Histopathology[JOURNAL]
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200 papers
A minor high-grade component in non-invasive papillary urothelial carcinoma is not associated with a more indolent behaviour.
Farag MS, Oghbaei N, Hussain J … +3 more , Lametti A, Kassouf W, Brimo F
Histopathology · 2026 Jun · PMID 41456876 · Full text
AIMS: The latest WHO edition proposed using a cut-off of ≥5% high-grade component (%HGc) as a criterion to label non-invasive papillary urothelial carcinomas as high-grade (pTaHG). It also suggested that tumours with min...
AIMS: The latest WHO edition proposed using a cut-off of ≥5% high-grade component (%HGc) as a criterion to label non-invasive papillary urothelial carcinomas as high-grade (pTaHG). It also suggested that tumours with minor high-grade component behave more indolently and are better labelled as mixed low- and high-grade papillary carcinomas. METHODS AND RESULTS: We investigated the prognostic value of %HGc along with other clinical and morphological parameters. 130 pTaHGs and 96 pTaLGs were included. 9% and 12% of pTaHGs had ≤5% and ≤10% HGc, respectively. Anaplasia was present in six cases (5%), necrosis in 18 cases (14%) and CIS in 5 cases (4%). On average, the highest mitotic count per 1 HPF was 2.4 (range = 0-18), and the mean number of mitoses per 10 HPF was 9 (range: 0-93). The mean tumour diameter was 2.1 cm. Tumour multifocality was observed in 32 cases (25%). Among the histological parameters, only mitotic activity showed a correlation with the %HGc (P < 0.001). While recurrence was not significantly different between pTaLGs and pTaHGs (25% vs 35%; P = 0.09), stage progression was significantly different (0% vs 8%; P = 0.005). The two parameters that were associated with recurrence in pTaHGs were tumour multifocality and BCG therapy, while none was associated with progression. %HGc ≤5% and ≤ 10% did not correlate with lower rates of recurrence nor progression. CONCLUSIONS: Those findings suggest that pTaHGs with minor HGc do not exhibit more indolent behaviour and should not be approached similar to pTaLGs. [Correction added on 13 April 2026, after first online publication: This version changes the preceding sentence from "should be approached" to "should not be approached".].
Correct diagnosis of patients with fibrolamellar carcinoma: A Dutch nationwide study.
Furumaya A, Gumede A, Weeda VB … +8 more , Cillessen S, van der Geest L, Erdmann J, Takkenberg RB, Doukas M, de Vos-Geelen J, Verheij J, Dutch Hepatocellular & Cholangiocarcinoma Group (DHCG)
Histopathology · 2026 May · PMID 41456874 · Publisher ↗
AIMS: Fibrolamellar carcinoma (FLC) is a rare primary liver cancer. Adequate diagnosis is essential for appropriate treatment. The current study evaluates the diagnosis of fibrolamellar carcinoma in a Dutch cohort. METHO...
AIMS: Fibrolamellar carcinoma (FLC) is a rare primary liver cancer. Adequate diagnosis is essential for appropriate treatment. The current study evaluates the diagnosis of fibrolamellar carcinoma in a Dutch cohort. METHODS AND RESULTS: Adult patients diagnosed with FLC between 1990 and 2020, with pathology slides and clinical data available, were included. Two expert hepatopathologists revised all slides, including CD68 and CK7 stainings. In total, 54 adult patients diagnosed with FLC were included. Biopsies were available for 31 patients (57%) and resection or transplantation specimens in 23 patients (43%). Upon expert review, in nine patients (17%), the diagnosis of FLC was unequivocally confirmed. Four additional lesions harboured characteristics of both FLC and conventional hepatocellular carcinoma (HCC). Three patients exhibited histomorphological features suggestive of FLC, yet with negative CD68 staining. In the remaining 38 patients, the diagnosis was revised to intrahepatic cholangiocarcinoma (iCCA, n = 7, 13%), combined HCC/iCCA (n = 5, 9.3%) and conventional HCC (n = 26, 48%, of which 11 were steatohepatitic and 10 scirrhous subtypes). CONCLUSIONS: The presence of extensive fibrosis in both iCCA and conventional HCC may result in misdiagnosis of FLC, in particular for the steatohepatitic and scirrhous variants of HCC. Misdiagnosis has important treatment consequences, as evidence supporting the efficacy of systemic treatments for FLC remains limited and extensive resection is the only curative option. Our Dutch historical cohort underlines the challenging diagnosis of FLC and emphasizes the critical role of expert review in accurate diagnosis.
Human papilloma virus infection and mismatch repair protein expression in sebaceous neoplasms of the genital area.
Wiedemeyer K, Al-Shamma Z, Köbel M … +3 more , Ferreira I, Harms PW, Brenn T
Histopathology · 2026 May · PMID 41456873 · Full text
AIMS: This study aimed to investigate the clinical and histopathological features of sebaceous tumours of the genital area and their association with human papilloma virus (HPV) infection and mismatch repair (MMR) protei...
