This Week in Pathology — Oct 31, 2026
Generated Oct 31, 2026 · 12:40
The week's practice-changing Pathology research, summarized for clinicians.
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Non-invasive tests in metabolic dysfunction-associated steatotic liver disease: the LITMUS prospective multicentre diagnostic accuracy study.
Among 1590 biopsied MASLD patients, only a proteomic panel adequately detected at-risk steatohepatitis, while several multimarker panels performed strongly for advanced fibrosis and cirrhosis versus central histology.
The Lancet · 2026 · PubMed
This week’s papers
- 01
Non-invasive tests in metabolic dysfunction-associated steatotic liver disease: the LITMUS prospective multicentre diagnostic accuracy study.
Among 1590 biopsied MASLD patients, only a proteomic panel adequately detected at-risk steatohepatitis, while several multimarker panels performed strongly for advanced fibrosis and cirrhosis versus central histology.
Vali Y, Wonders K, Lee J, et al. · The Lancet · 2026
From the briefingThe largest paper of the week comes from The Lancet, where Vali and colleagues report the LITMUS study, a prospective diagnostic accuracy study of 1590 adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease, recruited across 13 countries in Europe and the United States [1]. Every biopsy was centrally scored using the NASH Clinical Research Network system, and the investigators tested 12 single markers and 18 multimarker panels against a pre-set bar of an area under the curve above 0.80, the threshold they used to signal possible biopsy replacement. For at-risk steatohepatitis, meaning steatohepatitis with at least stage 2 fibrosis, only the proteomic SomaSignal panel cleared that bar, at about 0.83, and no test cleared it for steatohepatitis alone. Performance was much stronger for fibrosis: SomaSignal reached about 0.92 for advanced fibrosis, and FibroMeter combined with elastography led for cirrhosis at about 0.94, with several other panels including Agile 3+, ELF and liver stiffness measurement also performing well. A sequential approach using gamma-glutamyl transferase as a first step met the bar for both advanced fibrosis and at-risk disease. For pathologists, the message is nuanced: fibrosis staging is increasingly within reach of blood and imaging panels, but inflammatory activity and ballooning, the components that define steatohepatitis, remain poorly captured by anything other than a biopsy. The authors frame these data as informing future guidelines and trial design rather than settling biopsy replacement today. A small but striking paper in Histopathology makes the case for what only tissue can show.
If you only have time for one paper this week, make it the LITMUS study in The Lancet [1]. It provides the most rigorous benchmark yet of where non-invasive tests can and cannot stand in for liver histology, and it reopens the question of exactly which parts of the biopsy report remain irreplaceable.
Written by AI from the published abstract, for healthcare professionals. Not medical advice; check the paper before acting on it.
- 02
Lipidic obstruction of sinusoids (LOS): a potentially serious complication of steatotic liver disease.
Eight patients with steatotic liver disease showed extracellular fat obstructing sinusoids, a histologic pattern whose extent tracked clinical severity, ranging from subclinical to transplantation or death.
Endhardt K, Friemel J, Leblond AL, et al. · Histopathology · 2026
From the briefingEndhardt and colleagues describe eight patients with steatotic liver disease whose sinusoids were obstructed by extracellular lipid vacuoles, a pattern they name lipidic obstruction of sinusoids, resembling pseudopeliotic steatosis but occurring outside transplantation [2]. A collagen IV stain highlighting double sinusoidal contours supported the diagnosis, the lesion was associated with necrosis and macrophage activation, and the extent of the fat lakes tracked with clinical severity, which ranged from subclinical to liver transplantation or death. This is a retrospective case series, so it defines an entity rather than establishing its frequency, but it is a reminder that biopsy can reveal mechanisms no panel is designed to detect.
Written by AI from the published abstract, for healthcare professionals. Not medical advice; check the paper before acting on it.
- 03
BAP1 loss and TFE3 immunoexpression in high-grade clear cell renal cell carcinoma.
