Weeda YA, Salgado R, van Herpe F
… +36 more, Sur D, Vieth M, Loi S, Tafti AP, Alexandros H, Hida AI, Bhalla A, Khramtsov AI, Ehinger A, Tanaka A, Acs B, Ercan C, Focke CM, Ehinger D, Huang D, Khramtsova GF, Nishida H, Li N, Littlefield N, Steen S, Sevim S, Ichihara S, Morikawa S, Michiels S, Papathomas T, Haga T, Gu Q, Sheng W, Kervadec H, Horlings HM, Sanchez-Vega F, Janjigian YY, Chalabi M, van Laarhoven HWM, Kodach LL, Meijer SL
Histopathology
· 2026 May · PMID 41640295
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In the era of immune checkpoint inhibitors for cancers, the need for prognostic biomarkers to identify patients most likely to achieve a durable response has become increasingly more relevant. Tumour-infiltrating lymphoc...In the era of immune checkpoint inhibitors for cancers, the need for prognostic biomarkers to identify patients most likely to achieve a durable response has become increasingly more relevant. Tumour-infiltrating lymphocytes (TILs) have gained significant interest, as they can be evaluated using standard haematoxylin and eosin-stained slides, making it a widely accessible and cost-effective biomarker. In addition to their practicality, TILs provide prognostic insights into the interplay between the immune system and tumour cells. While the morphological assessment of TILs has been standardised in breast cancer, comprehensive guidelines for their evaluation in gastro-oesophageal carcinomas (GEC) are still lacking. This narrative review examines the current literature on the composition, clinical implications and therapeutic utility of TILs in GEC. These insights are used to propose a framework with recommendations for standardised evaluation and reporting of TILs in GEC, while also highlighting pitfalls specific to GEC pathology. These recommendations serve as a vital first step towards the widespread use and validation of TILs as a biomarker.
Booth AL, Torlakovic EE, Chetty R
… +11 more, Farris AB, Furth EE, Goldblum JR, Longacre TA, Mino-Kenudson M, Riddell RH, Rosty C, Srivastava A, Yantiss RK, Cox B, Gonzalez RS
Histopathology
· 2026 Jun · PMID 41622126
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AIMS: Many studies have highlighted interobserver variability in histologic distinction between colorectal sessile serrated lesion (SSL) and hyperplastic polyp (HP). In 2019, the WHO updated their criteria for the diagno...AIMS: Many studies have highlighted interobserver variability in histologic distinction between colorectal sessile serrated lesion (SSL) and hyperplastic polyp (HP). In 2019, the WHO updated their criteria for the diagnosis of SSL, requiring 'at least 1 unequivocal architecturally distorted serrated crypt'. Even with this simplified criterion, as well as experience accumulated in recognizing SSL over 25 years, SSL and HP remain difficult to distinguish in some instances. This study aimed to assess observer variability and preferred criteria in diagnosing SSL among gastrointestinal pathologists. METHODS AND RESULTS: We retrospectively identified 60 serrated colorectal polyps, produced uniform H&E recuts, and created whole-slide images for each case. Cases were selected to cover a spectrum of non-dysplastic serrated lesions, as confirmed via review by four pathologists who individually interpreted each as SSL, HP, or serrated polyp NOS (SP-NOS). The cases were then reviewed by nine additional pathologists. A second round of review followed after a 5-month washout period. A third round of reviews was completed after 5 additional months, at which time reviewers were provided information regarding polyp size and site. Fleiss and Cohen kappa values were calculated to determine overall inter- and intra-observer agreement. The top three criteria pathologists used to favour a diagnosis of SSL over HP included crypt distortion (13/13), polyp location (8/13) and size (4/13). There was moderate agreement among all 13 pathologists when classifying the 60 cases for rounds 1 (κ = 0.50) and 2 (κ = 0.46), and good agreement for round 3 (κ = 0.63), the round using criteria beyond those of the WHO; stratification by location showed agreement was worst for transverse polyps. Twenty-one (35%) cases were called SSL >80% of the time, and 16 (27%) cases were classified as HP >80% of the time. Agreement was moderate (κ = 0.43) for polyps measuring ≥1.0 cm and was good (κ = 0.63) for polyps measuring ≤0.4 cm. In keeping with current WHO criteria, crypt distortion was the only feature all pathologists considered useful to diagnose SSL. Overall interobserver agreement improved from moderate to good when pathologists were aware of the polyp size and site. Pathologists had the worst agreement when classifying lesions in the transverse colon or polyps ≥1.0 cm. CONCLUSIONS: Non-histologic criteria (e.g. polyp site and size) may be necessary to accurately and reproducibly distinguish SSL from HP, if properly validated.