AIMS: This study aimed to investigate the clinical and histopathological features of sebaceous tumours of the genital area and their association with human papilloma virus (HPV) infection and mismatch repair (MMR) protein deficiency. METHODS AND RESULTS: Ethical approval was obtained, haematoxylin and eosin (H&E)-stained sections were reviewed, and immunohistochemistry (IHC) for p16, p53, mismatch repair proteins and HPV RNA-in-situ hybridization or HPV genotyping were performed. Clinical follow-up was retrieved from patient records. Six tumours presented in adulthood (median: 69; range: 48-73 years; M:F = 2:1) and were located on the penis, mons pubis and labia majora (median size 1.3 cm). There were four sebaceous carcinomas, one sebaceoma and one sebaceous adenoma. Three of four sebaceous carcinomas showing an overlying in-situ component were positive for high-risk HPV-ISH or subtypes, p16 block positive and p53 wild-type by IHC. The sebaceous adenoma showed loss of mismatch repair proteins and was associated with Muir-Torre syndrome (MTS), while all remaining tumours showed intact MMR protein staining, were negative for HPV, and p16 and p53 wildtype by IHC. The patient with MTS died of oesophageal adenocarcinoma; all other patients were alive without recurrences (median follow-up: 16 months, range 7-60 months). CONCLUSIONS: In conclusion, the study emphasizes a pathogenetic role of HPV in genital sebaceous carcinomas that typically present with an in-situ component.
Tall cell carcinoma with reversed polarity of the breast harbouring IDH1 hotspot mutation: morphologic, immunohistochemical and genetic characterization of two cases.
Krings G, Hashem S, Apushkin MA … +2 more , Ang-Rabanes TL, Hoda RS
Histopathology · 2026 May · PMID 41456872 · Publisher ↗
AIMS: Tall cell carcinomas with reversed polarity (TCCRPs) are rare, indolent triple negative or oestrogen receptor (ER)-low positive breast cancers classically characterized by solid-papillary and papillary proliferatio...
AIMS: Tall cell carcinomas with reversed polarity (TCCRPs) are rare, indolent triple negative or oestrogen receptor (ER)-low positive breast cancers classically characterized by solid-papillary and papillary proliferations of eosinophilic columnar cells with reversed nuclear polarity. IDH2 R172 mutations are key oncogenic drivers in the majority of TCCRPs, exemplary of genotype-phenotype correlation among breast tumours. Other extramammary tumour types with IDH2 mutations can alternatively harbour analogous mutually exclusive IDH1 R132 mutations that appear to have similar effects on genome methylation, cellular differentiation and tumorigenesis. A prior report of a single IDH1-mutated TCCRP suggests extension of the IDH1/2 dichotomy to TCCRPs, but such exceedingly rare tumours have not been further characterized. METHODS AND RESULTS: We identified two cases of TCCRP with IDH1 R132C mutation presenting in postmenopausal females and herein detail their clinical, histomorphologic, immunophenotypic and genetic features. The tumours showed disparate histologic features, with one ER-positive case closely mimicking an intraductal papilloma with florid usual ductal hyperplasia (UDH) and the other triple negative case demonstrating more classic features of TCCRP. The immunoprofiles in both cases were similar to TCCRP with IDH2 mutation. By targeted next-generation sequencing, both tumours harboured IDH1 R132C and PIK3CA H1047R mutations. Both patients underwent surgical excision without radiation therapy and were without disease at last follow-up. CONCLUSIONS: This study expands the genetic and morphologic repertoire of TCCRP with implications and pitfalls for accurate diagnosis. The findings highlight the IDH1/IDH2 dichotomy with convergence of phenotype in these rare breast tumours.
Tumour budding in pretreatment cervical biopsies: a prognosticator for personalised therapy in the era of precision oncology.
Lee YS, Yim K, Kim CJ … +8 more , Kim JH, Lee YS, Jeong S, Lee SH, Bizzarri N, Permata TBM, Kim YS, Lee SW
Histopathology · 2026 Apr · PMID 41449070 · Publisher ↗
AIMS: Tumour budding (TB) is a noteworthy morphologic indicator for tumour microenvironment (TME) especially because it is detectable with routine haematoxylin and eosin (H&E) staining. Its prognostic relevance has been...
AIMS: Tumour budding (TB) is a noteworthy morphologic indicator for tumour microenvironment (TME) especially because it is detectable with routine haematoxylin and eosin (H&E) staining. Its prognostic relevance has been demonstrated across various cancers, but its significance in pretreatment biopsy specimens of cervical cancer is unknown. This is the first study to investigate the prognostic value of TB in pretreatment cervical biopsy. Additional TME features identifiable with H&E such as cell nest size (CNS) were evaluated. METHODS AND RESULTS: A retrospective review was conducted on the 2018 International Federation of Gynaecology and Obstetrics (FIGO) stage IIVA cervical cancer patients (N = 182) who had completed standard treatment. In multivariate analysis, TB (hazard ratio [HR], 2.06) and CNS (HR, 2.16) independently predicted overall survival. While TB (AUC, 0.7065) slightly outperformed CNS (AUC, 0.6975) in discriminating overall survival, the combination of TB and CNS demonstrated the highest performance (AUC, 0.7192) in time-dependent receiver operating characteristic analysis. CONCLUSIONS: This study is the first to suggest TB in pretreatment biopsy specimens as a reliable morphologic prognosticator in cervical cancer. TME features may enhance precision oncology by offering insights into the individual tumour biology. The fact that these morphologic features are available from routine H&E slides, reserving immunohistochemistry or molecular analysis for indeterminate cases, is of particular value in low-resource settings where the burden of cervical cancer is most significant.
