Van De Ginste L, Vandendriessche A, De Vriese AS
… +10 more, Wetzels J, Van Laecke S, Nguyen TQ, Delforge M, Gallardo R, Schymkowitz J, Rousseau F, Impens F, Devos S, Dendooven A
Histopathology
· 2026 May · PMID 42130199
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Alfonso-Rosa C, Machuca-Aguado J, González-Suarez M
… +2 more, Conde-Martín AF, García-Escudero A
Histopathology
· 2026 May · PMID 42115147
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This salivary mucinous adenocarcinoma with intraductal papillary mucinous neoplasm-like features demonstrates regional lymph node metastases and GNAS amplification. The findings suggest these lesions represent low-grade...This salivary mucinous adenocarcinoma with intraductal papillary mucinous neoplasm-like features demonstrates regional lymph node metastases and GNAS amplification. The findings suggest these lesions represent low-grade invasive mucinous neoplasms with secondary ductal extension rather than purely intraductal entities, supporting their classification within the mucinous adenocarcinoma spectrum.
Wang CI, Jobbagy S, Giersch AB
… +6 more, Greer JB, Liu KX, Cote GM, Hung YP, Nielsen GP, Chebib I
Histopathology
· 2026 May · PMID 42099000
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INTRODUCTION: Dedifferentiated liposarcoma (DDLPS) is a typically non-lipogenic malignant neoplasm that arises from progression of an underlying atypical lipomatous tumour/well-differentiated liposarcoma (ALT/WDLPS) and...INTRODUCTION: Dedifferentiated liposarcoma (DDLPS) is a typically non-lipogenic malignant neoplasm that arises from progression of an underlying atypical lipomatous tumour/well-differentiated liposarcoma (ALT/WDLPS) and is classically defined by amplification of chromosome 12q15, including MDM2 and frequently cyclin-dependent kinase 4 (CDK4). Detection of MDM2 amplification by fluorescence in situ hybridization (FISH) and/or MDM2 protein expression immunohistochemistry (IHC) has, therefore, become central to the diagnosis of DDLPS, particularly in small biopsies from the retroperitoneum. Rare exceptions to this paradigm have been described, but the clinicopathologic and molecular spectrum of MDM2 non-amplified DDLPS remains poorly characterized. We report a series of MDM2 non-amplified DDLPS to better define their diagnostic features, genomic alterations and clinical behaviour. METHODS: Pathology archives from 2010 to 2025 were queried for cases diagnosed as DDLPS. Inclusion criteria required a high-grade sarcoma arising in a histologically confirmed ALT/WDLPS background, absence of MDM2 overexpression by IHC and lack of MDM2 amplification by FISH and/or single nucleotide polymorphism array. Clinicopathologic features, immunophenotype, treatment and outcomes were reviewed. RESULTS: Among 253 cases of DDLPS identified during the study period, four (1.6%) fulfilled criteria for MDM2-negative DDLPS. All tumours arose in the retroperitoneum or intra-abdominal soft tissues and demonstrated high-grade sarcoma morphology with an associated WDLPS component on resection. Despite the absence of MDM2 amplification, all cases showed strong CDK4 expression by IHC. Molecular analysis revealed recurrent alterations involving cell-cycle regulation, including CDK4 copy number gain in all cases and loss of CDKN2A in three. Two cases harboured TP53 alterations. Clinically, outcomes were heterogeneous, ranging from aggressive disease with rapid recurrence and death within months to prolonged disease-free survival exceeding 5 years. CONCLUSION: MDM2 non-amplified DDLPS represents a rare subset of DDLPS that appear to be driven by alternative mechanisms of cell-cycle dysregulation, most commonly involving CDK4 gain and CDKN2A loss, with occasional TP53 alterations. Awareness of this variant is critical to avoid misclassification as other high-grade sarcomas, particularly on limited biopsies, and underscores the importance of integrating morphology, IHC and broad genomic profiling in diagnostically challenging retroperitoneal sarcomas.
