were classified as G/TF or non-G/TF by Dr Ian Ellis. Images were sent as a PowerPoint (Microsoft) file to the breast pathologists who participated in the original study and to 21 trainees. Participants were asked to classify the structures based on the expanded description and were also provided with the 58 images from the first study with annotation.
Results.—
Among the participating 28 of the original 35 breast pathologists, the mean concordance increased from 64% (range, 40%–97%) to 94% (range, 86%–100%). Trainees had a mean concordance of 90% (range, 52%–100%).
Conclusions.—
The expanded description assisted in the recognition of G/TF for both breast pathologists and trainees. The most important impact on grading will likely be for carcinomas with complex cribriform patterns or micropapillary patterns with “inverted tubules.” Participants endorsed that the expanded description of G/TF and the annotated images would be helpful reference material for pathologists.
Context.—
On May 14, 2024, the US Food and Drug Administration (FDA) approved self-collected vaginal samples for human papillomavirus (HPV) testing, expanding cervical cancer screening access.
Objective.—
To evaluate the feasibility and acceptability of HPV self-collection through community outreach programs targeting underscreened populations in Oregon.
Design.—
From October 2024 to June 2025, women aged 25 to 65 years were recruited through local organizations. Following instruction by pathologists, participants completed self-collection by using Copan swabs, which were transferred to ThinPrep media for high-risk HPV testing using the Cobas 8800 system. Postcollection surveys assessed user experience.
Results.—
Among 156 participants (mean age, 47.1 years), 87 (55.8%) identified as Hispanic and 69 (44.2%) as non-Hispanic. Racial groups included Hispanic White (87; 55.8%), Asian (33; 21.1%), Black (16; 10.3%), non-Hispanic White (14; 9.0%), Pacific Islander (2; 1.3%), and nondisclosed (4; 2.5%). All tests were valid; 10 participants (6.4%) were HPV-positive, including 1 with HPV-18 and 9 with non-16/18 types. Follow-up cytology showed 1 case of atypical squamous cells of undetermined significance and 2 negative results; the remainder are pending follow-up. Of 129 survey respondents, 8 (6.2%) had received the HPV vaccine. Overall, 117 (90.7%) found the self-collection kit easy to use, 114 (88.4%) would recommend it, and 91 (70.6%) were likely to choose self-collection over clinician-collected samples for future testing. Common feedback included convenience, comfort, and privacy.
Conclusions.—
HPV self-collection is a practical, user-friendly, and accessible screening option. Pathologist-led outreach may help close screening gaps. This study represents the first academic center-led implementation of FDA-approved self-collection in US community settings.
Context.—
Before adopting a new hematology analyzer in clinical laboratories, evaluating its platelet counting performance is critical.
Objectives.—
To assess the analytical performance of impedance (PLT-I), hybrid (PLT-H), and optical (PLT-O) platelet counts on the novel Mindray BC-7800 (BC-7800) and to compare platelet parameters obtained from the BC-7800 and Sysmex XN-3000 (XN-3000), including PLT-I, PLT-O, and PLT-F (optical fluorescent platelet count using oxazine dye), against the international reference method (IRM) in specimens with platelet interferences.
Design.—
Analytical parameters of the BC-7800, including limit of blank, linearity, reproducibility, and carryover, were evaluated. Interference testing included 126 specimens with red blood cell (RBC) microcytosis and 21 specimens from patients with blasts. Diagnostic performance against the IRM was assessed at platelet transfusion thresholds of 10 × 103/µL and 20 × 103/µL.
Results.—
The BC-7800 met acceptable criteria for most basic parameters, except within-run precision for PLT-I and PLT-H in some thrombocytopenic specimens. In RBC microcytosis, all methods showed strong correlations with the IRM, though PLT-I exhibited proportional bias. In leukemia specimens, PLT-O from the BC-7800 and PLT-F from the XN-3000 showed the strongest agreement with the IRM, while PLT-H and PLT-O from the XN-3000 exhibited systematic bias. Specificity and positive predictive value were excellent across all methods. Sensitivity, negative predictive value, and accuracy were highest for PLT-O from the BC-7800 and PLT-F.
Conclusions.—
The BC-7800 demonstrated reliable platelet analysis, particularly with PLT-O in thrombocytopenic and interference-prone specimens. PLT-H and optical fluorescent platelet methods showed strong reliability in specimens with RBC microcytosis, while PLT-O from the BC-7800 and PLT-F offered the highest accuracy for guiding platelet transfusion decisions.
Context.—
Despite studies indicating its importance to pathology practice, there is a perception that pathologists are poorly trained in management and business operational (MBO) skills. The College of American Pathologists charges its Practice Management Committee (PMC) with providing MBO intelligence. PMC activities included the online course “Pathology Business Fundamentals” (PBF) and a series of roundtable webinars.
Objective.—
To determine the degree to which the PMC meets its charge of providing MBO education.
Design.—
We conducted evaluation surveys following the PBF course and roundtables. From these surveys we selected several outcome metrics to evaluate our objective.