GREB1-rearranged uterine tumour shares a common DNA methylation signature with ESR1-rearranged UTROSCT.
Lee CH, Lee YS, Bennett JA … +10 more , Kolin DL, Lee JC, Huang HY, Köbel M, Sementsov M, Dickson BC, Koelsche C, Kommoss F, von Deimling A, Kommoss FKF
Histopathology · 2026 Apr · PMID 41424301 · Full text
BACKGROUND AND OBJECTIVES: GREB1-rearranged uterine tumours encompass a group of uterine mesenchymal tumours with varied histologic appearances. The fusion partners to GREB1 include NCOA1-3, SS18 and NR4A3. Given that so...
BACKGROUND AND OBJECTIVES: GREB1-rearranged uterine tumours encompass a group of uterine mesenchymal tumours with varied histologic appearances. The fusion partners to GREB1 include NCOA1-3, SS18 and NR4A3. Given that some GREB1-rearranged uterine tumours exhibit histologic features of uterine tumours resembling ovarian sex cord tumour (UTROSCT), there is a general belief that GREB1-rearranged uterine mesenchymal tumours are part of the UTROSCT family. METHODS: In this study, we applied global DNA methylation and copy number analyses to a series of 10 GREB1-rearranged uterine tumours and 21 classic UTROSCTs (7 of which were molecularly confirmed to harbour ESR1::NCOA2/3 fusions). RESULTS: We found that GREB1-rearranged uterine tumors show an overlap in their global methylation profiles with UTROSCT, including ESR1::NCOA2/3 positive cases. Together, these tumours form a DNA methylation cluster separate from uterine smooth muscle tumours (leiomyomas and leiomyosarcomas), endometrial stromal sarcomas (low-grade and high-grade), embryonal rhabdomyosarcoma and SMARCA4-deficient uterine sarcomas. However, despite their epigenetic similarity, there were two notable differences. First, GREB1-rearranged uterine tumours as a group displayed a greater degree of genomic complexity with more extensive copy number alterations than conventional UTROSCTs, including those harbouring ESR1::NCOA2/3. Second, GREB1-rearranged uterine tumours frequently lacked overt sex cord morphology: while all 7 ESR1::NCOA2/3 UTROSCTs demonstrated corded, nested, trabecular and/or tubular/sertoliform patterns, only 1 GREB1-rearranged uterine tumour displayed a prominent trabecular pattern, with the remaining cases showing exclusively or predominantly diffuse/solid growth. CONCLUSIONS: Overall, our findings confirm that GREB1-rearranged uterine tumours are part of the UTROSCT spectrum, though they frequently exhibit a more diffuse growth pattern and a higher degree of genomic instability.
Claudin-18 expression in gastric type adenocarcinoma and HPV-associated adenocarcinoma of the uterine cervix.
Yasutake N, Yokawa Y, Tanaka T … +10 more , Mishima R, Komamizu M, Kuga R, Jiromaru R, Kawatoko S, Sonoda K, Yahata H, Kato K, Oda Y, Yamamoto H
Histopathology · 2026 Apr · PMID 41424299 · Full text
AIMS: Claudin-18 (CLDN18) is both a marker for the gastric phenotype and a therapeutic target. However, little is known about its immunoexpression in endocervical adenocarcinomas (ECAs), particularly as detected using th...
AIMS: Claudin-18 (CLDN18) is both a marker for the gastric phenotype and a therapeutic target. However, little is known about its immunoexpression in endocervical adenocarcinomas (ECAs), particularly as detected using the clone 43-14A antibody, or about the gene expression of its isoforms in ECAs. METHODS AND RESULTS: We examined CLDN18, HIK1083, p16 and Rb expression by immunohistochemistry and high-risk human papillomavirus (HR-HPV) mRNA by in situ hybridization (ISH) in 121 ECAs, including 35 HPV-independent adenocarcinomas (gastric type [GAS], n = 24; non-GAS, n = 11) and 86 HPV-associated ECAs. We also analysed mRNA expression of the CLDN18.1 (lung type) and CLDN18.2 (gastric type) isoforms by quantitative polymerase chain reaction (qPCR) in selected cases. CLDN18 positivity was detected in 8/24 (33%) GASs, 0/11 (0%) non-GASs and 2/86 (2%) HPV-associated ECAs, with positivity defined as staining in ≥75% of tumour cells, as in gastric cancer. When a 5% cut-off was used, CLDN18 positivity was detected in 22/24 (92%) GASs, 0/11 (0%) non-GASs and 6/86 (7%) HPV-associated ECAs; CLDN18 expression was thus significantly associated with GAS histology (P < 0.0001). Among the 6 cases of HPV-associated ECAs with CLDN18 expression (ranging from 5% to 80%), the histological patterns included a mix of usual and mucinous features in 4 cases, pure usual type in 1 and villoglandular variant in 1. Otherwise features such as p16 overexpression and the Rb partial loss pattern were consistent with those of HPV-associated ECAs. Six of 22 (27%) CLDN18-positive GASs were also positive for p16, but their other features-such as CLDN18 expression and the Rb preserved pattern-were the same as in p16 negative GASs. Expression of CLDN18.2 mRNA but not CLDN18.1 mRNA was confirmed in both GASs and HPV-associated ECAs. CONCLUSIONS: CLDN18 (43-14A) emerged as a potential diagnostic and therapeutic marker for GAS. A minor subset of HPV-associated ECAs also can be immunoreactive for CLDN18 and express CLDN18.2 mRNA, suggesting divergent gastric phenotypic differentiation. The caution is that GAS and HPV-associated ECAs can share overlapping histological features and similar expression of CLDN18 and p16.