Histopathology
· 2026 May · PMID 41611646
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Phyllodes tumours of the breast present challenges in their diagnosis, classification and management. Further understanding of the molecular changes underpinning these tumours may lead to more precise classification and...Phyllodes tumours of the breast present challenges in their diagnosis, classification and management. Further understanding of the molecular changes underpinning these tumours may lead to more precise classification and potential treatment options. Similar to fibroadenomas, MED12 is the most frequently mutated gene in phyllodes tumour. However, in addition, there is a spectrum of molecular alterations from benign to malignant phyllodes tumours with increasing genomic complexity, high level copy number alterations and aberrations of cancer driver genes in malignant phyllodes tumours. This review summarizes the molecular pathology of phyllodes tumours, the use of these data in developing a model of phyllodes tumour pathogenesis, and how molecular pathology might be applied to aid diagnosis and guide treatment in this rare tumour type.
Giuseppe L, Marco B, Michele DDB
… +5 more, Marco G, Beatrice B, Simona R, Luigi C, Vincenzo M
Histopathology
· 2026 Jun · PMID 41607346
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AIMS: Differentiating intrahepatic cholangiocarcinoma (iCCA) from metastatic ductal adenocarcinoma of the pancreas (mPDAC) is challenging due to commonalities in histology and phenotype. Currently, available biomarkers a...AIMS: Differentiating intrahepatic cholangiocarcinoma (iCCA) from metastatic ductal adenocarcinoma of the pancreas (mPDAC) is challenging due to commonalities in histology and phenotype. Currently, available biomarkers are not completely satisfactory in supporting such differential diagnosis. The present study aims to evaluate aquaporin (AQP)-1 as a reliable biliary biomarker. METHODS AND RESULTS: A total of 151 pancreatobiliary adenocarcinomas, including 77 surgical resections and 74 needle biopsies, were considered, including 84 CCA and 67 PDAC. Immunohistochemistry was performed in two steps: (1) primary tumours, including CCA and PDAC, were compared; (2) data from primary tumours were subsequently validated on needle biopsies, comparing iCCA and mPDAC. The staining was examined according to the immunoreactive score (IRS). On surgical resections, our evaluation showed a mean IRS value of 11.07 in iCCA and 0.7 in PDAC; likewise, on needle biopsies, a mean IRS value of 10.54 in iCCA and 0.97 in mPDAC was observed. Combining surgical resections and needle biopsies, the mean IRS value resulted in 10.76 in iCCA; conversely, it was 0.84 in PDAC. Overall, the ROC curves showed the AQP1 diagnostic performance to be characterized by an AUC of 0.999, being a sensitivity of 100% and a specificity of 95.45%. CONCLUSIONS: AQP1 is a novel biliary biomarker which has been shown to outperform other biliary biomarkers. The main diagnostic scenario in which AQP1 staining should be used is to distinguish iCCA from mPDAC. Furthermore, differential diagnosis between eCCA and PDAC in surgical specimens and between PDAC and CP in needle biopsies should be considered.
Sharma AE, Wyvekens N, Neville G
… +4 more, Parra-Herrán C, Hornick JL, Fletcher CDM, Nucci MR
Histopathology
· 2026 May · PMID 41607084
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AIMS: Scarce literature exists regarding the spectrum of vascular neoplasms of the distal female genital tract. Herein, we describe the clinicopathologic features of a cohort of intermediate to malignant endothelial neop...AIMS: Scarce literature exists regarding the spectrum of vascular neoplasms of the distal female genital tract. Herein, we describe the clinicopathologic features of a cohort of intermediate to malignant endothelial neoplasms of the vulva and vagina. METHODS AND RESULTS: Specimens were identified retrospectively from in-house and consultation files at our institution. Clinicopathologic data was obtained from review of the chart and available histologic material. Nineteen cases were identified in total. Kaposi sarcoma (n = 2) was of the enigmatic 'sporadic' form in elderly non-HIV females. Kaposiform haemangioendothelioma (n = 1) presented at an older (rather than paediatric) age and was negative for HHV-8 by IHC; both Kaposi sarcomas were positive. Pseudomyogenic haemangioendothelioma (n = 2) presented in elderly females (rather than young males) with positivity for both FOSB and AE1/AE3. Epithelioid haemangioendothelioma (n = 8), showed variably well-developed chondromyxoid matrix and consistent positivity for CAMTA1 IHC. Angiosarcomas were disproportionately of the epithelioid subtype, with high-grade cytologic atypia, destructive infiltration and rare EMA positivity. CONCLUSIONS: While many morphologic features of vascular lesions at this site are shared with those of extra-genital soft tissues, pathologists must be aware that these tumours may occur in the vulvovaginal area and display unconventional clinical profiles. As such, a broad differential for epithelioid and spindle cell neoplasms at this site is prudent.