Zhao J, Yao J, Hosseini H
… +9 more, Baraban E, Lin R, Guo CC, Huo L, Lu W, Khan K, Wang S, Soto LMS, Ding Q
Histopathology
· 2026 May · PMID 42098986
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AIMS: Prostate cancer is one of the most common malignancies in men and a major cause of cancer-related mortality worldwide. While second-generation antiandrogens induce durable responses, they have also led to the emerg...AIMS: Prostate cancer is one of the most common malignancies in men and a major cause of cancer-related mortality worldwide. While second-generation antiandrogens induce durable responses, they have also led to the emergence of aggressive, androgen-independent subtypes of prostate cancer, including small cell carcinoma of the prostate. The diagnosis of these subtypes remains challenging due to the frequent loss of traditional prostatic markers, and novel prostate-specific markers are needed in routine pathology practice. METHODS AND RESULTS: Through analysis of the Cancer Genome Atlas (TCGA) database, we identified Forkhead box protein A1 (FOXA1) as a potential diagnostic marker for prostatic cancer. We compared FOXA1 and NKX3.1 expression in benign prostatic glands and prostatic adenocarcinoma; FOXA1 immunostaining demonstrated a similar nuclear staining pattern to NKX3.1 and a high sensitivity for prostatic adenocarcinoma. Notably, in small cell carcinoma of the prostate, which typically loses expression of traditional prostate markers, FOXA1 expression was detected in 8 of 10 (80%) primary cases and 12 of 21 (57%) metastatic cases in our cohort. We also evaluated FOXA1 expression across various tumour types and observed positivity in 25 of 44 (57%) breast carcinomas, 15 of 68 (22%) urothelial carcinomas and rarely in other tumour types. Among 106 neuroendocrine tumours/carcinomas from different organs, only 2 of 4 breast neuroendocrine carcinomas showed FOXA1 expression. CONCLUSIONS: FOXA1 is a highly sensitive diagnostic marker for prostate cancer. It can serve as a valuable adjunct for confirming prostatic origin in diagnostically challenging cases such as prostatic small cell carcinoma.
Na S, Lee KR, Jeon YK
… +6 more, Kim H, Lee JO, Lee JY, Kim SA, Yun H, Paik JH
Histopathology
· 2026 May · PMID 42093218
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AIMS: Triple-positive diffuse large B-cell lymphoma (TP-DLBCL), co-expressing CD10, BCL6 and MUM1, represents a rare subset with potential associations with IRF4 rearrangements. This study investigated the clinicopatholo...AIMS: Triple-positive diffuse large B-cell lymphoma (TP-DLBCL), co-expressing CD10, BCL6 and MUM1, represents a rare subset with potential associations with IRF4 rearrangements. This study investigated the clinicopathological spectrum and frequency of IRF4 rearrangements in TP-DLBCL and characterised large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4-R) in a Korean population. METHODS AND RESULTS: We retrospectively analysed 977 DLBCL cases diagnosed between 2003 and 2022. TP-DLBCL accounted for 4.9% (48/977) of all cases. Among 40 eligible TP-DLBCL cases, 17.5% (7/40) harboured IRF4 rearrangements by fluorescence in situ hybridization. Including two double-positive cases, nine LBCL-IRF4-R cases were characterized. TP-DLBCL showed a significant predilection for low-stage disease (stage I-II: 30/40, 75.0%) compared to non-TP-DLBCL (67/143, 46.9%; P = 0.002). LBCL-IRF4-R patients were significantly younger than TP-DLBCL without IRF4 rearrangement (mean age 40.6 versus 59.8 years, P = 0.049) with distinct features including preferential involvement of lymph nodes, tonsils and spleen (6/9, 66.7%), less frequent multiple extranodal involvement (P = 0.041) and conglomerated mass presentation. Most LBCL-IRF4-R cases achieved complete remission, though one adult case with MYD88 mutation showed aggressive behaviour. Genetic profiling revealed heterogeneous patterns with IRF4 mutations in all sequenced cases, and recurrent PIM1, HIST1H1E and CARD11 mutations. CONCLUSIONS: LBCL-IRF4-R represents a clinically and molecularly heterogeneous entity extending beyond paediatric populations and head-and-neck locations. IRF4 fluorescence in situ hybridization testing should be considered in TP-DLBCL cases, particularly in younger patients with localized disease.