Mucinous metaplasia in a mixed epithelial and stromal tumour of the seminal vesicle: a potential precursor to mucinous adenocarcinoma.
Tuffa NT, Sheldon E, Oliveira P
Histopathology · 2026 Apr · PMID 41424297 · Publisher ↗
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Well-differentiated papillary mesothelial tumour: histologic, molecular and genetic features support a benign clonal neoplasm despite diffuse peritoneal involvement.
Leduc C, Rahimi K, Mercier F … +5 more , Haegert A, Volik S, LeBihan S, Collins C, Churg A
Histopathology · 2026 Apr · PMID 41424264 · Publisher ↗
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The spectrum of breast in situ papillary carcinomas with invasion and invasive breast carcinomas with papillary features: an overview of histological subtypes and diagnostic challenges.
Rakha EA, Tan PH, Raymond WA
Histopathology · 2026 Mar · PMID 41404713 · Full text
Invasive breast carcinomas with papillary features (IBCP) constitute a distinct and morphologically diverse group of breast cancers characterised by varying degrees of papillary architecture and invasive behaviour. IBCP...
Invasive breast carcinomas with papillary features (IBCP) constitute a distinct and morphologically diverse group of breast cancers characterised by varying degrees of papillary architecture and invasive behaviour. IBCP encompass (1) papillary carcinoma in situ associated with invasion, (2) invasive solid papillary carcinoma (ISPC), (3) encapsulated papillary carcinoma (EPC)-like invasive carcinoma, (4) Papillary DCIS-like invasive carcinoma, (5) high-grade carcinomas with EPC-like or SPC-like morphology, and (6) invasive papillary carcinoma not otherwise specified (IPC), including the tubulopapillary pattern. This review summarises the evolving classification, histopathological features, diagnostic criteria, differential diagnoses, clinical prognosis, and treatment implications of various subtypes of IBCP. Particular attention is given to the diagnostic challenges and clinical relevance of recognising these tumour types. Standardised diagnostic criteria and further research into the biological behaviour of these entities are essential to guide appropriate management and improve prognostication.
Reconsidering clinical translation of margin clearance and ablation in Barrett's-related endoscopic mucosal resection.
Wu Q, Wang L, Gao F … +1 more , Lei T
Histopathology · 2026 Mar · PMID 41404710 · Publisher ↗
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Papillary renal cell carcinoma, formerly known as Type 2: a single institutional study addressing histologic and molecular features.
Tjota MY, Kwon JW, Wanjari P … +1 more , Antic T
Histopathology · 2026 Apr · PMID 41400361 · Full text
AIMS: Papillary renal cell carcinoma (pRCC) accounts for 15%-20% of RCC cases and is the second most common histologic subtype of RCC. In contrast to other common RCC subtypes, there continues to be ongoing debate about...
AIMS: Papillary renal cell carcinoma (pRCC) accounts for 15%-20% of RCC cases and is the second most common histologic subtype of RCC. In contrast to other common RCC subtypes, there continues to be ongoing debate about how to classify RCCs with papillary architecture and eosinophilic cytoplasm given the heterogeneity of histologic, IHC and molecular findings. Our study set out to characterize the histologic features and molecular alterations in cases that were originally diagnosed as pRCC, Type 2 or high-grade pRCC in a single institutional study (n = 63). METHODS AND RESULTS: Histologically, the vast majority of the cases had a papillary pattern (n = 59). There were three cases that had a mixed solid and papillary pattern and one case that had a sarcomatoid architectural pattern. The cases were composed of large cells with eosinophilic cytoplasm, pseudostratified or apically oriented nuclei and prominent nucleoli. Molecular analysis of these cases revealed a wide range of genes that were mutated, with the most common ones being SETD2 (n = 9), PBRM1 (n = 5), KDM6A (n = 7), PMS2 (n = 4), NF2 (n = 7) and TERT (n = 7). Our study further identified cases that had molecular mutations in the RTK/RAS pathway (KRAS and NRAS), PI3K pathway (TSC2), TP53 pathway (TP53 and CHEK2) and copy number alterations in the cell cycle pathway (CDKN2A and CCND3). CONCLUSIONS: These findings highlight the need to molecularly characterize these lesions as there is no specific histologic finding to identify cases that harbour different pathogenic alterations in specific genes.