In 350 high-grade clear cell renal carcinomas, BAP1 loss independently predicted native nuclear TFE3 expression, which lacked GPNMB, helping distinguish these tumours from Xp11 translocation carcinoma.
Oktay M, Yildirim NA, Dogan HN, et al. · Human Pathology · 2026
From the briefingIn Human Pathology, Oktay and colleagues studied 350 high-grade clear cell renal cell carcinomas from four centres with central immunohistochemistry [3]. BAP1 loss was present in about a quarter of tumours, and native nuclear TFE3 staining was found in roughly one in eight. Tumours with BAP1 loss had roughly three to four times the odds of TFE3 positivity, consistently across cohorts, and BAP1 loss was the only independent predictor on multivariable analysis. Crucially, GPNMB was absent in 40 of the 43 TFE3-positive tumours. The authors argue that GPNMB helps separate this native TFE3 expression from Xp11 translocation carcinoma, though as a retrospective tissue microarray study it does not include a direct head-to-head with confirmed translocation cases.
Written by AI from the published abstract, for healthcare professionals. Not medical advice; check the paper before acting on it.
- 04
Light Microscopy-Based Techniques to Identify TFEB-Altered Renal Cell Carcinoma: A Comparison Study With TFE3-Rearranged Renal Cell Carcinoma and Common Renal Cell Tumors.
TFEB RNA in situ hybridisation was positive in all 16 TFEB-altered renal carcinomas and negative in all controls, outperforming cathepsin K, GPNMB and TRIM63 as a FISH alternative.
Caliò A, Marletta S, Giacometti C, et al. · The American Journal of Surgical Pathology · 2026
From the briefingThat gap is partly addressed by a paper in The American Journal of Surgical Pathology, where Caliò and colleagues compared light microscopy techniques for TFEB-altered renal cell carcinoma across 16 molecularly confirmed cases and more than 200 controls [4]. TFEB immunohistochemistry was variable across clones, with the Bethyl assay most reliable. Cathepsin K and GPNMB were sensitive but labelled 40 and 50 percent of TFE3-rearranged tumours respectively, and TRIM63 RNA in situ hybridisation was likewise positive in TFE3-rearranged tumours. TFEB RNA in situ hybridisation, by contrast, was positive in every TFEB-altered case and negative in every control. Read together, these papers show that GPNMB is useful as a discriminator in one direction, flagging that TFE3-positive clear cell carcinoma is probably not a translocation tumour, while not being specific enough on its own to confirm a TFEB-altered tumour. The TFEB data come from a small series, so validation is still needed before RNA in situ hybridisation is accepted as a replacement for FISH, but the authors position it as a practical alternative where molecular testing is unavailable.
Written by AI from the published abstract, for healthcare professionals. Not medical advice; check the paper before acting on it.
- 05
Non-Conventional Histologic Components in Urothelial Carcinoma: Post-Neoadjuvant Chemotherapy Pathologic Outcomes in a Multi-institutional Radical Cystectomy Cohort.
Urothelial carcinomas with subtype or divergent components had lower complete response and downstaging after neoadjuvant chemotherapy, though the number of such components did not affect response.
Youssef R, Saeed OAM, Baniak N, et al. · Human Pathology · 2026
From the briefingIn Human Pathology, Youssef and colleagues examined 206 radical cystectomies performed after neoadjuvant chemotherapy, comparing patients whose earlier transurethral resection showed conventional urothelial carcinoma with those showing subtypes or divergent differentiation [5]. The presence of any non-conventional component was associated with statistically significantly lower rates of complete pathologic response and downstaging, with no difference in positive margins. Interestingly, the number of non-conventional components, one, two, or three or more, did not correlate with response. This retrospective cohort supports reporting the presence of these components on resection specimens as relevant to chemotherapy response, while suggesting that counting them adds little.