Results.—
Six hundred fifty individuals attended the PBF course, 186 (29%) of whom completed course evaluation surveys. On a scale of 1 to 5 (5 = highest score), the mean aggregate score for “overall value” was 4.64. On a scale of 1 to 5 (5 = very likely), the mean aggregate score for our outcome metric, “intent to apply” was 4.54. Of 1539 individuals who had access to post-roundtable evaluation questionnaires, 378 (25%) completed evaluations; of these, 233 (62%) indicated that the PMC is their “primary source” for MBO. Of the 132 individuals who completed a second year-end roundtable evaluation survey, 98 (74%) agreed that the sessions were “one of the best sources available for support/guidance related to practice management.”
Conclusions.—
To our knowledge, this is the first study evaluating MBO education effectiveness for postgraduate pathologists and laboratory professionals. Based on evaluation survey data, the PMC appears to achieve its mission of providing adequate laboratory and pathology MBO information.
Context.—
The latest WHO (World Health Organization) Classification of Bone and Soft Tissue Tumours (5th edition) has recently defined undifferentiated round cell sarcomas (URCSs) with EWSR1/FUS::NFATC2 (EWS RNA binding protein 1 or FUS RNA binding protein fused with nuclear factor of activated T cells 2) fusions. Given the rarity of this fusion, cytologic findings remain unreported, and information regarding clinical presentation, biological behavior, diagnostic markers, and molecular characteristics is scarce.
Objective.—
To provide a review of the clinicopathologic, molecular, and prognostic features of URCSs with EWSR1/FUS::NFATC2 fusions. Classic histopathologic findings, uncommon variations, and diagnostic pitfalls are addressed, along with the utility of recently developed immunohistochemical and molecular markers.
Data Sources.—
Bringing together our institutional expertise and a thorough evaluation of the literature, this review captures key findings and trends through an extensive PubMed search. By integrating our own practical insights with evidence-based data, we offer a well-rounded perspective that sheds light on both foundational concepts and new advancements in the field.
Conclusions.—
This review underscores the importance of integrating clinicopathologic features and immunohistochemical results with EWSR1/FUS testing to effectively identify sarcomas with rare gene fusions via next-generation sequencing, which carry prognostic significance. Additionally, URCS-harboring EWSR/FUS::NFATC2 fusions exhibit notable differences from Ewing sarcoma and other URCSs, including a limited response to neoadjuvant chemotherapy; unique morphologic characteristics; and distinct genomic, transcriptomic, and epigenetic (methylation) profiles. Given the potential differences in biological behavior, accurate subclassification of EWSR1/FUS fusion variants is essential.
Context.—
Core needle biopsies (CNBs) are among the most common biopsy procedures, yielding long, thin deformation-prone cores. Core deformation results in both distorted histologic features and tortuosity (ie, deviation from the ideal straight path) along the length of the core. Tortuosity creates challenges in slide preparation and downstream pathologist assessment (eg, absent diagnostically relevant tissue after sectioning), indicating a clinical need for its minimization. Despite this need, there is no standard protocol for reporting CNB tortuosity.
Objectives.—
To (1) establish an actionable protocol for scoring CNB tortuosity, (2) build BiopTort, a software tool assigning CNB images interpretable, tiered scores consistent with the protocol, and (3) investigate our protocol and BiopTort’s impact on interpathologist concordance and scoring time.
Design.—
Using a held-out CNB data set (N = 167), 3 pathologists assessed tortuosity in 3 sequential stages: (1) Baseline: a 3-tier scale based on prior experience, (2) Protocol: rescored with our 4-tier Tortuosity Scoring Protocol, (3) BiopTort-Aided: rescored with the protocol alongside BiopTort. Interrater concordance for each stage, using the Fleiss κ, was recorded.
Results.—
Fleiss κ was 0.19, 0.40, and 0.63, and average time per slide was 8.0, 24.2, and 13.3 seconds for stages 1 to 3, respectively. BiopTort was statistically noninferior to human interrater pairwise concordance.
Conclusions.—
These results suggest our protocol lessens interpathologist variability, with BiopTort further reducing variability and scoring protocol employment time cost. When deployed in CNB quality control workflows, our computer-aided protocol appears well situated to facilitate standardized, efficient, and actionable reporting of CNB tortuosity. BiopTort is open-source (http://bioptort.com).
Context.—
The identification of adipose tissue in endometrial biopsy or curettage specimens is an important yet rare histologic finding that may suggest uterine perforation, warranting careful pathologic evaluation to distinguish it from histologic mimickers.
Objective.—
To assess the presence of adipose tissue in endometrial samples and evaluate its diagnostic challenges and clinical implications.
Design.—
A retrospective cohort study was performed on cases from an 8-year period in which adipose tissue was identified in endometrial biopsy or curettage specimens. Hematoxylin-eosin–stained sections were reviewed, and relevant clinical data, including postoperative outcomes, were analyzed.