Apocrine encapsulated papillary carcinoma: a comprehensive clinicopathological analysis of 28 cases.
Zuo K, Shui R, Xu X … +7 more , Yu B, Tu X, Cheng Y, Tang S, Sun X, Bi R, Yang W
Histopathology · 2026 Apr · PMID 41395699 · Publisher ↗
AIMS: Encapsulated papillary carcinoma (EPC) is characterized by neoplastic epithelial cells of low-to-intermediate nuclear grade arranged along fibrovascular cores. Classical EPC typically expresses oestrogen receptor (...
AIMS: Encapsulated papillary carcinoma (EPC) is characterized by neoplastic epithelial cells of low-to-intermediate nuclear grade arranged along fibrovascular cores. Classical EPC typically expresses oestrogen receptor (ER) and usually progesterone receptor (PR), while lacking human epidermal growth factor receptor 2 (HER2) overexpression and gene amplification. In contrast, apocrine encapsulated papillary carcinoma (AEPC), an exceptionally rare tumour with only a few well-characterized cases, exhibits a triple-negative phenotype (ER-, PR-, HER2-). The purpose of this study is to investigate whether the clinicopathological characteristics of AEPC differ from those of classical EPC. METHODS: Since 2014, 28 cases of AEPC have been identified at the Department of Pathology, Fudan University Shanghai Cancer Centre. We conducted a comprehensive clinicopathological evaluation and prognostic assessment in this case series. RESULTS: All 28 patients in our study were female, with a median age at diagnosis of 61.5 years (range: 34-90). Fifteen cases were consultation referrals, while 13 cases were diagnosed and treated at our centre. Histologically, all AEPC cases demonstrated cystic architecture with papillary growth patterns. The papillary structures were lined by cells exhibiting uniform apocrine differentiation. The degree of cellular atypia ranged from mild-to-moderate, with no severe atypia identified. Notably, myoepithelial cells were absent in both the papillary structures and lesion peripheries. Among the 28 AEPC cases, 18 were non-invasive, 8 demonstrated microinvasion (<1 mm), and 2 exhibited frank invasion (1-4 mm). The tumour cells exhibited a triple-negative profile and most cases presented with diffuse positivity for androgen receptor (AR) and gross cystic disease fluid protein 15 (GCDFP15). The median Ki-67 proliferation index was 10% (range: 5%-20%). Among the 28 patients, 19 received no adjuvant therapy, while 9 underwent postoperative radiotherapy and/or chemotherapy. With a median follow-up of 44.3 months (range: 7.4-135.5 months) for 27 patients, no recurrences or metastases were observed. CONCLUSION: Classical EPC typically demonstrates favourable prognosis and is managed as ductal carcinoma in situ. In our study, none of the AEPC patients developed recurrence or metastasis, regardless of adjuvant therapy administration. Although AEPC exhibits a triple-negative immunophenotype, it differs biologically from conventional triple-negative breast cancer (TNBC). The indolent behaviour of AEPC aligns more closely with classical EPC rather than TNBC. Therefore, it may be more appropriate to treat AEPC patients using the same strategies applied to classical EPC.
Next-generation sequencing-based IG clonality analysis to discriminate reactive infiltrates from minimal lymphoma involvement in paired lymphoma and bone marrow biopsies; a EuroClonality-NGS Working Group study.
van den Brand M, Leenders M, Rijntjes J … +4 more , Luijks JACW, Langerak AW, Hebeda KM, Groenen PJTA
Histopathology · 2026 Apr · PMID 41395696 · Full text
AIMS: Bone marrow (BM) biopsy is an important procedure in B-cell lymphoma staging. In most biopsies, the presence or absence of a lymphoma infiltrate can reliably be determined by standard histology. However, in a subse...
AIMS: Bone marrow (BM) biopsy is an important procedure in B-cell lymphoma staging. In most biopsies, the presence or absence of a lymphoma infiltrate can reliably be determined by standard histology. However, in a subset of cases with limited infiltration, this assessment remains inconclusive, requiring an alternative approach. Next-generation sequencing (NGS)-based detection of immunoglobulin (IG) gene rearrangements has the potential for resolving these difficult cases because of its high sensitivity. In this study, we tested the NGS-based IG clonality protocol developed by the EuroClonality-NGS Working Group on BM staging biopsies. METHODS AND RESULTS: Forty-nine BM biopsies ranging from morphologically and immunohistochemically evidently involved to negative were analysed and compared to the original lymphoma. A clear distinction in the abundance of overlapping clonal IG rearrangements was observed between BM biopsies that were positive versus negative for lymphoma based on morphology and immunohistochemistry. In the 12 BM biopsies in which morphology and immunohistochemistry were insufficient to differentiate between the presence or absence of lymphoma, the estimated B-cell infiltration ranged from 1% to 5%. In these cases, NGS-based IG clonality analysis of paired primary lymphoma/BM biopsies provided a binary outcome; a subset of cases with hardly or no primary lymphoma-derived IG gene rearrangements in the BM biopsy could be distinguished from cases with clear presence of primary lymphoma-derived IG gene rearrangements. CONCLUSIONS: Our data demonstrated that paired NGS-based IG clonality analysis of lymphoma and BM samples can be a valuable additional tool for difficult BM staging biopsies in patients with B-cell lymphoma.