Saka B, Memis B, Balci S
… +13 more, Erbarut Seven I, Pehlivanoglu B, Bagci P, Esmer R, Tarcan Z, Cheng JD, Maithel SK, Kooby DA, Sarmiento J, El-Rayes B, Reid MD, Basturk O, Adsay NV
Histopathology
· 2026 Jun · PMID 41589621
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AIMS: Accurate determination of tumour size is critical for pT staging in pancreatic ductal adenocarcinoma (PDAC), yet gross measurement alone often underestimates the true tumour extent because of the tumour's ill-defin...AIMS: Accurate determination of tumour size is critical for pT staging in pancreatic ductal adenocarcinoma (PDAC), yet gross measurement alone often underestimates the true tumour extent because of the tumour's ill-defined and infiltrative nature. This study aimed to evaluate the diagnostic and prognostic value of incorporating microscopic rectification into tumour size assessment in PDAC. METHODS AND RESULTS: A total of 342 therapy-naïve pancreatoduodenectomies were analysed using a grossing protocol that includes separate sampling of anterior and posterior soft tissues via the 'orange-peeling' technique to retrieve lymph nodes and document soft tissue involvement. Peripancreatic soft tissue involvement was present in 91% of cases, and isolated microscopic foci distant from the main mass in 48%. Of the 266 tumours grossly classified as pT1/T2 (≤4 cm), 39 (14%) showed carcinoma in both anterior and posterior soft tissues, and were reclassified as pT3. This subset showed significantly worse survival (P = 0.04) and higher nodal positivity (87% versus 69%, P = 0.02) than the remaining pT2 cases, comparable to conventional pT3 tumours (86%, P = 0.77). Multivariable Cox regression adjusted for age, sex, nodal status, margin, and lymphovascular/perineural invasion confirmed the survival disadvantage of this subgroup. Reclassification yielded a more balanced distribution of T categories (pT2 66% → 52%, pT3 22% → 34%) and modestly improved prognostic discrimination (C-index: 0.592 versus 0.574). CONCLUSIONS: This study elucidates that PDAC frequently extends beyond the visible mass ('horses out of the barn' phenomenon); peripancreatic soft tissue involvement is common, and gross size often underestimates the true tumour extent, making microscopic correction crucial. Approximately one in six pT1/T2 tumours (≤4 cm) shows carcinoma in both anterior and posterior soft tissues and behave like pT3 in outcomes and nodal status. Therefore, gross-micro rectification is essential to avoid understaging, particularly for T2 tumours. The orange-peeling protocol should classify tumours with foci in both anterior and posterior soft tissues as pT3, while other approaches may employ mapping techniques to enable microscopic reconstruction and biologically accurate staging.
Repetto F, Cornejo KM, O'Donnell P
… +3 more, Toyohara JP, Ferry JA, Nazarian RM
Histopathology
· 2026 May · PMID 41537415
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AIMS: Cutaneous plasmablastic lymphoma (cPBL) is a rare and aggressive neoplasm that presents as skin nodules. Despite occurring in ~5% of PBL cases, the World Health Organization (WHO) does not distinguish primary cutan...AIMS: Cutaneous plasmablastic lymphoma (cPBL) is a rare and aggressive neoplasm that presents as skin nodules. Despite occurring in ~5% of PBL cases, the World Health Organization (WHO) does not distinguish primary cutaneous PBL (pcPBL) from secondary cutaneous PBL (scPBL), and their clinical differences remain poorly defined. To determine whether pcPBL represents a distinct clinical entity, we compare the clinicopathologic features, immunohistochemical profiles, and survival outcomes of pcPBL and scPBL. METHODS AND RESULTS: Retrospective comparative study analysing 40 cases of cPBL (6 newly identified institutional cases and 34 cases from the literature), categorized as pcPBL (n = 25; no extracutaneous disease at diagnosis) or scPBL (n = 15; concurrent extracutaneous disease). Patients with pcPBL were older than those with scPBL (median 62 vs. 43 years; Mann-Whitney P = 0.018). Leg involvement was significantly associated with pcPBL (OR = 6.22; 95% CI: 1.21-31.9; P = 0.031). Disease-specific survival (DSS) analysis included 17 evaluable cases (pcPBL n = 11; scPBL n = 6). Median DSS was 42.0 months in pcPBL and 8.0 months in scPBL (log-rank χ = 3.98; p = 0.046). Median follow-up (reverse Kaplan-Meier) was 20.0 months in pcPBL and not reached in scPBL. Cox models were directionally consistent but underpowered. CONCLUSION: In this pooled analysis, cases presenting with primary cutaneous involvement tended to occur in older patients and more often involved the legs. However, these observations should be interpreted cautiously given small numbers and heterogeneity of the available data. Within pcPBL, EBV positivity correlated with better survival. These hypothesis-generating findings provide a basis for prospective, multi-centre studies to clarify classification, staging implications, and management of this rare lymphoma.
