This Week in Pathology — Jul 19, 2026

Welcome to This Week in Pathology. This week we're covering 10 notable papers spanning digital and biomarker advancements in breast oncology, novel prognostic and diagnostic markers in gastrointestinal and gynecologic pathology, and key clinical updates in cytopathology and pulmonary pathology. Let's dive in.

We begin in the breast pathology suite, where the rapid transition to digital pathology is reshaping how we perform fundamental diagnostic tasks. Writing in Histopathology, Dr. Rakha outlines a practical, evidence-informed framework for adapting the traditional Nottingham grading system of invasive breast carcinoma to whole slide imaging [2]. While assessing tubule formation remains highly reproducible and well-suited to low-power digital evaluation, nuclear pleomorphism and mitotic counts present unique digital challenges. Nuclear pleomorphism shows moderate variability due to display and perceptual factors on different screens. Mitotic assessment, however, remains the primary hurdle. The lack of physical z-axis focusing, along with challenges in hotspot identification and area calibration, can lead to a systematic underestimation of mitotic counts on digital screens compared to traditional light microscopy. This underestimation is particularly critical for cases sitting near grading thresholds. To improve reproducibility, the framework recommends defining mitotic counting areas in square millimeters, with an optimal target of two to three square millimeters, prioritizing areas of high tumor cellularity, and utilizing calibrated high-power screen fields.

Staying with breast biomarkers in Histopathology, Shaaban and colleagues present updated United Kingdom recommendations for the immunohistochemical staining and interpretation of Ki-67 [1]. Although Ki-67 is an invaluable prognostic and predictive marker, especially in hormone receptor-positive, HER2-negative breast cancers, its clinical utility has historically been hampered by interobserver and interlaboratory variability. To address this, the authors recommend a simplified, calibrated global assessment method as a highly accurate, time-saving alternative to exhaustive manual visual quantification. Additionally, the guidelines strongly advocate for the use of validated image analysis and artificial intelligence algorithms where available. The authors highlight the limitations of rigid, single-value cutoffs, suggesting instead that tiered classifications or continuous modeling provide a safer and more biologically accurate representation of tumor proliferation. This standardized approach is increasingly vital as Ki-67 results are used to guide neoadjuvant therapy responses, calculate prognostic scores, and select patients for adjuvant CDK4/6 inhibitor therapy.

To round out our breast oncology focus, a study published in Modern Pathology by Riggi and colleagues proposes an immunohistochemistry-based decision flowchart designed to safely de-escalate axillary surgery for patients with a biopsy diagnosis of pure ductal carcinoma in situ [10]. Currently, many patients with ductal carcinoma in situ undergo sentinel lymph node biopsy, particularly when treated with mastectomy, despite the low rate of true invasive disease. By retrospectively analyzing 258 cases, the researchers identified solid architectural pattern and a radiological size greater than 20 millimeters as independent risk factors for upstaging to invasive carcinoma. They developed two predictive models. The second model, which defines high risk as the presence of solid architecture or the absence of histological calcifications, proved highly promising. It classified 55 percent of hormone receptor-positive, HER2-negative patients undergoing mastectomy as low risk. Across both models, only a single patient classified as low risk was upstaged to invasive disease, and none of the low-risk patients had a positive sentinel lymph node. These findings suggest that for a substantial portion of low-risk patients, axillary surgery can be safely omitted.

Moving into the gastrointestinal and gynecologic tracts, we find new tools for risk stratification and diagnostic screening. In Histopathology, Reitsam and colleagues present a meta-analysis evaluating the prognostic significance of direct tumor-adipocyte contact, also known as Stroma AReactive Invasion Front Areas, or SARIFA [5]. This hematoxylin and eosin-based biomarker is characterized by direct contact between tumor cells and adipocytes at the invasive front, completely lacking intervening fibrous stroma or inflammatory cells. Analyzing data from over 5,900 patients across multiple retrospective cohorts, the investigators found that tumor-adipocyte contact positivity is an independent and powerful predictor of poor clinical outcomes. Specifically, patients with tumor-adipocyte contact positivity experienced roughly a 77 percent increase in the risk of cancer-specific mortality and a 53 percent increase in the risk of overall mortality. The biological mechanism likely reflects active metabolic programming of the tumor by adjacent adipocytes. The authors suggest adopting the descriptive term "tumor-adipocyte contact" to standardize reporting of this simple, low-cost, and highly prognostic feature in routine pathology reports.