Written by AI from the published abstract, for healthcare professionals. Not medical advice; check the paper before acting on it.
- 06
Histological and molecular characterization of lateral extension in papillary urothelial carcinoma: implications for classification and management.
Flat lateral extension from high-grade papillary urothelial carcinoma reached about a centimetre, was usually clonally related, and could mimic carcinoma in situ immunohistochemically, risking overdiagnosis.
Pacheco RR, Peterson DJ, Thong A, et al. · Histopathology · 2026
From the briefingIn Histopathology, Pacheco and colleagues used 37 en bloc resection specimens to characterise lateral extension, the flat atypical urothelium that spreads from the base of a high-grade papillary tumour [6]. Lateral extension averaged just under 5 millimetres and reached up to about a centimetre, and it reached the mucosal margin in 12 of 13 tumours. Sequencing showed shared alterations with the papillary tumour in 9 of 11 pairs, supporting clonality, and abnormal CK20 staining was seen in every case tested, with aberrant p53 in about a quarter. Because lateral extension can mimic the immunoprofile of carcinoma in situ, the authors suggest that recognising it could reduce overdiagnosis of carcinoma in situ after papillary tumours. The cohort is small and single-institution, so this is a framework for consistent terminology rather than established criteria.
Written by AI from the published abstract, for healthcare professionals. Not medical advice; check the paper before acting on it.
- 07
Worldwide variation in pathology reporting of esophageal endoscopic resections: a survey and a literature review.
An international survey of 171 pathologists found near-universal reporting of core curability features but wide variation in specimen pinning, intramucosal carcinoma subclassification, tumour budding and structured reporting.
Marginean EC · Virchows Archiv · 2026
From the briefingMarginean surveyed 171 gastrointestinal pathologists who handle esophageal endoscopic resections across North America, Europe, Asia and Australasia [7]. Agreement was high on the core determinants of curability, with tumour type, depth of invasion, margins and lymphovascular invasion each reported by more than 95 percent of respondents. Variation lay elsewhere: routine pinning by the clinician was near universal in Asia but uncommon in the United States, roughly half of respondents used no recognised M-level system for intramucosal carcinoma, and only about a third reported tumour budding. The author argues that harmonisation should target reproducible, clinically actionable features rather than adoption of any single regional system.
Written by AI from the published abstract, for healthcare professionals. Not medical advice; check the paper before acting on it.
- 08
HER2 protein expression patterns in gallbladder adenocarcinoma and extrahepatic cholangiocarcinoma.
Strong HER2 staining occurred in about 8.5 percent of gallbladder and extrahepatic bile duct cancers, metastases often scored higher than primaries, and HER2 status did not predict outcomes.
Fleming JH, Nunez MM, Jenkins SM, et al. · Virchows Archiv · 2026
From the briefingAlso in Virchows Archiv, Fleming and colleagues assessed HER2 in 59 gallbladder adenocarcinomas and extrahepatic cholangiocarcinomas, prompted by the tissue-agnostic approval of trastuzumab deruxtecan for HER2 3+ tumours [8]. Strong HER2 staining was seen in five cases, about one in twelve, and just over a third of cases scored 1+ or 2+. The metastasis scored higher than its primary in 7 of 18 paired events, and poorly differentiated tumours were more likely to be HER2 negative. HER2 status was not associated with progression-free survival or mortality. The small cohort limits firm conclusions, but the primary-to-metastasis discordance raises the question of which specimen best reflects eligibility for targeted therapy.
Written by AI from the published abstract, for healthcare professionals. Not medical advice; check the paper before acting on it.
- 09
Bone Marrow Cell Depletion in Myelofibrosis Is Associated With High-Risk Features and Shortened Survival: A Bone Marrow Pathology Group Study.
Cell-depleted advanced myelofibrosis marrows were linked to cytopenias, osteosclerosis, ASXL1, U2AF1, EZH2 and MPL mutations, and significantly shorter overall survival than cellular myelofibrosis.