Results.—
Twenty-three patients were included (mean age ± standard deviation, 60.6 ± 13.3 years); 18 of 23 patients (78.3%) underwent curettage. Endometrial polyp was the most common concurrent diagnosis (8 of 23; 34.8%). Uterine perforation was clinically identified intraoperatively in 6 cases (6 of 23; 26.1%), all managed without complications. Most samples (16 of 23; 69.6%) contained a small amount of adipose tissue (1%–25%). Common risk factors included fibroids (5 of 23; 21.74%); cervical stenosis, polyps, intrauterine synechiae (4 of 23; 17.39% each); and history of prior cesarean delivery (10 of 23; 43.48%). The mean interval to notify clinicians of the adipose finding was 2.79 ± 1.65 days. One patient developed a postoperative abscess, successfully treated with antibiotics. No significant associations were found between risk factors or adipose proportion and intraoperative detection or postoperative complications (all P ≥ .05).
Conclusions.—
While adipose tissue in endometrial specimens may indicate uterine perforation, it was not associated with significant adverse outcomes in this cohort. Pathologists must remain vigilant, as benign mimics such as pseudolipomatosis or lipomatous tumors should be excluded during evaluation.
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.—
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.—
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.—
Pathology reports are essential for guiding clinical decisions but are often complex and lengthy. Artificial intelligence tools like ChatGPT may offer a way to distill these reports into clear, concise summaries to improve communication and efficiency in clinical settings.
Objective.—
To evaluate the performance of ChatGPT-4o in summarizing detailed pathology reports into 1-sentence diagnoses that retain critical clinical information and are accessible to medical professionals.
Design.—
We retrospectively analyzed 120 anonymized pathology reports from 2022–2023, focusing on 40 complex cases from 3 subspecialties: breast pathology, melanocytic lesions, and lymphomas. Using a standardized brief prompt, ChatGPT-4o generated 1-sentence summaries for each report. Two independent pathologists assessed each summary for inclusion of essential information, exclusion of irrelevant details, presence of critical errors, and overall readability.
Results.—
The mean scores for inclusion of essential information were 8.09 (melanocytic lesions), 8.15 (breast cancers), and 9.55 (lymphomas). Critical error-free rates were 62.5%, 77.5%, and 95%, respectively. Exclusion of nonessential information scored consistently high across subspecialties, and readability was rated 10/10 in 119 of 120 cases.
Conclusions.—
ChatGPT-4o, when used with a standardized prompt and expert oversight, shows promising ability to generate concise and readable summaries of pathology reports. While overall performance was strong, occasional errors and limitations in handling complex or multipart cases were noted. Further refinement and domain-specific model training may enhance the reliability and clinical utility of artificial intelligence–assisted reporting.
Context.—
Ensuring equitable laboratory patient care within diverse populations is a priority. The cytopathology laboratory has an important role in providing gender-inclusive care, particularly with regard to screening and prevention of human papillomavirus–related carcinoma, for individuals who are transgender, gender nonbinary, intersex, and with same-gender sexual orientation. Providing equitable care necessitates an understanding of gender-inclusive processes within the cytopathology laboratory. Many barriers to implementation exist and include sociocultural, legal, ethical, and financial hurdles.
Objective.—
To review the current literature regarding gender-inclusive care within a multi-institutional setting and identify challenges and opportunities for future growth in cytopathology. Specific areas of focus include appropriate terminology in laboratory information systems and requisitions, and variables affecting Papanicolaou test interpretation, human papillomavirus testing, and anal Papanicolaou test screening.
Data Sources.—
Primary literature was searched within the areas highlighted throughout the article. Multi-institutional experience from the authors, in addition to editorials and expert opinion, were used.
Conclusions.—
The cytopathology laboratory has an important role in providing care that is inclusive and accurate for all patients. Gaps in care exist and further work is needed to address these disparities. This review attempts to increase awareness, educate, share our own multi-institutional experiences, and calls for improvements in cytopathology to optimize quality in gender-inclusive patient care.
Context.—
Clot waveform analysis (CWA) is a method that provides a detailed view of the clotting process for simple clotting tests such as prothrombin time (PT) or activated partial thromboplastin time (aPTT). Coagulometers with optical clot detection systems capture detailed information during each analysis, which can be used for CWA at no additional reagent expense.
Objective.—
To investigate (1) whether CWA can detect a hypercoagulable state in different clinical conditions similar to the thrombin generation (TG) assay, and (2) whether there are differences in the texture of in vitro clots by scanning electron microscopy (SEM).
Design.—
PT INR (international normalized ratio), aPTT ratio, CWA, D-dimer, fibrinogen, von Willebrand factor antigen (vWF:Ag), von Willebrand factor ristocetin cofactor (vWF:RiCo) activity, TG assays, and clot scans by SEM were obtained for 191 patients (65 with COVID-19, 51 with systemic sclerosis, 51 with liver cirrhosis, 13 with high Padua Prediction Score [PPS] without antithrombotic prophylaxis, and 11 with low PPS). A texture analysis for images acquired by SEM was performed with MATLAB software. Data are described as median and range.
Results.—
Compared to healthy controls, patients with COVID-19, systemic sclerosis, high PPS, and low PPS had higher levels of CWA, fibrinogen, D-dimer, and TG, as well as thicker clots by SEM. The highest values of both vWF:Ag and vWF:RiCo were found in patients with COVID-19.