Jha S, Lobo A, Sangoi AR
… +18 more, Kandukuri SR, Mishra SK, Arora S, Aggarwal A, Sharma S, Jain E, Akgul M, Acosta AM, Pattnaik N, Kaushal S, Baisakh M, Routa S, Shaker N, Dhillon J, Parwani AV, Williamson SR, Mohanty SK, Cheng L
Histopathology
· 2026 May · PMID 41537408
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BACKGROUND: Clear cell adenocarcinoma (CCA) of the urinary tract is a rare genitourinary malignancy that primarily arises in the urethra and bladder. Due to its rarity, the molecular landscape of these tumours remains po...BACKGROUND: Clear cell adenocarcinoma (CCA) of the urinary tract is a rare genitourinary malignancy that primarily arises in the urethra and bladder. Due to its rarity, the molecular landscape of these tumours remains poorly characterized. In this large series, we aimed to molecularly characterize CCA to gain insights into its pathogenesis and identify potential targets for therapy. DESIGN: Formalin-fixed, paraffin-embedded tumour tissue blocks from 19 cases of CCA were subjected to molecular profiling using a targeted next-generation sequencing (NGS) panel. RESULTS: The most common alteration was a gain-of-function mutation in PIK3CA (74%), followed by mutations in KRAS (26%), ERBB2 (21%), SMAD4 (21%), RB1 (16%), TP53 (5%), MET (5%) and APC (5%). Thirteen tumours harboured co-mutations. Five cases showed concurrent PIK3CA and KRAS mutations, while the remaining tumours had either isolated PIK3CA alterations or co-occurring loss-of-function mutations in tumour suppressor genes, including RB1 point mutation, SMAD4 inactivation, APC truncation or TP53 inactivation. Eight patients died of disease, with a mean follow-up of 14 months (range, 3-31 months). Notably, all eight deceased patients and two of the surviving patients harboured PIK3CA mutations. CONCLUSIONS: In summary, we identified a distinct oncogenic pathway in CCA of the urinary bladder, most commonly involving activation of the PI3K/AKT/mTOR pathway through gain-of-function mutations in PIK3CA (74%) and/or KRAS (26%). These tumours frequently harbour loss-of-function mutations in tumour suppressor genes (TP53, SMAD4, RB1 and APC) and point/missense mutations of proto-oncogenes (ERBB2 and MET). Our study also highlights potential therapeutic targets for this aggressive malignancy.