Yaprak Bayrak B, Kosemehmetoglu K, Ozbek B
… +20 more, Simsek S, Oktay M, Coban G, Arslan Kahraman DI, Akıncıoglu E, Buyukgok M, Colak S, Dogan HN, Gurel B, Kabul S, Karaca K, Ozsagir E, Ozturk E, Toru HS, Turan G, Yıldırım NA, Yıldız ON, Karabulut YY, Cheng L, Akgul M
Histopathology
· 2026 May · PMID 42086287
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AIMS: Plasmacytoid urothelial carcinoma (PUC) is an aggressive morphological subtype characterized by discohesive single-cell infiltration and frequent loss of epithelial adhesion. Although p63 is widely regarded as a re...AIMS: Plasmacytoid urothelial carcinoma (PUC) is an aggressive morphological subtype characterized by discohesive single-cell infiltration and frequent loss of epithelial adhesion. Although p63 is widely regarded as a reliable urothelial lineage marker in conventional urothelial carcinoma, its expression may be reduced or absent in plasmacytoid tumours, creating an important diagnostic pitfall. This multi-institutional study aimed to characterize the clinicopathological and immunohistochemical profile of PUC, with particular emphasis on p63 immunoreactivity and its relationship to adhesion-related markers and other diagnostically relevant immunophenotypes. METHODS AND RESULTS: A total of 93 cases initially diagnosed as PUC were retrospectively reviewed across multiple centres. After histopathological re-evaluation, 70 confirmed cases were included. Immunohistochemical analysis was performed for p63, e-cadherin, p120 catenin, TRPS1, HER2/Neu. The cohort comprised 70 patients with a median age of 66.5 years (IQR, 59.8-72.0) and a strong male predominance of 85.7% (60/70). Most specimens were obtained from transurethral resections (64.3%, 45/70) and radical cystectomy specimens (34.3%, 24/70). The median tumour size was 3.0 cm (IQR, 1.0-5.0), and the median proportion of plasmacytoid differentiation was 80% (IQR, 20-100). Morphologically, tumours were classified as classic plasmacytoid in 65.7% (46/70), pleomorphic in 22.9% (16/70) and desmoplastic in 11.4% (8/70). Concurrent variant histology was identified in 21.4% (15/70), most commonly micropapillary (12.9%, 9/70) and sarcomatoid (7.1%, 5/70) components. Lymphovascular invasion was present in 51.4% (36/70), and concomitant carcinoma in situ was detected in 35.7% (25/70). Immunohistochemically, p63 expression was retained in only 10.0% of tumours (7/70). HER2 membranous overexpression was observed in 58.6% (41/70), while loss of E-cadherin expression was highly prevalent (84.3%, 59/70). Aberrant p120 catenin expression was common, with cytoplasmic localization in 72.9% (51/70) and complete loss in 17.1% (12/70). TRPS1 immunostaining was available in 54 tumours and was negative in 92.6% of evaluable cases (50/54). CONCLUSION: PUC demonstrates a distinctive immunophenotype characterized by frequent loss of p63 and disruption of the e-cadherin/p120 adhesion complex. Recognition of p63 attenuation, together with adhesion-related markers and HER2 status, provides a useful diagnostic framework for distinguishing this aggressive subtype from conventional urothelial carcinoma and its mimickers.