Conclusions.—
We have shown that similar to the TG assay, CWA can detect a hypercoagulable state in patients at increased risk of clotting. Furthermore, we identified differences of in vitro clot texture by SEM that may provide further insight into the underlying pathology. Even though CWA is currently considered a research tool, it might one day become a clinically accepted test and provide value-added information to PT or aPTT testing at minimal computational costs.
Context.—
A clinic was created for patients to review their explanted organs with a pathologist.
Objective.—
To prospectively investigate the benefits of this type of clinic as perceived by both transplant patients and their pathologists.
Design.—
In this prospective study, patients participated in a videotaped viewing of heart and/or lung explants by the patient and their guest(s) and pathologist (December 2017–August 2022). Patients received a 3D-printed replica of their explant. After viewing the explanted organ, patients and their guests participated in an interview to assess their experiences. Video-reflexive ethnography was used by pathologists for data collection and practice improvement.
Results.—
Of 143 patients who viewed their explanted organ, 21 patients consented to having the organ-viewing session taped and to participate in a postviewing interview. The study group was comprised of 12 men; the median age was 57.5 years (range, 29–67 years). Five pathologists took part in reflexive sessions. The clinics were viewed positively by patients, providing an opportunity to better understand their disease. Pathologists had a similarly positive experience and gained important insights to patient journeys. Proposals for improvement were brought forward from both patients and pathologists.
Conclusions.—
Video-reflexive ethnography provided the opportunity for patients and pathologists to reflect on patient-pathology clinic appointments. This work serves as a template to build out pathology-based clinics.
Context.—
Atypical apocrine adenosis (AAA) is a rare breast lesion defined as presence of cytologic atypia in apocrine adenosis. World Health Organization Classification of Tumours, 5th edition, defines cytologic atypia as at least 3-fold variation in nuclear size and prominent nucleoli. Currently, owing to the rarity of the lesion, the clinical behavior of AAA is not well understood.
Objective.—
To further investigate the risk of upgrade to malignant histology on follow-up excision after a diagnosis of isolated atypical apocrine adenosis (iAAA) on core needle biopsy (CNB).
Design.—
We identified 22 female patients with diagnosis of iAAA on CNBs across 3 institutions between 2000 and 2024, with an average age of 58 years. The most common indication for CNB was presence of a mass. We reviewed pathology reports and available histology slides of CNBs and subsequent surgical excisions.
Results.—
Of 22 patients, 17 underwent surgical excision and 5 were followed up with mammogram for an average of 38 months. The diagnosis for 2 of 17 patients (12%) who underwent excision was upgraded to malignancy (ductal carcinoma in situ), 3 had atypical ductal hyperplasia (1 with AAA), and 2 additional cases had residual iAAA. iAAA was the target lesion in 7 of 21 cases (33%); among these 7 cases, 5 presented with a mass: 2 of 5 (40%) were upgraded to DCIS and 1 of 5 had residual iAAA. The 5 patients who were followed up did not have any adverse outcomes.
Conclusions.—
We recommend surgical excision of iAAA when found on CNB, especially when the target lesion is a mass. However, larger studies are necessary to further understand this entity.
Challenges in Consistent Histologic Diagnosis of Superficially Invasive Anal Squamous Cell Carcinoma
Context.—
Superficially invasive squamous cell carcinoma of the anus (SISCCA) is defined as a minimally invasive cancer measuring less than 3 mm in depth and less than 7 mm in horizontal spread. Its subtle morphologic alterations pose a significant challenge for histologic diagnosis.
Objective.—
To evaluate the diagnostic agreement among pathologists for SISCCA and to identify potential areas for improvement.
Design.—
Four gastrointestinal (GI) and 4 gynecologic (GYN) pathologists independently reviewed digitized hematoxylin-eosin images of 20 anal high-grade squamous intraepithelial lesions with suspected early invasion. Participants classified each lesion as either invasive or noninvasive and selected features indicative of invasion from a list compiled from major textbooks. Cohen κ coefficient was calculated to assess interobserver agreement.
Results.—
Of the 20 lesions, 8 (40%) received unanimous diagnoses, while 12 (60%) had discrepancies. Overall agreement was moderate (κ = 0.46; 95% CI, 0.29–0.48), with similar levels between the GI (κ = 0.53; 95% CI, 0.45–0.74) and GYN (κ = 0.46; 95% CI, 0.25–0.48) groups (P > .01). The GYN group diagnosed a higher number of lesions as invasive than did the GI group (median, 14.5 versus 10.5; P > .01). In consensus SISCCA diagnoses, the most commonly noted feature was the presence of small irregular tumor nests, followed by desmoplastic response and paradoxical maturation.
Conclusions.—
Variability in recognizing histologic features indicative of early invasion contributed to the poor reproducibility in the diagnosis of SISCCA. Efforts should focus on refining diagnostic criteria and integrating features that have proved effective in identifying early invasive cancer at other anatomic sites.