Toussieng T, Kozak M, Burch M
… +7 more, Gangi A, Gong J, Guindi M, Lai KK, Hutchings DA, Larson BK, Waters KM
Histopathology
· 2026 Feb · PMID 41521654
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BACKGROUND: Autoimmune metaplastic atrophic gastritis (AMAG) causes pulmonary trans-differentiation of the gastric mucosa and is known to increase the risk of developing gastric adenocarcinoma. AMAG-associated gastric ad...BACKGROUND: Autoimmune metaplastic atrophic gastritis (AMAG) causes pulmonary trans-differentiation of the gastric mucosa and is known to increase the risk of developing gastric adenocarcinoma. AMAG-associated gastric adenocarcinomas were examined for immunoreactivity for TTF-1 and Napsin A. DESIGN: Eighteen AMAG-associated gastric adenocarcinomas and 36 non-AMAG-associated gastric adenocarcinomas were stained for TTF-1 (clones SP141 and 8G7G3/1) and Napsin A (clone 1P64) by immunohistochemistry. AMAG stage and staining patterns were characterized. RESULTS: The AMAG group was older (mean age 74 vs. 65 years) and was not significantly different with regard to sex or tumour differentiation. Zero (0%) AMAG cases were classified as early phase, four (22%) as florid phase and 14 (78%) as end stage. AMAG-associated adenocarcinomas showed more frequent TTF-1 immunoreactivity compared to control adenocarcinomas in both clone SP141 (39% vs. 11%; P = 0.04) and 8G7G3/1 (22% vs. 6%; P = 0.17). AMAG-associated adenocarcinomas showed more frequent Napsin A immunoreactivity compared to control adenocarcinomas (28% vs. 0%; P < 0.01). Immunoreactivity in AMAG-associated adenocarcinomas was patchy, ranging from 1% to 20% of tumour cells staining positive (1+ to 3+ intensity). In the AMAG cases with background gastric mucosa (n = 14), the background showed TTF-1 positive foci in seven (50%) cases (both clones) versus one (3%; clone SP141) to two (6%; clone 8G7G3/1) of 33 controls (P < 0.01) and Napsin A positive foci in five (36%) cases versus zero (0%) controls (P < 0.01). Staining in background mucosa was also patchy, involving 1%-10% of gastric glands without intestinal metaplasia. CONCLUSION: TTF-1 and Napsin A immunoreactivity was present in the background gastric mucosa almost exclusively in the AMAG-associated cases. This immunoreactivity is also present in AMAG-associated adenocarcinomas more commonly than non-AMAG-associated adenocarcinomas. This knowledge may aid pathologists in avoiding the pitfall of diagnosing metastatic lung cancer, as the expression is patchy and may also be seen in atrophic background mucosa.
Wang JC, Wang C, Chen FF
… +11 more, Zhang WF, Yu ZQ, Wang XJ, Li SL, Chen MS, Zhong LH, Lin LY, Chen YP, Chen X, Chen LH, Chen G
Histopathology
· 2026 Jun · PMID 41508985
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AIMS: Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is a rare, indolent malignant neoplasm. Due to its rarity, a comprehensive assessment of its immunophenotypic spectrum a...AIMS: Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is a rare, indolent malignant neoplasm. Due to its rarity, a comprehensive assessment of its immunophenotypic spectrum and molecular analysis is still lacking. This study aimed to characterize the immunophenotypic and genetic alterations of EBV+ IFDCS to improve understanding of its cell of origin and molecular pathogenesis and to identify potential therapeutic targets. METHODS AND RESULTS: Immunohistochemical staining for a panel of follicular dendritic cell (FDC) and fibroblastic reticular cell (FRC) lineage markers, along with targeted next-generation sequencing, was performed. Nineteen cases of EBV+ IFDCS were classified into four immunophenotypes: nine FDC, two FRC, three biphasic and five null phenotypes. Morphologically, cases with a null phenotype more frequently exhibited a lymphoma-like growth pattern (4/5, 80%) compared with those with a definite FDC and/or FRC phenotype (1/14, 7.1%, P = 0.006). Moreover, a scattered distribution of neoplastic cells was more commonly observed in null phenotype cases (4/5, 80%) than in FDC and/or FRC phenotype cases (3/14, 21.4%, P = 0.038). Targeted sequencing revealed somatic variants in chromatin modifier-related genes in 60.0% (9/15), homologous recombination repair (HRR)-related genes in 53.3% (8/15) and Hippo pathway-related genes (FAT2 and FAT1) in 26.7% (4/15) of cases. CONCLUSIONS: These findings demonstrate the wide morphological and immunophenotypic spectrum of EBV+ IFDCS. Furthermore, variants in chromatin modifier and HRR-related genes may participate in its pathogenesis, and PARP inhibition may represent a potential therapeutic strategy for patients with unresectable disease.