AIMS: Tumours harbouring FET::CREB fusions, particularly those involving EWSR1/FUS and CREM, represent an emerging group that is distinct from and unclassifiable into established categories such as angiomatoid fibrous hi...AIMS: Tumours harbouring FET::CREB fusions, particularly those involving EWSR1/FUS and CREM, represent an emerging group that is distinct from and unclassifiable into established categories such as angiomatoid fibrous histiocytoma, clear cell sarcoma of soft tissue, or malignant gastrointestinal neuroectodermal tumour. This study aims to further delineate the clinicopathological, immunohistochemical, and molecular features of these rare mesenchymal neoplasms with EWSR1/FUS::CREM fusions, focusing on diagnostic challenges and aggressive potential. METHODS AND RESULTS: We analysed seven cases of mesenchymal neoplasms with EWSR1/FUS::CREM fusions through detailed clinicopathological evaluation, extensive immunohistochemical profiling, and molecular genetic analysis [RNA sequencing and fluorescence in situ hybridization (FISH)]. The cohort included five females and two males (age range: 5-55 years) with tumours involving diverse intra-abdominal and extra-abdominal locations. Histologically, all tumours were composed predominantly of monomorphic epithelioid to round cells, with one case showing focal spindling. The neoplastic cells were arranged in solid sheets, nests, and trabeculae, set within a variably collagenous stroma. Mitotic activity was variable, and tumour necrosis was present in two cases. A prominent lymphoplasmacytic infiltrate was noted in three cases. Immunohistochemistry revealed a strikingly heterogeneous profile, which directly led to a wide spectrum of initial misdiagnoses. These included: epithelial malignant mesothelioma in two intra-abdominal tumours co-expressing AE1/AE3 and WT1; Ewing sarcoma in one CD99-positive tumour; a sex cord-stromal tumour in one ovarian neoplasm co-expressing S100, SOX10, and α-inhibin; epithelioid hemangioendothelioma in one case co-expressing CD34 and ERG; a neurogenic tumour in one case with synaptophysin expression; and metastatic carcinoma in a lymph node in one case, which was misdiagnosed due to diffuse expression of AE1/AE3 and a dense lymphoplasmacytic infiltrate mimicking a nodal metastasis. Molecular analysis via targeted RNA sequencing identified in-frame EWSR1::CREM fusions in five cases and a FUS::CREM fusion in two cases, all of which were confirmed by FISH. Clinically, two patients presented with disseminated disease, and all three with follow-up had aggressive courses (recurrence or metastasis). CONCLUSIONS: Our series solidifies epithelioid mesenchymal neoplasms with EWSR1/FUS::CREM fusions, which constitute a distinct sarcoma characterized by a misleading immunophenotype, with potential for aggressive clinical behaviour. Accurate diagnosis requires molecular confirmation to avoid diagnostic pitfalls and guide management.
AIMS: Serrated epithelial change (SEC) in inflammatory bowel disease (IBD) is most commonly defined as hyperplastic polyp-like mucosal changes lacking morphological evidence of dysplasia, identified on random or non-targ...AIMS: Serrated epithelial change (SEC) in inflammatory bowel disease (IBD) is most commonly defined as hyperplastic polyp-like mucosal changes lacking morphological evidence of dysplasia, identified on random or non-targeted colon biopsies. While some SEC cases harbour molecular abnormalities (e.g., TP53 mutations or aneuploidy) and are associated with an increased risk of synchronous and/or metachronous neoplasia, often in the same colonic segment as SEC, most patients with SEC do not develop colorectal neoplasia. Whether SEC constitutes a true precursor lesion or relates to neoplasia through alternative mechanisms remains unclear. METHODS AND RESULTS: We performed p53 immunohistochemistry on 112 SEC biopsies from two cohorts: 75 biopsies from 28 IBD patients who had synchronous/metachronous dysplasia (study group) and 37 biopsies from 28 IBD patients without a history of colorectal neoplasia (control SEC group). None of the SEC biopsies in the study group showed dysplasia on the stained slides. Additionally, we stained all 76 available colon biopsies from 20 IBD patients without a history of SEC or colorectal neoplasia (control IBD group). Nuclear staining intensity was graded as weak (1+), moderate (2+), or strong (3+), while the extent of staining was categorized as negative (<10%), patchy (10%-50%), or diffuse (>50%). Compared with the control SEC group, the study group was older at the time of first SEC diagnosis (mean age: 57 vs. 47 years, P = 0.006), more frequently had Crohn's disease (CD) (21% vs. 0%, P = 0.023), and had a longer disease duration (mean: 26 vs. 13 years, P < 0.001). Also, SEC in the study group was more often multifocal (68% vs. 14%, P < 0.001) and distributed throughout the entire colon rather than predominantly