This Week in Pathology — Jun 9, 2026

Welcome to This Week in Pathology. This week we're covering 9 notable papers spanning evolving diagnostic classifications in hematopathology and pulmonary pathology, practical solutions for diagnostic dilemmas from renal cancer to Lyme disease, and new insights into the fundamental immune mechanisms driving inflammation and neurodegeneration. Let's dive in.

We begin with a theme central to pathology practice: the constant evolution of diagnostic classification systems. A review in *Human Pathology* provides a practical guide for navigating the contemporary diagnosis of acute myeloid leukemia, or AML [7]. It directly addresses the questions pathologists face with the advent of two major systems, the 2022 International Consensus Classification and the WHO 5th Edition. The authors distill the growing complexity of AML biology, focusing on which genetic lesions are now considered class-defining versus prognostic, and aim to provide clarity for patient care while the field works to unify these schemes. A case report in *Virchows Archiv* perfectly illustrates the clinical value of these genetics-integrated classifications [3]. The case involves a patient with myelodysplastic/myeloproliferative neoplasm, where significant marrow fibrosis made the aspirate a dry tap. This precluded the morphologic assessment of ring sideroblasts, a key feature required for diagnosis under the older WHO 2017 criteria. However, next-generation sequencing identified key mutations, including SF3B1 and JAK2. This molecular signature allowed the diagnosis of MDS/MPN with SF3B1 mutation and thrombocytosis to be confidently made under the newer ICC 2022 framework, highlighting how a genetics-first approach can overcome limitations of traditional morphology, especially in fibrotic marrows. Shifting from the bone marrow to the lungs, an important preview of the 2025 ATS/ERS international classification of interstitial pneumonias was published in *Histopathology* [6]. This update signifies a major shift, expanding beyond idiopathic diseases to include secondary causes. For pathologists, the key changes include a new subclassification system based on fibrotic versus non-fibrotic patterns, the addition of new histologic entities like bronchiolocentric interstitial pneumonia, and an emphasis on reporting diagnostic confidence levels. The guidelines also address the interpretation of cryobiopsies and stress the importance of identifying histologic clues that may point toward a secondary cause, moving pathology reports toward a more integrated and clinically useful format.

Our next theme addresses specific diagnostic dilemmas and the development of algorithmic solutions, both at the microscope and in the clinical laboratory. In surgical pathology, a report in the *American Journal of Clinical Pathology* details the diagnostic challenges in staging renal cell carcinoma after treatment with immune checkpoint inhibitors [4]. Based on a series of 13 cases, the authors describe a spectrum of treatment-related histologic changes, including fibrosis, myxoid stroma, and, most critically, abundant foamy histiocytes. These histiocytes were reported to be moderately or very difficult to distinguish from residual clear cell carcinoma in 9 of the cases, necessitating immunohistochemistry for clarification in 5 of them. This finding underscores a significant pitfall in assessing pathologic response and determining the final ypT stage, and highlights an urgent need for consensus guidelines for grossing and microscopic evaluation in this setting. Also in the *American Journal of Clinical Pathology*, a study addresses an algorithmic challenge in Lyme disease diagnostics [5]. Researchers reevaluated the modified two-tier testing algorithm, confirming that the quantitative index value from the first-tier serologic test is highly predictive of the second-tier confirmatory result. In their expanded dataset, an index cutoff that previously yielded 100% confirmation now confirmed positive in 98.7% of cases. The authors propose that laboratories could report the first-tier index value along with a calculated probability of confirmation. This simple addition could provide clinicians with more immediate, actionable information, potentially speeding up diagnosis and the initiation of antimicrobial therapy for patients with a high pre-test probability and a high index value. Broadening the concept of algorithmic solutions, a policy paper in *The Lancet Global Health* addresses a challenge in preventative medicine: how to develop new tuberculosis vaccines for young adolescents [2]. This age group is an ideal target for vaccination, as it offers an opportunity to protect individuals before the age-related rise in TB risk. However, low disease incidence makes traditional efficacy trials in this population slow and difficult. The authors propose an alternative trial design that would leverage higher rates of TB case accrual by focusing on individuals with recent household exposure. This novel strategy represents an algorithmic solution to an evidence-generation problem, aiming to provide efficacy data more rapidly to support the implementation of new vaccines for this crucial demographic.