AIMS: Extramammary Paget disease (EMPD) is an intraepidermal carcinoma that typically involves the urogenital, perineal and perianal skin. EMPD is classified as primary if arising directly in the skin, or secondary if sp...AIMS: Extramammary Paget disease (EMPD) is an intraepidermal carcinoma that typically involves the urogenital, perineal and perianal skin. EMPD is classified as primary if arising directly in the skin, or secondary if spreading from another malignancy, most commonly urothelial carcinoma and colorectal adenocarcinoma. Prostein (p501s) immunoreactivity was initially described as sensitive and specific for prostatic epithelial cells including prostatic adenocarcinoma. Herein, we investigated the expression of prostein in primary EMPD of the external genitalia, secondary EMPD involving the external genitalia or perineum, and mammary Paget disease (MPD). METHODS AND RESULTS: Prostein was negative by immunohistochemistry in all cases of MPD (n = 0/11) and secondary EMPD (n = 0/5). Conversely, prostein was positive in all cases of primary EMPD (n = 11/11), including non-invasive and invasive components and including one nodal metastasis. Among these cases, 5/11 (45%) showed non-focal moderate-to-strong staining, 3/11 (27%) showed focal weak staining, and 3/11 (27%) cases showed weak diffuse staining. All cases of primary EMPD additionally showed diffuse 2-3+ staining for GATA3, and 10/11 cases of primary EMPD showed diffuse 2-3+ staining for androgen receptor (AR). CONCLUSIONS: These findings suggest that prostein may be a promising immunohistochemical marker for the diagnosis of primary EMPD.
Rust M, Farkouh N, Beusker P
… +4 more, Eissing-Al-Mukahal A, Böker C, Mall J, Wilkens L
Histopathology
· 2026 May · PMID 41502169
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AIMS: Treatment and outcomes in colorectal carcinoma (CRC) depend on the UICC classification, depth of invasion, and distant metastases. However, it is not clear whether an extensive workup of lymph nodes (LNs) is import...AIMS: Treatment and outcomes in colorectal carcinoma (CRC) depend on the UICC classification, depth of invasion, and distant metastases. However, it is not clear whether an extensive workup of lymph nodes (LNs) is important for the adequate determination of metastases. Therefore, we compared the number of LNs and metastases obtained by a standard protocol (SP) and an extended protocol (EP) in two series with a total of 105 CRC cases and 2417 LNs. METHODS AND RESULTS: In the first series, the EP included complete stepwise sectioning of all LN-bearing paraffin blocks in each case, increasing the total number of LNs from 1247 in the SP to 1333 in the EP and the number of metastases from 69 to 80. One pTNM pN1a case became pN1b, and two pN1b cases became pN2a. The staging, and thus the therapy, changed in none of them. Furthermore, no relevant effect of embedding one versus both halves of large LNs >5 mm was evident. In the second series, the EP included immunohistochemical staining for pan-cytokeratin (monoclonal antibodies AE1/AE3) of all LN-bearing paraffin blocks in a given case. The number of detected metastases rose from 82 to 89, with a constant total 1084 LNs. In two cases, the pTNM classification changed from pN2a to pN2b. Staging and therapy changed in none. CONCLUSION: An extensive workup of LNs is not mandatory in patients with CRC. A straightforward protocol is sufficient to guide clinicians to the appropriate therapy.
The grading and staging of liver biopsies from patients with steatotic liver disease, in particular metabolic dysfunction-associated steatotic liver disease (MASLD), is of fundamental importance in the execution of clini...The grading and staging of liver biopsies from patients with steatotic liver disease, in particular metabolic dysfunction-associated steatotic liver disease (MASLD), is of fundamental importance in the execution of clinical trials of new therapeutic agents in this condition. Several semi-quantitative scoring systems have been designed for this purpose, of which the most used is the NASH Clinical Research Network (NASH CRN) system, in which the grade of disease is assessed on the severity of steatosis, hepatocyte ballooning and lobular inflammation. There has been recent interest in the role of portal inflammation (PI) in MASLD. The arguments for and against the inclusion of a semi-quantitative score for PI in grading MASLD activity are discussed in detail.
Mucin-producing breast lesions encompass a diverse range of entities with varied morphologies, distinct molecular genetics and different outcomes. Mucocele-like lesions (MLLs) are being increasingly recognised and sample...Mucin-producing breast lesions encompass a diverse range of entities with varied morphologies, distinct molecular genetics and different outcomes. Mucocele-like lesions (MLLs) are being increasingly recognised and sampled due to advancements in imaging techniques. These lesions can present with or without epithelial proliferation and atypia, which hold prognostic significance. Diagnosing MLLs on limited core needle biopsy (CNB) samples can be challenging. Mucinous breast carcinoma (MuBC) generally has an excellent prognosis in its pure form. Recent studies indicate that mucin-producing invasive cancers with micropapillary growth pattern, high nuclear grade or HER2 overexpression/amplification may not fare as well as their pure counterparts, suggesting that they should be distinguished from pure MuBCs. Invasive lobular carcinoma with extracellular mucin (ILCEM) is an emerging subtype of ILC characterised by neoplastic cells in cords, nests and trabeculae, often with signet ring morphology, floating in extracellular mucin. This can lead to misdiagnosis as a ductal phenotype due to varied architectural patterns or a MuBC due to the presence of extracellular mucin. This review highlights the spectrum of mucin-producing breast lesions, focusing on the above-mentioned entities along with recent molecular updates, potential mimics and diagnostic pitfalls on CNB specimens. Awareness of these entities, a practical approach to their diagnosis, combined with judicious use of immunohistochemistry, are crucial for accurate diagnosis by pathologists, which is in turn essential for guiding clinical decision making for optimal patient outcomes.