Ovarian Sertoli-Leydig cell tumors with heterologous rhabdomyosarcoma: Clinicopathologic features and molecular analysis highlighting recurrent genetic alterations.
Zou YS, Mohammed SY, Zhu J … +6 more , Dashti NK, Smith C, Sun Y, Vang R, McCluggage WG, Xing D
Histopathology · 2026 Apr · PMID 41395670 · Publisher ↗
AIMS: Ovarian Sertoli-Leydig cell tumor (SLCT) with heterologous rhabdomyosarcoma (RMS) is exceptionally rare. While the presence of heterologous elements in SLCT is highly predictive of an underlying DICER1 mutation, th...
AIMS: Ovarian Sertoli-Leydig cell tumor (SLCT) with heterologous rhabdomyosarcoma (RMS) is exceptionally rare. While the presence of heterologous elements in SLCT is highly predictive of an underlying DICER1 mutation, the molecular alterations in these tumors, including in SLCTs with heterologous RMS, remain largely unknown. In this study, we aimed to characterize the clinicopathologic features of these rare tumors, and in a subset of cases, we analyzed in detail their molecular changes to investigate potential recurrent and component-specific genetic alterations. METHODS AND RESULTS: We report clinicopathologic features of 11 ovarian SLCTs with heterologous RMS (positivity for desmin and myogenin); 10 were in keeping with embryonal and 1 with pleomorphic RMS. The patients showed a bimodal age distribution: seven patients (64%) were aged 33 years or younger (mean 20) and four patients (36%) were aged 52 years or older (mean 60). All tumors were unilateral. In addition to the RMS components, 8 of 11 cases (73%) contained other heterologous elements, including gastrointestinal-type mucinous epithelium (5 cases) and immature cartilage (3 cases). Seven of 11 cases (64%) underwent next-generation sequencing analysis. All tumors tested molecularly (7/7, 100%) harbored hotspot DICER1 mutations. Of these, six cases (86%) also carried a second nonsense or frameshift loss-of-function DICER1 mutation. One case had only a p.D1810Y hotspot mutation and consisted of high-grade sarcoma with focal rhabdomyoblastic differentiation (focal expression of desmin and myogenin) in keeping with pleomorphic RMS; the pleomorphic sarcoma component also exhibited mutation-type p53 expression. In addition to DICER1 mutations, TERT c.-124C>T promoter (4 cases) or TP53 mutations (3 cases) were present in all cases and were mutually exclusive. Component-specific analysis in two cases revealed shared common DICER1 hotspot mutations in both the SLCT and RMS components, supporting a clonal origin. In 1 case, a TERT promoter c.-124C>T somatic mutation was present only in the RMS component. In the other case, the TERT promoter mutation was found in both components, while a BRAF p.V600E mutation was exclusive to the RMS component. CONCLUSION: Our study demonstrates that the majority (86%) of SLCTs with heterologous RMS harbor double DICER1 mutations (a hotspot mutation and a nonsense or frameshift loss-of-function mutation), supporting the existing knowledge on DICER1 mutations associated with RMS heterologous elements, the presence of which should trigger genetic counselling. Our findings also suggest that molecular alterations other than DICER1, namely, TERT promoter and TP53 mutations, may contribute to component-specific oncogenic transformation.
New insights in metaplasia in autoimmune gastritis.
Driva TS, Sakellariou S, Theochari I … +3 more , Gadetsakis G, Koutsoumpas A, Delladetsima I
Histopathology · 2026 Apr · PMID 41395669 · Publisher ↗
AIMS: Metaplastic alterations of oxyntic mucosa in autoimmune gastritis (AIG) remain under investigation. This study aimed to characterize pyloric gland-like and intestinal metaplasia (IM) in AIG and assess their origin...