Our final theme explores fundamental immune mechanisms with clear translational potential. In *Nature*, researchers identified a specific subset of regulatory T-cells that control intestinal inflammation in inflammatory bowel disease [1]. These are CD8 T-cells guided by the G protein-coupled receptor GPR15, which acts as a homing receptor to the colon. Once there, these cells kill activated inflammatory macrophages. The study provides strong human correlation, showing that deleterious GPR15 gene variants are associated with severe, early-onset IBD and that these regulatory cells are depleted in the mucosa of patients with sporadic IBD. This discovery offers new insights into organ-specific immune regulation and identifies the GPR15 pathway as a potential therapeutic target. From the gut to the brain, a study in *Nature Medicine* used spatial transcriptomics to investigate the cellular responses to Alzheimer's pathology [9]. By analyzing brain tissue from elderly individuals, they identified a key inflection point where the cellular environment shifts from an amyloid-beta-associated inflammatory state to one dominated by tau-associated programs. This transition was marked by a change in microglial states, from an early inflammatory program to a late antigen-presenting program. Critically, the study revealed two distinct paths to cognitive resilience: some individuals without dementia simply lacked the late microglial program, while cognitively intact centenarians with high amyloid burden showed activation of this late program but in a way that was uncoupled from tau accumulation. This positions the microglial state transition as a critical juncture that determines progression to dementia and a potential point for therapeutic intervention. Finally, a paper in *Cell* uncovers a fundamental innate immune barrier to xenotransplantation, a potential solution to the organ shortage [8]. The researchers found that when attempting to grow donor cells from one species in the embryo of another, host macrophages selectively identify and eliminate the foreign cells in a process they name 'xenophagocytosis.' The mechanism involves the 'eat-me' signal phosphatidylserine on donor cells being recognized by the Axl receptor on host macrophages. By demonstrating three different ways to block this interaction—genetically removing macrophages or the Axl receptor in the host, or overexpressing 'don't-eat-me' signals in the donor cells—they significantly improved the survival and chimerism of rat and human cells in mouse embryos. This work provides a key mechanistic insight and a clear roadmap for strategies to enhance the generation of human organs in livestock.

If you only have time for one paper this week, make it the 2025 ATS/ERS update on the classification of the interstitial pneumonias in *Histopathology* [6]. This is a comprehensive international consensus that expands beyond idiopathic diseases and will fundamentally change the terminology and framework we use for reporting these complex cases, impacting both diagnosis and research.

Here are the key takeaways from this week in Pathology. First, be aware that diagnostic classifications for both hematologic neoplasms and interstitial lung diseases are evolving rapidly. The new ICC and WHO systems for AML and MDS/MPN place a greater emphasis on molecular genetics, which can be crucial for diagnosis in challenging cases like fibrotic marrows. Similarly, the upcoming 2025 classification for interstitial pneumonias broadens the scope beyond idiopathic disease and refines histologic patterns, requiring updated reporting. Second, when evaluating post-treatment specimens from patients who received immune checkpoint inhibitors, particularly in renal cell carcinoma, be vigilant for treatment-related mimics of residual tumor. Foamy histiocytes, fibrosis, and myxoid changes can obscure or resemble carcinoma, necessitating careful evaluation and a low threshold for using immunohistochemistry to confirm findings and ensure accurate staging. Third, in the clinical lab, quantitative data from first-tier screening tests may offer opportunities to streamline diagnostic algorithms. For Lyme disease, a high index value on the initial serology is strongly predictive of a positive confirmatory test, suggesting that reporting this probability could accelerate clinical decision-making. Finally, emerging research continues to highlight specific immune cell subsets as key players and potential therapeutic targets in major diseases. This week, new findings implicate GPR15-positive regulatory T-cells in controlling IBD, and microglial state transitions as a critical inflection point in the progression from amyloid pathology to dementia in Alzheimer's disease.

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.

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