Context.—
Infantile pyknocytosis (IP) is an uncommon cause of transient neonatal hemolytic anemia and hyperbilirubinemia occurring in approximately 10% of cases of unexplained neonatal hemolytic anemia.
Objective.—
To study cases of IP with focus on long-term follow-up, perinatal events, and family history.
Design.—
Cases were prospectively identified during review of peripheral blood smears for neonatal hyperbilirubinemia during an 11-year period. Clinical and laboratory parameters, follow-up data, and family history were recorded.
Results.—
Nine cases of IP were identified from the morphologic recognition of pyknocytes and clinical and laboratory evidence of hemolysis, and included 6 males and 3 females. Age at diagnosis ranged from 1 to 18 days (median, 4 days), and gestational age at birth ranged from 29 to 38 weeks (median, 35 weeks). Hemoglobin nadir ranged from 4.9 to 8.1 g/dL (median, 6 g/dL), and maximum total bilirubin concentration ranged from 7.7 to 27.5 mg/dL (median, 22.0 mg/dL). All 9 patients required phototherapy and transfusions. Hemolysis spontaneously resolved without recurrence in all cases, with time to resolution ranging from 13 to 70 days (median, 33 days) and median follow-up of 7 years (range, 1–11 years). Six patients (67%) had a sibling with neonatal jaundice as well. A similar proportion had significant perinatal events.
Conclusions.—
IP is associated with spontaneous resolution without long-term complications. The underlying etiology is unknown. Perinatal events may expose red blood cells to an overwhelming oxidative stress. Strong family history suggests familial predisposition causing transient red blood cell defect, making them more susceptible to hemolysis.
Context.—
Gestational choriocarcinoma is the most common form of gestational trophoblastic neoplasm. It is characterized by aggressive, destructive growth and a marked tendency for hematogenous spread, leading to high mortality if left untreated. However, with the advent of effective clinical treatment for postmolar gestational trophoblastic neoplasms in recent decades, the clinicopathologic presentation of gestational choriocarcinoma has significantly changed. Today, it more frequently presents at extrauterine sites and/or in an unexpected manner, posing considerable diagnostic challenges for pathologists. Nonetheless, prompt and accurate pathologic diagnosis remains essential for effective clinical management and optimal patient outcomes.
Objective.—
To review the clinical features and pathologic diagnosis of gestational choriocarcinoma, including its early manifestations.
Data Sources.—
This review is based on literature and the author’s personal diagnostic experience.
Conclusions.—
In the era of precision medicine, gestational choriocarcinoma has become a rare encounter, largely owing to the implementation of postmolar surveillance programs and timely initiation of chemotherapy. Diagnostic recognition of the tumor requires a high index of suspicion, familiarity with its histologic features and early forms, awareness of the unexpected extrauterine presentations, and appropriate use of immunohistochemical and molecular biomarkers. These tools are essential in distinguishing gestational choriocarcinoma from nongestational mimics of germ cell or somatic origin, which have a profound therapeutic and prognostic implications.
Context.—
Human epidermal growth factor receptor 2 (HER2)–low breast carcinoma is a clinical entity that has targeted therapy.
Objectives.—
To evaluate the effect of antibody clone/sample size on HER2 status and reinterpret archived HER2-stained slides following current guidelines.
Design.—
We collected 86 estrogen-receptor+/HER2− breast carcinoma core needle biopsy (CNB) samples with archived slides stained with HER2 (HercepTest) and for Oncotype DX (ODX) assay. These slides were scored by 3 pathologists (consensus score) and then compared to the reported scores. The CNB and excisional biopsy (EB) samples were stained with 4B5. We performed a 3-way comparison between CNB-4B5, CNB-HercepTest, and EB-4B5. The mRNA values were abstracted from the ODX report. The mRNA values were compared with the EB-4B5 scores (semiquantitative [H-score] and categorical [zero, 1+, and 2+] system), the consensus score of CNB-HercepTest, and then with the consensus scores of CNB-4B5.
Results.—
Upon rescoring the archived CNB-HercepTest slides, 45.3% were discordant; 12 of 19 (63.2%) reported as 1+ were HER2-zero. The discordance rate between CNB-4B5 and EB-4B5 was 24.4%; between CNB-4B5 and CNB-HercepTest, 59.3%; and between CNB-HercepTest and EB-4B5, 62.8%. The mRNA values correlated with EB-4B5 when using the H-score (P = .003) or the categorical system (zero, 1+, 2+) (P = .008), and with CNB-4B5 (P = .002), but did not correlate with CNB-HercepTest.
Conclusions.—
The discordance of HER2 staining depended on the sample size and antibody clone. Tissue stained with 4B5 (CNB or EB), but not with CNB-HercepTest, correlated with mRNA values.
Context.—
Pathologic evaluation of intestinal biopsies or resection specimens is often part of the diagnostic workup for patients with pseudo-obstruction or other forms of severe intestinal dysmotility. Some of these patients have one of several types of primary intestinal myopathy, but the pathologic features that identify and/or distinguish these conditions have been incompletely defined and need to be readdressed in the context of newly recognized genetic etiologies.