Geyer JT, Abu-Zeinah G, Sy C, et al. · Modern Pathology · 2026
From the briefingIn haematopathology, a Bone Marrow Pathology Group study in Modern Pathology from Geyer and colleagues compared 141 patients with cell-depleted advanced myelofibrosis to 100 with cellular myelofibrosis across eleven institutions [9]. Cell-depleted marrows were associated with lower haemoglobin and platelet counts, more circulating blasts, more osteosclerosis, enrichment for ASXL1, U2AF1, EZH2 and MPL mutations, and statistically significantly shorter overall survival. The design is retrospective, and the abstract notes that some associated features were not independently prognostic, but the study supports formally reporting marrow cellularity alongside fibrosis grade and osteosclerosis in advanced disease.
Written by AI from the published abstract, for healthcare professionals. Not medical advice; check the paper before acting on it.
- 10
Contextual diagnostic framework for evaluating histopathology grey zones: a proposal with medicolegal implications using breast pathology as a model.
A proposed contextual diagnostic standard would judge disputed histopathology diagnoses against a range of reasonable interpretations by comparable peers, countering hindsight bias in medicolegal expert review.
Rakha EA, Shaaban AM, Van Bockstal MR, et al. · Virchows Archiv · 2026
From the briefingFinally, a conceptual piece in Virchows Archiv from Rakha and colleagues tackles how diagnostic grey zones should be judged after the fact, using breast pathology as a model [10]. The authors argue that expert reviewers who know the outcome are prone to hindsight bias, and they propose a contextual diagnostic standard that recognises a range of reasonable interpretations supported by similarly competent pathologists working under comparable conditions, rather than a single retrospectively optimal answer. It is a proposal rather than an evidence base, but it speaks directly to the interobserver variability that runs through this week's renal, bladder and esophageal papers.
Written by AI from the published abstract, for healthcare professionals. Not medical advice; check the paper before acting on it.
The full briefing
This AudioScholar briefing is generated by artificial intelligence for healthcare professionals and trainees. It is not medical advice.
Welcome to This Week in Pathology. This week we're covering 10 notable papers spanning liver disease and the limits of non-invasive testing, renal and bladder tumour classification, and the standards that shape how we report and how our reports are judged. Let's dive in.
We start in the liver, where the role of histology is being both challenged and reaffirmed. The largest paper of the week comes from The Lancet, where Vali and colleagues report the LITMUS study, a prospective diagnostic accuracy study of 1590 adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease, recruited across 13 countries in Europe and the United States [1]. Every biopsy was centrally scored using the NASH Clinical Research Network system, and the investigators tested 12 single markers and 18 multimarker panels against a pre-set bar of an area under the curve above 0.80, the threshold they used to signal possible biopsy replacement. For at-risk steatohepatitis, meaning steatohepatitis with at least stage 2 fibrosis, only the proteomic SomaSignal panel cleared that bar, at about 0.83, and no test cleared it for steatohepatitis alone. Performance was much stronger for fibrosis: SomaSignal reached about 0.92 for advanced fibrosis, and FibroMeter combined with elastography led for cirrhosis at about 0.94, with several other panels including Agile 3+, ELF and liver stiffness measurement also performing well. A sequential approach using gamma-glutamyl transferase as a first step met the bar for both advanced fibrosis and at-risk disease. For pathologists, the message is nuanced: fibrosis staging is increasingly within reach of blood and imaging panels, but inflammatory activity and ballooning, the components that define steatohepatitis, remain poorly captured by anything other than a biopsy. The authors frame these data as informing future guidelines and trial design rather than settling biopsy replacement today. A small but striking paper in Histopathology makes the case for what only tissue can show. Endhardt and colleagues describe eight patients with steatotic liver disease whose sinusoids were obstructed by extracellular lipid vacuoles, a pattern they name lipidic obstruction of sinusoids, resembling pseudopeliotic steatosis but occurring outside transplantation [2]. A collagen IV stain highlighting double sinusoidal contours supported the diagnosis, the lesion was associated with necrosis and macrophage activation, and the extent of the fat lakes tracked with clinical severity, which ranged from subclinical to liver transplantation or death. This is a retrospective case series, so it defines an entity rather than establishing its frequency, but it is a reminder that biopsy can reveal mechanisms no panel is designed to detect.