Lin LH, Devins KM, Turashvili G
… +9 more, Kolin DL, Diaz PS, Diaz CF, Banet N, Morrison J, Hui P, Bridge JA, Young RH, Oliva E
Histopathology
· 2026 May · PMID 41498302
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INTRODUCTION: Teratomas are the most common germ cell tumours in the gynaecological tract, the vast majority arising in the ovary. Limited information is available on uterine teratomas. METHODS: We evaluated clinicopatho...INTRODUCTION: Teratomas are the most common germ cell tumours in the gynaecological tract, the vast majority arising in the ovary. Limited information is available on uterine teratomas. METHODS: We evaluated clinicopathological features of five uterine teratomas, fluorescence in situ hybridization for isochromosome 12p [i(12p)], short tandem repeat (STR) analysis, and targeted DNA sequencing in a subset. RESULTS: Patients' age ranged from 29 to 60 (median: 40) years. Three underwent hysterectomy and two conservative cervical excisions. All tumours were uterine confined with four centred in the cervix and one in the corpus, ranging from 2.4 to 6.5 (median: 3.75) cm. Three tumours only had mature elements with one associated with mature glial tissue in the peritoneum and endometrium. The other two tumours also showed immature neural tissue, warranting a diagnosis of Grade 2 immature teratoma based on ovarian criteria. Four patients were alive with no evidence of disease with median follow-up of 13 (range 2-42) years. i(12p) was not detected in two tumours with available material (one mature and one immature). STR analysis showed heterozygosity in one mature and complete homozygosity in one immature teratoma. Targeted DNA sequencing revealed no pathogenic or likely pathogenic alterations in one immature teratoma and a pattern consistent with genome-wide loss of heterozygosity. CONCLUSIONS: Uterine teratomas display either mature or an admixture of mature and immature elements and can rarely be associated with gliomatosis. Limited data show no association with i(12p). The malignant potential of immature uterine teratomas is not well established and they appear to be more akin to sacrococcygeal than ovarian teratomas based on limited STR results from this cohort and the literature.
Willner J, Khan I, Tarcan Z
… +15 more, Aly R, Solanki P, Basturk O, Bellizzi AM, Baine MK, Armstrong SM, Travis WD, Tang LH, Wilson C, Bodd F, Thummalapalli R, Cooper AJ, Lee JJ, Rudin CM, Rekhtman N
Histopathology
· 2026 May · PMID 41489019
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AIMS: ASCL1, NEUROD1, POU2F3 and YAP1 are recently described markers of transcriptional subtypes in small cell lung carcinoma (SCLC), while DLL3, regulated by ASCL1, is a target of novel therapeutic agents in various neu...AIMS: ASCL1, NEUROD1, POU2F3 and YAP1 are recently described markers of transcriptional subtypes in small cell lung carcinoma (SCLC), while DLL3, regulated by ASCL1, is a target of novel therapeutic agents in various neuroendocrine neoplasms. The expression of these markers in lung carcinoids is not well established. METHODS AND RESULTS: We examined these markers in 109 lung carcinoids and compared their expression with that in 191 enteropancreatic neuroendocrine tumours (EP-NETs) and with lung carcinoid markers (OTP, TTF1). ASCL1, NEUROD1, OTP and TTF1 were positive in 56%, 0%, 84% and 35% of lung carcinoids, respectively. Of the OTP-negative lung carcinoids (n = 18), 4 (22%) were ASCL1-positive, of which one was TTF1-positive. In contrast, 59% of EP-NETs were NEUROD1-positive, whereas only rare tumours focally expressed ASCL1 (1.1%) and OTP (0.5%) and none expressed TTF1. DLL3 was positive in 57 (52%) lung carcinoids versus 5 (2.6%) EP-NETs. All lung carcinoids and EP-NETs were completely negative for POU2F3 and YAP1. We also analysed clinicopathologic correlates of ASCL1, OTP, TTF1 and DLL3 expression in lung carcinoids, expanding on several previously suggested associations, including ASCL1 and TTF1 with peripheral location, OTP with low Ki67 (P = 0.002) and low stage (P = 0.002) and DLL3 with high Ki67 (P = 0.002). CONCLUSION: Unlike SCLC, lung carcinoids and EP-NETs completely lack the expression of POU2F3 and YAP1, which offers diagnostic applications. Our findings also nominate ASCL1 and NEUROD1 as site of origin markers for lung versus digestive NETs/carcinoids, respectively. Finally, the divergent expression of DLL3 in lung carcinoids and EP-NETs has therapeutic implications.