Objective.—
To convey a practical approach to surgical pathology diagnosis of primary intestinal myopathy based on a comprehensive review of pathology findings in patients with primary intestinal myopathy, including data collected from patients with intestinal myopathy–related pathogenic gene variants.
Data Sources.—
A review of the literature as well as cases from multiple institutions that were examined by the author.
Conclusions.—
Microscopic alterations indicative of primary intestinal myopathy must be distinguished from nonspecific findings associated with chronic distension, surgical procurement, or preanalytic tissue processing. Most histopathologically recognizable forms of primary intestinal myopathy can be grouped as either structural alterations of the muscularis propria or degenerative leiomyopathies. Some histopathologic findings correlate with specific types of primary intestinal myopathy, but biopsies or resections from many patients with pathogenic variants in genes that encode smooth muscle contractile proteins show no diagnostic alterations. In some situations, an invasive procedure to obtain tissue for histopathologic evaluation has limited utility and molecular genetic testing may be a superior initial diagnostic approach.
Context.—
Complexity of ordering and transfusing blood is particularly evident in the pediatric population. Simplification, clarification, and standardization of blood orders can decrease complexity and improve patient safety.
Objective.—
To improve patient safety by optimizing electronic ordering of blood components in pediatrics through a collaborative process improvement initiative.
Design.—
A multidisciplinary working group, formed as part of a value stream analysis to improve transfusion safety at Children’s Healthcare of Atlanta (Atlanta, Georgia), focused on decreasing variability and providing clarity when ordering, preparing, and transfusing blood using the electronic health record. Through benchmarking with other pediatric institutions and a collaborative design process with multiple local stakeholders, an extensive redesign in the existing orders and order sets occurred. Metrics were collected to determine if a change was an improvement.
Results.—
Nurse and laboratory informaticists, a pathology informaticist, and a transfusion medicine specialist built the new orders based on the design. The new orders focused on the following changes: standardization, introduction of logic, naming conventions, clarifying definitions, adding calculations, improving transparency of history and laboratory data, removing aliquots, clarifying communication, and implementing additional modules to inform the provider of necessary information about the patient. Metrics included a decrease in the number of orders changed within an hour, decreased calls from the blood bank to the provider to clarify the order, and an absence of overtransfusions and transfusion-related serious safety events for a year following implementation.
Conclusions.—
This collaborative initiative, using standard process improvement tools, resulted in standardized blood orders improving transfusion safety.
Context.—
Following the validation of a multicolor flow cytometry (MFC) assay for measurable residual disease (MRD) in acute myeloid leukemia (AML), this study examines its clinical applicability.
Objective.—
To evaluate the practicality and performance of MFC-based MRD detection in AML.
Design.—
Prospectively assessed AML MRD MFC in unselected AML patients achieving morphologic remission with follow-up studies, molecular genetics, and survival data.
Results.—
Among 379 patient bone marrow samples in this cohort, an interpretable result was obtained in 359 (95%). A total of 57 of the 359 cases (16%) were positive for MRD, and the most frequently observed immunophenotype was CD34+CD117+ myeloid (n = 46; 81%), followed by CD34−/CD117+ myeloid (n = 8; 14%) and monocytic (n = 3; 5%). Of 57 MRD+ cases, 6 (11%) had no leukemia-associated immunophenotypes available, and 16 of 51 (31%) with leukemia-associated immunophenotype for comparison exhibited significant immunophenotypic drift/switch, highlighting the importance of the “deviation from normal” approach. The remaining 302 cases were MRD negative; among these, 21 (6%) displayed a preleukemic immunophenotype that was associated with persistent clonal hematopoiesis in 18 patients (86%). A positive MFC result was strongly associated with subsequent follow-up positive MRD (41 of 45 [91%] versus 14 of 240 [6%], P < .01), morphologic relapse (42 of 55 [76%] versus 48 of 301 [16%], P < .01), an inferior overall survival (12.5 months versus not reached, P < .01), and leukemia-free survival (6.5 months versus not reached, P < .01). Among MRD-negative patients, a preleukemic phenotype was associated with a shorter overall survival (P = .03), but not leukemia-free survival (P = .16).
Conclusions.—
Our study provides data-driven technical insights for laboratories considering MFC AML MRD implementation and offers strong evidence supporting the utility of MRD assessment by MFC in patients with AML undergoing various stages of treatment and surveillance.
Context.—
Autoimmune atrophic gastritis (AIAG) is a chronic, immune-mediated inflammation restricted to the gastric body. Despite well-defined histologic features, the pathologic progression is still not fully understood.
Objective.—
To evaluate the pathologic progression of AIAG.
Design.—
AIAG cases with at least 2 follow-up biopsies were reviewed. Clinical data, including anemia and autoimmune antibody status, were collected. Gastric samples were analyzed to assess inflammation, atrophy, enterochromaffin-like cell hyperplasia, and the development of neuroendocrine tumors (NETs) or carcinoma.