left-sided (P < 0.05). Regardless of association with synchronous/metachronous dysplasia, most SEC biopsies demonstrated weak or moderate p53 staining (>80% of biopsies or patients). There was no significant difference in p53 staining patterns, including the frequency of strong p53 staining, between the study and control SEC groups (P > 0.05). While the combined SEC group showed a significantly higher frequency of moderate p53 staining (71% of biopsies vs. 13%, P < 0.001) and a lower frequency of weak p53 staining (17% of biopsies vs. 79%, P < 0.001) compared with the control IBD group, the frequency of strong p53 staining was similar between the two groups (13% of biopsies in the combined SEC group vs. 8% in the control IBD group, P = 0.315). CONCLUSIONS: Although the absence of aberrant, strong p53 staining in most SEC cases, regardless of association with dysplasia, may argue against classifying SEC as a form of dysplasia potentially driven by TP53 alterations, it does not fully exclude a potential precursor role for SEC in a subset of cases. This finding also suggests that p53 immunohistochemistry may have limited clinical value for risk stratification of SEC. However, given its association with neoplasia in the same colonic segment and documented molecular abnormalities in some cases, a careful follow-up colonoscopy may be warranted following a new SEC diagnosis. This may be particularly important for patients with additional risk factors such as older age (>50 years), longer disease duration (>20 years), CD, or multifocal SEC.
Primary carcinomas of the vagina are uncommon tumours, accounting for <1% of female cancers; these are also less common than metastatic carcinoma, which constitutes a significant majority of vaginal epithelial neoplasms....Primary carcinomas of the vagina are uncommon tumours, accounting for <1% of female cancers; these are also less common than metastatic carcinoma, which constitutes a significant majority of vaginal epithelial neoplasms. The most common primary tumour type is squamous cell carcinoma. Primary adenocarcinomas of the vagina are extremely rare and of various morphological types, many of which are broadly similar to those arising in the cervix. When faced with a probable primary vaginal adenocarcinoma, the pathologist faces a dilemma since the normal vagina does not contain glands, making the origin difficult to explain, and a metastasis should always be excluded. In this review, we discuss primary vaginal adenocarcinomas and provide practical points for the pathologist in typing and reporting these neoplasms and in excluding a metastasis. We also review rare benign vaginal glandular lesions, neoplastic and non-neoplastic.
AIMS: PLAG1 gene fusions have been identified in a subset of uterine sarcomas and were historically associated with myxoid morphology. However, recent evidence shows that not all cases demonstrate myxoid features or conv...AIMS: PLAG1 gene fusions have been identified in a subset of uterine sarcomas and were historically associated with myxoid morphology. However, recent evidence shows that not all cases demonstrate myxoid features or conventional smooth muscle immunophenotype. Herein, we present 11 cases of PLAG1-rearranged uterine mesenchymal tumours to further characterize their clinicopathologic, immunohistochemical and molecular profiles. METHODS: Eleven cases of PLAG1-rearranged uterine mesenchymal tumours were included from Fudan University Shanghai Cancer Center, comprising nine consultation referrals and two primary diagnoses. Clinicopathological features were reviewed, and all cases underwent targeted RNA sequencing with a 631-gene panel. RESULTS: The median patient age was 43 years (range: 31-58). Tumours occurred in the uterine corpus (n = 10) or broad ligament (n = 1), with a median size of 10 cm (range: 5.8-19 cm). Most presented at FIGO stage I. During follow-up, 27.3% (3/11) of patients developed recurrence or metastasis. Histologic evaluation revealed significant heterogeneity: myxoid morphology in 54.5% (6/11), epithelioid morphology in 27.3% (3/11) and spindle cell morphology in 18.2% (2/11). Immunohistochemically, 81.8% (9/11) expressed at least one smooth muscle marker (desmin, h-caldesmon or SMA). RNA sequencing confirmed PLAG1 rearrangements with multiple partners, including RAB2A, TRPS1, PBX1, PRLR, BOC, CSDE1, TMEM68, PHLPP1, UBC, ESPL1 and NCOR2. The most frequent fusions were TRPS1::PLAG1 (27.3%, n = 3) and CSDE1::PLAG1 (18.2%, n = 2). CONCLUSION: PLAG1-rearranged uterine mesenchymal tumours demonstrate notable morphologic heterogeneity, predominantly presenting as myxoid leiomyosarcoma. We recommend using the integrated diagnostic term 'PLAG1-rearranged uterine mesenchymal tumour with features of [specific morphology]' to capture both the genetic alteration and histologic spectrum, accompanied by a comment regarding the limited experience and potential for recurrence.