Our second theme is the renal tumours driven by the MiT family of transcription factors, where two papers sharpen the line between true translocation carcinomas and their mimics. In Human Pathology, Oktay and colleagues studied 350 high-grade clear cell renal cell carcinomas from four centres with central immunohistochemistry [3]. BAP1 loss was present in about a quarter of tumours, and native nuclear TFE3 staining was found in roughly one in eight. Tumours with BAP1 loss had roughly three to four times the odds of TFE3 positivity, consistently across cohorts, and BAP1 loss was the only independent predictor on multivariable analysis. Crucially, GPNMB was absent in 40 of the 43 TFE3-positive tumours. The authors argue that GPNMB helps separate this native TFE3 expression from Xp11 translocation carcinoma, though as a retrospective tissue microarray study it does not include a direct head-to-head with confirmed translocation cases. That gap is partly addressed by a paper in The American Journal of Surgical Pathology, where Caliò and colleagues compared light microscopy techniques for TFEB-altered renal cell carcinoma across 16 molecularly confirmed cases and more than 200 controls [4]. TFEB immunohistochemistry was variable across clones, with the Bethyl assay most reliable. Cathepsin K and GPNMB were sensitive but labelled 40 and 50 percent of TFE3-rearranged tumours respectively, and TRIM63 RNA in situ hybridisation was likewise positive in TFE3-rearranged tumours. TFEB RNA in situ hybridisation, by contrast, was positive in every TFEB-altered case and negative in every control. Read together, these papers show that GPNMB is useful as a discriminator in one direction, flagging that TFE3-positive clear cell carcinoma is probably not a translocation tumour, while not being specific enough on its own to confirm a TFEB-altered tumour. The TFEB data come from a small series, so validation is still needed before RNA in situ hybridisation is accepted as a replacement for FISH, but the authors position it as a practical alternative where molecular testing is unavailable.
Staying in the genitourinary tract, two bladder papers address what pathologists see before and after treatment. In Human Pathology, Youssef and colleagues examined 206 radical cystectomies performed after neoadjuvant chemotherapy, comparing patients whose earlier transurethral resection showed conventional urothelial carcinoma with those showing subtypes or divergent differentiation [5]. The presence of any non-conventional component was associated with statistically significantly lower rates of complete pathologic response and downstaging, with no difference in positive margins. Interestingly, the number of non-conventional components, one, two, or three or more, did not correlate with response. This retrospective cohort supports reporting the presence of these components on resection specimens as relevant to chemotherapy response, while suggesting that counting them adds little. In Histopathology, Pacheco and colleagues used 37 en bloc resection specimens to characterise lateral extension, the flat atypical urothelium that spreads from the base of a high-grade papillary tumour [6]. Lateral extension averaged just under 5 millimetres and reached up to about a centimetre, and it reached the mucosal margin in 12 of 13 tumours. Sequencing showed shared alterations with the papillary tumour in 9 of 11 pairs, supporting clonality, and abnormal CK20 staining was seen in every case tested, with aberrant p53 in about a quarter. Because lateral extension can mimic the immunoprofile of carcinoma in situ, the authors suggest that recognising it could reduce overdiagnosis of carcinoma in situ after papillary tumours. The cohort is small and single-institution, so this is a framework for consistent terminology rather than established criteria.