Results.—
The cohort included 180 cases from 32 patients (21 females, 11 males), with an average follow-up of 6.8 years and 5.7 biopsies per patient. Inflammation, atrophy, and intestinal metaplasia remained stable in 59.4% (19 of 32), 78.1% (25 of 32), and 50% (16 of 32) of follow-up biopsies, respectively. Six patients had NETs in the AIAG index cases, with 5 experiencing recurrence after endoscopic excision. During follow-up, 6 additional patients developed NETs, half of whom had recurrence following endoscopic excision. The NETs were well differentiated with a Ki-67 index less than 3%. Two patients were initially diagnosed with adenocarcinoma in the background of AIAG, and 2 more developed adenocarcinoma during follow-up. No significant changes were observed in the antrum during follow-up, which consistently showed minimal to mild inflammation and reactive gastropathy.
Conclusions.—
Long-term follow-up indicates that AIAG is linked to the pathologic progression of NETs and gastric adenocarcinoma. The NETs arising in the background of AIAG are well differentiated and show no evidence of metastasis. These findings may provide guidance on optimal endoscopic surveillance intervals for patients with AIAG.
Context.—
Although pathology at McGill’s teaching hospitals famously began with William Osler, he left Montreal before the medical school had established a pathology department.
Objective.—
To explore the early history of academic pathology and its leadership at McGill, with a primary focus on the second department head, Horst Oertel.
Design.—
Available primary and secondary historical resources were reviewed.
Results.—
John George Adami, the first professor of pathology, recruited Oertel in 1914, and Oertel became acting department head when Adami enlisted. At the end of World War I, Adami did not return, and Oertel was appointed department head. In the early 1920s, using Rockefeller Foundation and other philanthropic funding, Oertel oversaw the establishment of a new McGill Pathological Institute; unfortunately, he based the institute upon an autopsy-centric 19th-century German model, even though surgical pathology and clinical pathology were beginning to blossom elsewhere in North America. As a result, McGill missed an opportunity to lead in these arenas. The paper dissects Oertel’s fascinating but tumultuous professional career at McGill, including his battles with renowned neurosurgeon/neuropathologist Wilder Penfield, medical museum/congenital heart disease specialist Maude Abbott, and McGill’s Dean of Medicine Charles Martin, who expected the newly created institute to raise the faculty’s research profile by promoting collaborative clinical research. Oertel was a legendary educator who wove history, philosophy, and humanities into his pathology lectures.
Conclusions.—
Oertel’s legacy at McGill was mixed. Although he was considered strong academically, more forward-looking and collaborative leadership could have positioned McGill near the forefront of North American pathology.
Context.—
Trastuzumab in combination with standard chemotherapy has been included in the guideline recommendations for human epidermal growth factor receptor 2 (HER2)–positive advanced-stage and recurrent endometrial carcinomas since 2019. A novel antibody drug conjugate, trastuzumab deruxtecan, gained tumor agnostic approval for HER2-positive metastatic solid tumors, including endometrial, ovarian, and cervical cancer in 2024.
Objective.—
To provide a detailed overview of HER2 protein expression, gene amplification, and mutation in gynecologic malignancies in light of the newly available anti-HER2 therapies. Tumor-specific HER2 testing and scoring algorithms are discussed, including the implications of the DESTINY-PanTumor02 trial results and the significance of the HER2-low tumor category.
Data Sources.—
Review of the literature and personal experience of the author.
Conclusions.—
The clinical indications and demand for HER2 testing in gynecologic malignancies beyond endometrial cancer are expanding. It is essential for practicing pathologists to stay up-to date on the latest clinical developments and use evidence-based HER2 testing and scoring criteria.
Context.—
Pancreatic neuroendocrine tumors (PanNETs) are the second most common primary pancreatic neoplasms. Tumors in their classical state are characterized by monotonous plasmacytoid epithelial cells featuring moderate amounts of eosinophilic cytoplasm and eccentrically placed round to oval nuclei with stippled “salt-and-pepper” chromatin. Tumors may exhibit diverse architectural patterns such as nests, pseudorosettes, and trabeculae. Nontraditional morphologic patterns have been described, but their prognostic and clinical relevance and molecular correlations have not been explored.
Objective.—
To elucidate the morphologic spectrum of PanNETs, emphasizing the various subtypes that may mimic other neoplasms, highlighting their unique diagnostic challenges, and exploring the clinical significance of these variants.
Data Sources.—
The review synthesizes findings from a thorough literature review of published studies and incorporates the authors’ own research.
Conclusions.—
PanNETs represent a group of neoplasms with significant histologic and cytologic variability that may complicate and confound diagnosis. Accurate recognition of these variants is crucial for effective diagnosis and in some cases carries important prognostic implications, particularly for more aggressive tumor forms (oncocytic, hepatoid, lipid rich, rhabdoid/plasmacytoid, and papillary). Additionally, certain morphologic variants or adjacent precursors may be linked to syndromic diseases or specific hormone expressions. Integrating detailed morphologic analysis with advanced molecular techniques is essential for diagnosis, predicting patient outcome, and improving patient management.