In Human Pathology, Hatano and colleagues explore a highly practical solution for mismatch repair screening in colorectal and endometrial cancers [3]. Traditional screening utilizes single immunohistochemistry for four mismatch repair proteins. The authors evaluated the feasibility of a double immunohistochemistry protocol using PMS2 and MSH6 on a single tissue section. In a retrospective study of 794 colorectal and endometrial cancer cases evaluated via tissue microarrays, the double immunohistochemistry index test demonstrated excellent diagnostic concordance with traditional single-antibody staining. For the detection of microsatellite instability-high status, the double stain achieved a sensitivity of 100 percent and a specificity of 98.1 percent. This single-section approach not only preserves precious tissue, making it ideal for small biopsy specimens, but also reduces laboratory resource consumption while maintaining the ability to identify rare cases of heterogeneous mismatch repair protein expression.

In the gynecologic tract, pathologists often grapple with smooth muscle tumors excised during pregnancy or delivery. These specimens, referred to as leiomyomas presenting during pregnancy and delivery, can show alarming morphologic features that closely mimic malignant leiomyosarcoma. In a comprehensive study published in The American Journal of Surgical Pathology, Olkhov-Mitsel and colleagues characterized 97 such cases to establish reassuring diagnostic boundaries [4]. They found that while these tumors frequently exhibit ischemic necrosis in over half of cases, along with features typically associated with coagulative tumor cell necrosis, such as sharp viable-to-nonviable transitions and perivascular tumor preservation, they lack the hallmarks of true malignancy. The tumors showed very low mitotic activity, averaging just 0.5 mitoses per 10 high-power fields, and nuclear atypia was almost exclusively mild or focal. Furthermore, immunohistochemical testing showed completely wild-type p53 expression and retained expression of key tumor suppressors like ATRX, RB1, and PTEN. Clinical follow-up over an average of 56 months confirmed zero recurrences or malignant transformations. Pathologists should be aware of these pregnancy-induced changes and avoid diagnosing these benign mimics as leiomyosarcoma or smooth muscle tumors of uncertain malignant potential.

Next, we turn to cytopathology, neuropathology, and pulmonary pathology, where diagnostic accuracy relies on integrating morphology with advanced ancillary studies. In Modern Pathology, Pusztaszeri and Baloch review the evolving paradigm of thyroid nodule evaluation [9]. Once viewed as a simple morphologic screening tool, thyroid fine-needle aspiration biopsy now functions as a central component of a highly integrated, multidimensional diagnostic pathway. Modern evaluation requires seamless integration of ultrasound-based risk stratification systems, the refined cytologic categories of the third edition of the Bethesda System, and the upcoming World Health Organization Reporting System for Head and Neck Cytopathology. Furthermore, the routine incorporation of molecular testing and the updated tumor classifications from the fifth edition of the WHO endocrine tumor volume have transformed how indeterminate nodules are managed. This shift enables highly personalized, risk-adapted management strategies, ranging from active surveillance and thermal ablation to lobectomy or total thyroidectomy.

In neuropathology, diagnosing spinal cord tumors in the conus-cauda-filum terminale region can be exceptionally difficult due to overlapping histological features. Writing in The American Journal of Surgical Pathology, Zhang and colleagues identify HOXB13 as a highly sensitive and specific immunohistochemical marker for myxopapillary ependymoma [8]. Evaluating a large cohort of spinal tumors, the authors demonstrated that HOXB13 was strongly positive in nearly 98 percent of myxopapillary ependymomas, compared to only 4.5 percent of other spinal ependymomas and 11.4 percent of nonependymal tumors. The marker achieved a sensitivity of nearly 98 percent and a specificity of over 92 percent. Interestingly, while DNA methylation profiling is considered a diagnostic standard, the study found that tissue artifacts such as hemorrhage, sclerosis, or dural components can cause classic myxopapillary ependymomas to miscluster. In contrast, HOXB13 immunohistochemistry remained highly robust and reliable, highlighting its utility as a simple and accessible surrogate marker in routine pathology panels.