AIMS: Chronic active antibody-mediated rejection (caABMR) is a major cause of late kidney allograft failure, yet reliable histological indicators of microvascular injury and therapeutic response remain insufficient. Comp...AIMS: Chronic active antibody-mediated rejection (caABMR) is a major cause of late kidney allograft failure, yet reliable histological indicators of microvascular injury and therapeutic response remain insufficient. Complement C4d deposition reflects complement activation but does not fully capture endothelial remodelling, particularly in ABO-incompatible transplantation. Plasmalemma vesicle-associated protein-1 (PV-1), encoded by PLVAP and normally absent from glomerular endothelium, is upregulated during endothelial remodelling. We investigated whether glomerular PV-1 complements C4d in identifying active endothelial injury in caABMR. METHODS AND RESULTS: A total of 429 allograft biopsies from 126 patients with caABMR and 345 surveillance biopsies from 94 stable recipients were analysed. Glomerular PV-1 and C4d immunofluorescence intensities were quantified and correlated with histopathological lesions, renal function, and donor-specific antibodies, with stratification by ABO compatibility. Both PV-1 and C4d were associated with microvascular inflammation and transplant glomerulopathy. While C4d reflected cumulative complement activation and showed staining in ABO-incompatible grafts, PV-1 specifically identified endothelial remodelling, particularly in lesions with double-contour formation, and demonstrated dynamic reduction following B-cell-directed therapy. Low-vacuum scanning electron microscopy correlated with the presence of de novo PV-1 expression in glomerular endothelial cells. In multivariable Cox models incorporating ΔPV-1 and ΔC4d with clinical covariates, ΔPV-1 remained independently associated with death-censored graft survival, whereas ΔC4d did not. CONCLUSIONS: Glomerular PV-1 functions as a dynamic marker of endothelial remodelling that complements the static C4d footprint of complement activation. Combined assessment of PV-1 and C4d captures distinct dimensions of microvascular pathology and may refine histopathological evaluation of injury and treatment response in caABMR.
AIMS: Langerhans cell sarcoma (LCS) is a rare malignant neoplasm that relatively frequently presents with primary cutaneous involvement. Owing to its extreme rarity, it is necessary to characterize the clinicopathologica...AIMS: Langerhans cell sarcoma (LCS) is a rare malignant neoplasm that relatively frequently presents with primary cutaneous involvement. Owing to its extreme rarity, it is necessary to characterize the clinicopathological features of cutaneous LCS. METHODS: We analysed the clinicopathological features of five cutaneous LCS cases from our institution and reviewed an additional 38 cutaneous LCS cases and 69 extracutaneous LCS cases from the literature. RESULTS: In our patients, disease progression exceeded 3 years in four patients (4/5, 80%) who were diagnosed with progressed cutaneous LCS, while one (1/5, 20%) experienced rapid progression within 2 months and was diagnosed with de novo cutaneous LCS. Tumour cells were medium to large in size, with atypical mitotic figures, and nuclear pleomorphism was noted in the former four patients; round-to-ovoid nuclei were seen in the latter one patient. Eosinophils were sparse and observed in four patients (4/5, 80%). S100, CD1a and Langerin expression were not consistently diffuse, with Langerin expressed in <5% of tumour cells in one patient (1/5, 20%) whose ultrastructural examination revealed Birbeck granules. In the combined cohort of 43 cutaneous LCS cases, 32 (74.42%) were progressed cutaneous LCS and 6 (13.95%) were de novo cutaneous LCS. The progressed cutaneous LCS cases exhibited higher rates of lymph node metastasis (56.25% vs. 0%; P = 0.021), a trend toward more frequent ulceration (43.75% vs. 0%; P = 0.067) and a higher Ki-67 proliferation index (P = 0.046). Compared with extracutaneous LCS cases, cutaneous LCS cases demonstrated a malignant transformation course (84.62% vs. 19.57%; P < 0.001) and tended to have a more favourable prognosis (P = 0.077). CONCLUSIONS: We summarize the clinicopathological features of cutaneous LCS. Recognition plays a crucial role in preventing misdiagnosis and guiding appropriate treatment.