Our next theme concerns gastrointestinal reporting and biomarker testing, both from Virchows Archiv. Marginean surveyed 171 gastrointestinal pathologists who handle esophageal endoscopic resections across North America, Europe, Asia and Australasia [7]. Agreement was high on the core determinants of curability, with tumour type, depth of invasion, margins and lymphovascular invasion each reported by more than 95 percent of respondents. Variation lay elsewhere: routine pinning by the clinician was near universal in Asia but uncommon in the United States, roughly half of respondents used no recognised M-level system for intramucosal carcinoma, and only about a third reported tumour budding. The author argues that harmonisation should target reproducible, clinically actionable features rather than adoption of any single regional system. Also in Virchows Archiv, Fleming and colleagues assessed HER2 in 59 gallbladder adenocarcinomas and extrahepatic cholangiocarcinomas, prompted by the tissue-agnostic approval of trastuzumab deruxtecan for HER2 3+ tumours [8]. Strong HER2 staining was seen in five cases, about one in twelve, and just over a third of cases scored 1+ or 2+. The metastasis scored higher than its primary in 7 of 18 paired events, and poorly differentiated tumours were more likely to be HER2 negative. HER2 status was not associated with progression-free survival or mortality. The small cohort limits firm conclusions, but the primary-to-metastasis discordance raises the question of which specimen best reflects eligibility for targeted therapy.
In haematopathology, a Bone Marrow Pathology Group study in Modern Pathology from Geyer and colleagues compared 141 patients with cell-depleted advanced myelofibrosis to 100 with cellular myelofibrosis across eleven institutions [9]. Cell-depleted marrows were associated with lower haemoglobin and platelet counts, more circulating blasts, more osteosclerosis, enrichment for ASXL1, U2AF1, EZH2 and MPL mutations, and statistically significantly shorter overall survival. The design is retrospective, and the abstract notes that some associated features were not independently prognostic, but the study supports formally reporting marrow cellularity alongside fibrosis grade and osteosclerosis in advanced disease.
Finally, a conceptual piece in Virchows Archiv from Rakha and colleagues tackles how diagnostic grey zones should be judged after the fact, using breast pathology as a model [10]. The authors argue that expert reviewers who know the outcome are prone to hindsight bias, and they propose a contextual diagnostic standard that recognises a range of reasonable interpretations supported by similarly competent pathologists working under comparable conditions, rather than a single retrospectively optimal answer. It is a proposal rather than an evidence base, but it speaks directly to the interobserver variability that runs through this week's renal, bladder and esophageal papers.
If you only have time for one paper this week, make it the LITMUS study in The Lancet [1]. It provides the most rigorous benchmark yet of where non-invasive tests can and cannot stand in for liver histology, and it reopens the question of exactly which parts of the biopsy report remain irreplaceable.
Here is what this week's evidence adds up to in Pathology. First, large prospective data show that blood and imaging panels now approach biopsy for staging advanced fibrosis and cirrhosis, while steatohepatitis activity remains largely a histologic diagnosis, and new tissue-only entities like lipidic sinusoidal obstruction continue to emerge from small series. Second, in MiT family renal tumours, native TFE3 staining is enriched in BAP1-deficient clear cell carcinoma and lacks GPNMB, while TFEB RNA in situ hybridisation looked highly specific in a small series; both findings await wider validation. Third, retrospective bladder data link non-conventional histology to poorer chemotherapy response, and lateral extension offers a possible explanation for some apparent carcinoma in situ after papillary tumours. Fourth, marrow cell depletion in advanced myelofibrosis marks a higher-risk molecular and clinical group, based on a multi-institutional retrospective cohort. And fifth, international practice agrees on core reporting elements but diverges on handling and terminology, a variability that a new medicolegal framework argues should be treated as reasonable rather than as error.
That's your roundup for This Week in Pathology. The full transcript and references are available on the episode page. This is an AI-curated summary — for clinical decisions, always consult primary sources and current guidelines. See you next week.
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