In pulmonary pathology, the spectrum of vaping-associated lung injury, or EVALI, continues to evolve. A study by Manchen and colleagues in The American Journal of Surgical Pathology provides an important update on vaping-related pathology, examining both patients with clinically diagnosed EVALI and otherwise healthy vapers [7]. Among 36 patients meeting EVALI criteria, the authors identified novel histologic features, including coarse lipid vacuolization in over a third of cases and grungy proteinosis-like deposits in nearly a fifth. Patients with a history of prior EVALI who presented with chronic symptoms showed airway-centered macrophages and variable airway-centered fibrosis. Crucially, the study also examined a cohort of 16 otherwise healthy vapers who presented with spontaneous pneumothorax. In these patients, the lung parenchyma showed minimal changes beyond rare foamy or lightly pigmented macrophages, with no specific vaping-induced injury pattern. This suggests that while vaping can cause severe injury in the form of EVALI, it does not produce a distinct, subclinical parenchymal pathology in healthy individuals presenting with pneumothorax.

Finally, we look at quality assurance in cytogenetics. The Archives of Pathology and Laboratory Medicine has published a comprehensive 20-year retrospective review of fluorescence in situ hybridization proficiency testing for hematologic neoplasms, conducted by the College of American Pathologists and the American College of Medical Genetics Cytogenetics Committee [6]. Analyzing 124 challenges distributed to clinical laboratories between 2005 and 2024, the authors report an exceptional consensus rate. Over 97 percent of the challenges exceeded the 80 percent participant consensus required for grading, and all 36 formalin-fixed paraffin-embedded tissue challenges achieved grading consensus. The rare failed challenges typically involved the interpretation of highly complex, atypical signal patterns or processing errors. This long-term review provides reassuring evidence that clinical cytogenomic laboratories maintain extremely high proficiency and accuracy in detecting and interpreting complex genetic rearrangements in hematologic malignancies.

If you only have time for one paper this week, make it the practical framework for digital breast grading by Dr. Rakha in Histopathology [2]. As laboratories worldwide transition to digital workflows, this paper provides crucial, evidence-based guidance on how to calibrate screen fields and adjust mitotic count thresholds to prevent the systematic underestimation of tumor grade on whole slide images.

Here are the key takeaways from this week in Pathology:

First, when performing histological grading of invasive breast carcinoma on digital whole slide images, pathologists must actively calibrate high-power screen fields and define mitotic counting areas in square millimeters, keeping in mind that digital platforms can systematically underestimate mitotic counts near critical grading thresholds [2].

Second, in patients with a biopsy diagnosis of pure ductal carcinoma in situ, particularly those with estrogen receptor-positive, HER2-negative disease, sentinel lymph node biopsy may be safely omitted by utilizing a risk flowchart based on the absence of solid architecture and the presence of histological calcifications [10].

Third, direct tumor-adipocyte contact, or TAC, at the invasive front of colorectal cancer is a powerful, independent, hematoxylin and eosin-based prognostic marker associated with significantly worse cancer-specific and overall survival, representing a simple tool for risk stratification [5].

Fourth, HOXB13 is a highly sensitive and specific immunohistochemical marker that reliably distinguishes myxopapillary ependymoma from histological mimics in the spinal region, serving as a robust diagnostic surrogate especially when tissue artifacts interfere with molecular methylation assays [8].

Fifth, uterine leiomyomas excised during pregnancy or delivery frequently exhibit worrisome features such as ischemic necrosis, ghost nuclei, and focal atypia that mimic leiomyosarcoma; however, their low mitotic activity, wild-type p53 expression, and excellent clinical outcomes confirm their benign nature [4].

That's your roundup for This Week in Pathology. The full transcript and references are available on the episode page in your AudioScholar library. This is an AI-curated summary — for clinical decisions, always consult primary sources and current guidelines. See you next week.

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This is an automated summary generated by artificial intelligence, which can make mistakes. Always review the original source materials.