The 6th edition of the WHO Classification of Breast Tumours introduces both major and minor changes based on recent advances in our understanding of breast biology, developments in diagnostic modalities, identification o...The 6th edition of the WHO Classification of Breast Tumours introduces both major and minor changes based on recent advances in our understanding of breast biology, developments in diagnostic modalities, identification of specific molecular targets and new treatment regimens necessitating modifications to pathology reporting and tumour biomarker categorisation. This review summarises the main changes that strive towards a classification of global relevance. In invasive carcinoma, predictive factors increasingly inform modern breast cancer treatment. The 6th edition provides an update on HER2 reporting categories following the DESTINY-Breast 04 and 06 trials. Terminologies used to classify invasive tumours are clarified, with the term 'variant' now reserved for molecular/genetic alterations. Invasive lobular carcinoma (ILC) with extracellular mucin is recognised as a new diagnostic entity with prognostic implications. The diagnosis of mucinous carcinoma (MC) is reserved for mucin secreting carcinomas with grade 1 or 2 morphology and a favourable biomarker profile. The diagnosis of malignant phyllodes tumours requires only four of the original five adverse histological criteria. Classification of neuroendocrine tumours (NETs) is revised, recognising that the unified model, promoted in the 5th edition, is difficult to apply to the breast. New approaches to the classification of adenomyoepithelioma are discussed but the 5th edition system is broadly retained. A new section on 'Small Diagnostic Samples' outlines the merits of non-operative biopsy diagnosis, the B coding system and the importance of multidisciplinary review. Changes to diagnostic practice and the emerging role of artificial intelligence, with advantages and challenges, are discussed in a new section on 'Digital Pathology'.
AIMS: TERT promoter mutations are late molecular events associated with tumour dedifferentiation and aggressive behaviour in thyroid carcinomas (TCs). Although certain adverse histologic features, particularly tall cell...AIMS: TERT promoter mutations are late molecular events associated with tumour dedifferentiation and aggressive behaviour in thyroid carcinomas (TCs). Although certain adverse histologic features, particularly tall cell morphology, are enriched in TERT promoter-mutated papillary thyroid carcinoma (PTC), their independent prognostic significance within the American Thyroid Association (ATA) high-risk group remains uncertain. This study aimed to assess its prognostic relevance and characterize the histologic spectrum of TERT promoter-mutated TCs, including differentiated high-grade thyroid carcinoma (DHGTC), to refine risk stratification. METHODS AND RESULTS: We retrospectively analysed 151 TCs harbouring TERT promoter mutations, reclassified according to the WHO 2022 classification, which includes newly defined DHGTC. The low frequency of TERT promoter mutations in PTC (2.4%) likely reflects the reclassification of cases previously diagnosed as PTC to DHGTC. Tall cell morphology remained strongly associated with TERT promoter mutations but did not confer additional prognostic significance within this ATA high-risk group. Furthermore, applying the stricter WHO criteria for TC-PTC (≥3× height criteria) did not enhance risk stratification. Importantly, histologic features indicative of tumour progression, including loss of polarity/cohesiveness and early necrotic change, were frequently observed and significantly associated with aggressive clinicopathologic features. Accordingly, tumours exhibiting these features may not only reflect progression toward high-grade disease but also serve as surrogate histologic indicators of underlying TERT promoter mutations. CONCLUSIONS: Our study provides valuable insights into TERT promoter-mutated TCs, broadening their recognized morphologic spectrum and highlighting the importance of incorporating such features into routine evaluation to improve risk stratification and better identify aggressive tumours.