Ingyin H, Solomon JP, Li Y
… +13 more, Xu D, Racchumi J, Wang A, Allard G, Gao G, Ma Z, Lin CY, Chen YY, Krings G, Troxell ML, Hoda SA, Bean GR, Boyraz B
Histopathology
· 2026 May · PMID 41456879
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AIMS: Tubular adenoma of the breast (TAB) is a rare and understudied neoplasm, initially thought to represent a fibroadenoma (FA) variant. Recently, it has been shown that TABs lack MED12 mutations indicating a distinct...AIMS: Tubular adenoma of the breast (TAB) is a rare and understudied neoplasm, initially thought to represent a fibroadenoma (FA) variant. Recently, it has been shown that TABs lack MED12 mutations indicating a distinct pathogenesis, and an association between multiple TABs and Cowden syndrome (CS) has been described. We sought to evaluate PTEN status in TABs with immunohistochemistry (IHC) and identify other potential molecular alterations. METHODS AND RESULTS: Forty-nine TABs from 43 patients (3 with CS, 40 without known CS) were retrieved. All patients were female, and ages ranged from 15 to 54 years old (median: 25). All TABs were well circumscribed and composed of closely packed, bilayered tubules with minimal intervening stroma. CS patients had multiple, bilateral TABs. PTEN IHC showed loss of expression in the luminal cells in TABs from all CS patients while the expression was retained in sporadic/non-CS TABs. Whole exome and/or Sanger sequencing was performed on 34 sporadic TABs and identified somatic missense mutations at codon 95 of the beta-actin gene, ACTB, in 19 cases (56%). No pathogenic MED12 mutations were identified in 29 TABs with next-generation sequencing results. CONCLUSIONS: Overall, our findings highlight recurrent somatic ACTB mutations in more than half of sporadic TABs. CS-associated TABs but not sporadic TABs showed loss of PTEN expression. The presence of bilateral and/or multiple TABs should prompt PTEN IHC to rule out the possibility of CS.
Zhang X, Wang Z, Wang L
… +8 more, Gong S, Pang L, Zhang S, Li M, Zhang C, Chen Y, Li Z, He W
Histopathology
· 2026 May · PMID 41456878
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AIMS: The incidence and mortality rates of colorectal cancer (CRC) are increasing worldwide. We aimed to construct a novel classification system, Risk Score, based on the histopathological tumour microenvironment and ass...AIMS: The incidence and mortality rates of colorectal cancer (CRC) are increasing worldwide. We aimed to construct a novel classification system, Risk Score, based on the histopathological tumour microenvironment and assess its prognostic value in primary operable CRC. METHODS AND RESULTS: Patients with stage I-III CRC who underwent radical resection between January 2020 and September 2021 were recruited. Eligible patients were randomized in a 1:1 ratio into a training cohort and a validation cohort. Tumour budding, tumour-stromal type, tumour-infiltrating lymphocytes, and tumour-stroma ratio were evaluated using the H&E sections of all excised specimens. The Risk Score was then developed on the basis of these four histopathological features, and its prognostic value was analysed. In the training cohort, patients with a high-Risk Score had shorter disease-free survival (DFS; HR 2.58, 95% CI: 1.78-3.72, P < 0.001) and overall survival (OS; HR 2.85, 95% CI: 1.74-4.67, P < 0.001) compared with those with a low Risk Score. Multivariate analysis revealed that the Risk Score remained an independent prognostic indicator of DFS and OS. These findings were confirmed in the validation cohort. A nomogram integrating all independent variables was also established to predict the individual risk of recurrence. CONCLUSION: In this study, we developed a prognostic model to accurately predict disease progression and mortality in operable CRC and to guide adjuvant chemotherapy.