AIMS: Metaplastic alterations of oxyntic mucosa in autoimmune gastritis (AIG) remain under investigation. This study aimed to characterize pyloric gland-like and intestinal metaplasia (IM) in AIG and assess their origin and prognostic significance. METHODS: A retrospective analysis of 147 H. pylori-negative AIG gastric biopsies was conducted. Twenty cases underwent immunohistochemical staining for MUC5AC, MUC6 and TFF2, and double immunostaining for MUC6-CDX2, MUC5AC-CDX2 and TFF2-CDX2. RESULTS: Corpus mucosa showed pyloric gland-like metaplasia in 98.6% (145/147) and IM in 81.6% (120/147) of cases; IM was complete in 99.2% (119/120). Epithelial dysplasia was absent; one signet-ring cell carcinoma was identified. Most cases were OLGA stage II (92.5%) and OLGIM stage I (58.5%). Metaplastic pyloric-like glands expressed MUC6, the mucin of normal antral glands, but also MUC5AC, the mucin of gastric pits and surface epithelium, a combination congruent with a distinct metaplastic subtype. All cases exhibited biphenotypic gastric mucous cells co-expressing MUC5AC-CDX2 (median 4.8% of MUC5AC-positive cells) and MUC6-CDX2 (median 3.1% of MUC6-positive cells) in glands and surface/foveolar epithelium. Glands with a mixed cellular population showing mucinous, biphenotypic, intestinal and intermediate 'transition' features provided further evidence of intestinal trans-differentiation. TFF2 was present in 25% (5 cases), in few glandular cells without CDX2 co-expression. CONCLUSIONS: Oxyntic mucosa metaplasia in AIG constitutes a complex phenomenon of successive phases of cellular plasticity characterized by the appearance of a distinct pyloric-like metaplastic subtype followed by intestinal trans-differentiation. The autoimmune metaplastic background appears non-carcinogenic regarding intestinal-type adenocarcinoma development.
Prostate cancer molecular subtypes in systematic versus MRI-targeted biopsy cores at active surveillance: association of PTEN and ERG status with extreme grade reclassification.
de la Calle CM, Dairo OO, Su ZT … +11 more , Jing Y, Wang Z, Nishimura A, Amaral A, Oliveira LD, Erak E, Landis P, Macura KJ, Trock BJ, Pavlovich CP, Lotan TL
Histopathology · 2026 Apr · PMID 41395658 · Publisher ↗
AIMS: Biomarkers are needed to identify patients with favourable-risk prostate cancers who could benefit from treatment versus active surveillance (AS). MRI-targeted biopsies may allow for better sampling of the 'dominan...
AIMS: Biomarkers are needed to identify patients with favourable-risk prostate cancers who could benefit from treatment versus active surveillance (AS). MRI-targeted biopsies may allow for better sampling of the 'dominant' tumour and therefore more accurate risk stratification. We evaluated ERG fusions and PTEN loss for predicting subsequent grade reclassification (GR) in a multiparametric MRI-screened cohort, comparing results in systematic versus targeted biopsies. METHODS AND RESULTS: Validated immunohistochemistry assays for ERG and PTEN were performed on all cancer-containing cores of early AS biopsies, in a cohort of 127 Grade Group (GG) 1 AS patients with targeted and systematic biopsies. ERG fusions were identified in 43% of the cohort- 24% of these cases exhibited heterogeneous (subclonal or multi-clonal) ERG expression in sampled tumour. PTEN loss was identified in 16% of the cohort and all cases were heterogeneous. Neither ERG fusions nor PTEN loss were more likely to be found in targeted versus systematic cores. On multivariable Cox proportional hazard regression, PTEN loss was associated with extreme GR on subsequent biopsy (to GG ≥3) (hazard ratio [HR] 9.27, 95% confidence interval [CI] 2.10-40.9, P = 0.003) but ERG fusion was not (HR 2.82, CI 0.73-10.9, P = 0.13). PTEN loss was most strongly associated with this outcome when measured in systematic biopsy cores. CONCLUSIONS: Frequent ERG heterogeneity suggests prevalent multiclonal disease in MRI-visible low-risk prostate cancers. Higher risk AS patients might benefit from PTEN loss evaluation to predict extreme GR, in both targeted and systematic biopsies, since targeted biopsies were not more likely to identify PTEN loss.
RB1 inactivation in cutaneous carcinomas.
Liv T, Touzé A, Schrama D … +6 more , Guyétant S, Samimi M, Tetzlaff MT, Wood BA, Harms PW, Kervarrec T
Histopathology · 2026 Mar · PMID 41395640 · Full text
RB1 was the first identified tumour suppressor gene, named for its crucial role in opposing retinoblastoma oncogenesis. The RB1 gene encodes the retinoblastoma protein pRB, which is a well-known negative regulator of the...
RB1 was the first identified tumour suppressor gene, named for its crucial role in opposing retinoblastoma oncogenesis. The RB1 gene encodes the retinoblastoma protein pRB, which is a well-known negative regulator of the cell cycle. However, pRB also contributes to cell differentiation by restricting reprogramming and stem cell properties. Accordingly, RB1 inactivation in tumours can induce phenotypic modifications, contributing to tumour progression. Indeed, RB1 pathogenic alterations, either point mutations or deletions, leading to pRB loss of function are observed in 5% of all human cancers. Mutations are much more prevalent in some histologic subgroups, including retinoblastoma, spindle cell lipoma, neuroendocrine prostate cancer and small cell lung carcinoma. In such entities, molecular investigation of tumour samples and mechanistic studies strongly suggest that early RB1 inactivation contributes not only to dysregulation of cell cycle control, but also to the tumour cell phenotype. Among skin carcinomas, RB1 inactivation is the hallmark of primary cutaneous neuroendocrine carcinoma commonly known as Merkel cell carcinoma (MCC), but it has also been described in other tumours including a subset of squamous cell carcinomas, sebaceous carcinomas and the recently described Wnt/beta-catenin-activated non-pilomatrical carcinomas. In this context, we provide a brief overview of the contribution of RB1 inactivation to oncogenesis and tumour cell phenotypes in general and summarise current knowledge regarding RB1-deficient cutaneous carcinomas, highlighting the potential uses of RB1 pathway characterisation for diagnosis, prognosis and therapeutic purposes.