Characterization of molecular features of cholangiocarcinoma (CCA) has questioned the traditional, anatomy-based classification scheme and has alternatively suggested biology-based classifications. Intrahepatic CCA has b...Characterization of molecular features of cholangiocarcinoma (CCA) has questioned the traditional, anatomy-based classification scheme and has alternatively suggested biology-based classifications. Intrahepatic CCA has been classified into small-duct and large-duct types, and the latter is histologically and molecularly almost identical to perihilar CCA. Although distal and perihilar CCA have been classified together, they have different molecular abnormalities, with MDM2 amplification observed in 15% of perihilar CCA cases but in none of the distal CCA cases. FGFR2 and IDH1 are two main drug targets in small-duct intrahepatic CCA, and mismatch repair (MMR) deficiency is most common in small-duct intrahepatic CCA. In contrast, HER2 is a promising target for extrahepatic CCA and gallbladder cancer, as HER2 overexpression is seen in 17%-30% of cases. Classification of intrahepatic CCA is often challenging on biopsy specimens; however, recognition of pitfalls (e.g., hybrid morphology) will help avoid misclassification. Staining for ancillary markers, including CRP, albumin-ISH, and S100P, is also useful. Accurate distinction between distal CCA and pancreatic head cancer has become increasingly important, particularly in unresectable or borderline resectable cases, as systemic treatment strategies differ between these entities. Although these two neoplasms share many morphological and immunohistochemical features, the presence of clear or foamy cancer cells in biopsy specimens is uncommon in dCCA and may favour pancreatic ductal carcinoma.
AIMS: Germ cell neoplasia in situ (GCNIS) is the precursor of GCNIS-derived testicular germ cell tumours, including seminomas and non-seminomas. Most non-seminomas show mixed histology, often including components of semi...AIMS: Germ cell neoplasia in situ (GCNIS) is the precursor of GCNIS-derived testicular germ cell tumours, including seminomas and non-seminomas. Most non-seminomas show mixed histology, often including components of seminoma. A small subset presents as pure non-seminomatous germ cell tumors. In these neoplasms, the absence of invasive seminoma. raises the possibility that reprogramming to non-seminoma may occur at an early in-situ stage (i.e., within the spermatogonial niche). This study examined GCNIS associated with pure embryonal carcinoma (EC) and postpubertal-type yolk sac tumour (YST) using immunohistochemistry for transcription factors characteristic of GCNIS/seminoma, EC, and YST phenotypes to determine if reprogramming to non-seminoma occurs within the spermatogonial niche. METHODS: GCNIS associated with pure testicular YST and EC was assessed using OCT4, FOXA2 (only YST), CD30 (only EC), SOX2 (only EC), SOX17, and NANOG immunohistochemistry. Adjacent foci of intratubular and invasive tumour were also evaluated, if present. RESULTS: Sixty-seven pure non-seminomas (63 EC, 4 YST) were evaluated. In all cases, GCNIS expressed OCT4, SOX17, and NANOG. GCNIS associated with EC was consistently negative for CD30 and SOX2, and GCNIS associated with YST was consistently negative for FOXA2. Adjacent invasive EC (62/67 cases) and intratubular EC (19/67) showed the classic EC immunophenotype: OCT4+/NANOG+/SOX17-/SOX2+/CD30+. Similarly, invasive YST adjacent to GCNIS was OCT4-/NANOG-/SOX17+/FOXA2+. CONCLUSIONS: Assessment of transcription factors involved in the induction and maintenance of EC and YST phenotypes suggests that, in pure non-seminomas, reprogramming occurs outside the spermatogonial niche.