Context.—
Between 5% and 30% of malignant neoplasms involving the ovary are metastatic. A variety of neoplasms can metastasize to the ovary, including those from the colorectum, endometrium, breast, appendix, stomach, and cervix.
Objective.—
To summarize the clinical, gross, and histologic features that aid in distinguishing primary ovarian neoplasms from metastatic neoplasms. Additionally, to discuss the immunohistochemical features that help identify the primary site of origin.
Data Sources.—
Sources include literature review and cases identified from the authors’ practice.
Conclusions.—
There are many features that can help distinguish a primary ovarian neoplasm from a metastatic lesion. The patient’s clinical symptoms and history may suggest the primary site. On radiology, the absence of ascites is suggestive of metastasis. Laboratory tests such as cancer antigen 125 (CA 125) and carcinoembryonic antigen (CEA) are helpful in distinguishing a primary versus metastatic neoplasm. Gross features that favor metastasis are bilaterality and small tumor size. Metastatic lesions often have multinodular growth and involve the surface or superficial cortex. Histologic features favoring metastasis include a nodular or infiltrative pattern, stromal desmoplasia, hilar involvement, lymphovascular invasion, and an absence of benign or borderline components. The presence of extracellular mucin and signet ring cells also suggests metastasis. Distinct histologic features can be suggestive of the primary site. Immunohistochemical stains, such as cytokeratin (CK) 7, CK20, SATB homeobox 2 (SATB2), p16, paired box 8 (PAX8), WT1 transcription factor (WT1), estrogen receptor (ER), progesterone receptor (PR), and GATA-binding protein 3 (GATA3), can also be useful in evaluating the site of origin. Distinguishing between a primary ovarian tumor and metastasis is critical for determining prognosis and treatment.
Context.—
Cervical squamous neoplasia runs the gamut from low-risk intraepithelial processes to aggressive invasive malignancies. A variety of biomarkers can be enlisted to help diagnose, prognosticate, and inform treatment of these lesions. There are ongoing controversies about diagnostic and prognostic biomarker use in squamous intraepithelial lesions, and many pathologists are new to predictive biomarker interpretation in invasive cervical lesions.
Objective.—
To provide practical guidance on the appropriate use of diagnostic, prognostic, and predictive biomarkers in cervical squamous intraepithelial lesions and invasive carcinomas.
Data Sources.—
Peer-reviewed literature and the author’s personal experience.
Conclusions.—
Diagnostic biomarkers such as p16 and human papillomavirus E6/E7 messenger RNA in situ hybridization can have value in the diagnosis of squamous intraepithelial neoplasia, but there are important caveats to their use and interpretation. No prognostic biomarkers have yet demonstrated statistically durable significance for risk stratification of low-grade squamous intraepithelial lesions. Programmed death ligand-1 immunohistochemistry and tumor mutational burden testing are US Food & Drug Administration–approved predictive biomarkers that can be enlisted for the identification of invasive cervical squamous carcinomas that may respond to checkpoint inhibitor–based immunotherapy, whereas human epidermal growth factor receptor 2 (HER2) immunohistochemistry can identify optimal candidates for conjugated anti-HER2 therapies.
Context.—
Pancreatic neuroendocrine neoplasia (panNEN) is a tumor disease with distinctive morphology and often poses diagnostic challenges.
Objective.—
To present and discuss the current diagnostic criteria of PanNEN.
Data Sources.—
PanNENs are classified by the World Health Organization (WHO) criteria into well-differentiated neuroendocrine tumor (panNET) and poorly differentiated neuroendocrine carcinoma (panNEC) of large or small cell type. panNETs are graded as G1-G3 on the basis of their proliferation capacity by mitotic count and/or Ki-67 proliferation index. Differentiation and grading are overlapping tools essentially directed to the definition of tumor cell resemblance to the normal cell counterpart (differentiation) and its proliferation capacity (grading). Both tools aim at defining the panNEN malignant potential, and ultimately the overall and event-free survival. The 2 panNEN families mirror different molecular backgrounds. The panNET genotype consistently displays mutation/copy number variation of DAXX (death domain associated protein), ATRX (ATRX chromatin remodeler), and MEN1 (menin 1) genes, while in panNEC the usual cancer drivers TP53 (tumor protein 53), RB1 (RB transcriptional corepressor 1), and KRAS (KRAS proto-oncogene, GTPase) genes are mutated/abnormal. The more subtle differences measured by grade in panNET G1-G3 reflect a progressive gene disorder, with G3 often involving TP53. This rare genetic setting is usually associated with a difficult differential diagnosis between panNET G3 and panNEC. Immunohistochemistry for the informative genes DAXX, ATRX, TP53, RB1, P16 (cyclin-dependent kinase inhibitor 2A), and SST2 (somatostatin receptor 2) are the key to separating panNETG3 and panNEC; however, molecular investigation is often required and decisive. Nonetheless, ambiguous cases may remain unresolved.
Conclusions.—
The WHO diagnostic criteria for panNEN are simple and effective tools for a clinically meaningful patient stratification. Areas of uncertainty remain and deserve further investigation.
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