Diagnosing oncocytic renal tumours on renal mass biopsy; pathological concordance and the impact of evolving classification.
Al Qa'qa' S, Cheung CC, Krishna S … +2 more , Finelli A, Prendeville S
Histopathology · 2026 Apr · PMID 41393004 · Full text
AIMS: Renal tumours with oncocytic morphology are among the most difficult to classify at renal mass biopsy (RMB), and a number of emerging entities with low-grade oncocytic morphology have been recently described. This...
AIMS: Renal tumours with oncocytic morphology are among the most difficult to classify at renal mass biopsy (RMB), and a number of emerging entities with low-grade oncocytic morphology have been recently described. This study aimed to evaluate pathological concordance between RMB and subsequent nephrectomy or repeat biopsy for oncocytic renal neoplasms and to identify pathological factors contributing to diagnostic discordance, including the impact of evolving tumour classification. METHODS AND RESULTS: We retrospectively reviewed 145 cases of oncocytic renal neoplasms diagnosed on RMB, including 114 with subsequent nephrectomy and 31 with repeat biopsy only. Overall concordance was 92.9% between RMB and nephrectomy and 96.7% between initial and repeat RMB. Concordance for oncocytoma at nephrectomy was lower (81.4%), likely reflecting selection bias, but was 100% in cases with repeat biopsy. Review of discordant cases (n = 9) revealed that 55% (5/9) were reclassified as emerging tumour entities, specifically low-grade oncocytic tumour (LOT) and eosinophilic vacuolated tumour (EVT). Additional discordant cases were due to heterogeneous tumour morphology in chromophobe renal cell carcinoma (ChRCC) and incomplete immunohistochemical work-up leading to misclassification of rarer renal cell carcinoma subtypes. CONCLUSIONS: Despite inherent diagnostic challenges, there was overall good concordance between RMB and nephrectomy or subsequent biopsy for the diagnosis of oncocytic tumours. Recognition of emerging tumour entities may reduce diagnostic uncertainty, improve classification in challenging cases, and further improve diagnostic concordance over time. Nonetheless, limitations of RMB, particularly related to tumour heterogeneity, highlight the importance of integrating pathological, clinical, and radiologic data to inform patient management.
Interobserver variability of histopathological assessment in pT1 colorectal carcinoma.
de Gordoa KS, Daca-Alvarez M, Rodrigo-Calvo M … +22 more , Archilla I, Lopez-Prades S, Aguirre JJ, Alarcón-Molero L, Jurado MC, Canosa A, Giner F, González-Lois C, Jimeno M, Jurado I, Machado I, Martínez-Ciarpaglini C, Musulen E, Naranjo D, Papaleo N, Peña C, Rosiñol Ò, Sánchez-Yuste R, Benítez GTV, Pellisé M, Cuatrecasas M, EpiT1 Consortium
Histopathology · 2026 Mar · PMID 41392996 · Full text
AIMS: Pathological evaluation of colorectal carcinoma (CRC) diagnosed at stage pT1 is challenging. Nevertheless, it is crucial for treatment guiding and to determine the patient's prognosis. This study aimed to assess th...
AIMS: Pathological evaluation of colorectal carcinoma (CRC) diagnosed at stage pT1 is challenging. Nevertheless, it is crucial for treatment guiding and to determine the patient's prognosis. This study aimed to assess the interobserver variability in the histopathological evaluation of pT1 CRC. METHODS AND RESULTS: A retrospective multicentre pT1 CRC cohort study was designed (EpiT1 consortium). A task force comprising 20 experienced pathologists conducted the histopathological evaluation using digitalized haematoxylin-eosin (H&E) slides. A pilot study was performed with 10 cases, and afterwards, a consensus meeting was held to assess interobserver variability. Then, a concordance study was performed by assessing 70 new pT1 CRC cases. We used percentage agreement and Gwet's Agreement Coefficient 1 for categorical variables, and intraclass correlation coefficient (ICC) for continuous variables. In the pilot study, histological grade and perineural invasion (PNI) demonstrated 100% agreement, with good concordance for lymphovascular invasion (LVI), tumour budding (TB), poorly differentiated clusters (PDC) and margin assessment. The concordance study showed high agreement (≥90%) on histological grade, PDC, PNI and LVI. Submucosal invasion depth showed excellent reliability in the concordance study (ICC = 0.97). Notably, in both studies, the agreement of PDC was higher than for TB. Lower concordance was observed on stromal lymphocytes and the status of muscularis mucosae. CONCLUSIONS: Our results emphasize the need for standardization in evaluating pT1 CRC to improve the concordance among pathologists, and the precision of digital measurements. Moreover, the addition of PDC assessment in pT1 CRC diagnostic guidelines could help to improve the accuracy of risk stratification and reliably predict prognosis.
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