Morphological Subtypes Research Articles

Genetic alterations are related to clinicopathological features and risk of recurrence/metastasis of hepatocellular carcinoma.

Lack of efficient biomarkers and clinical translation of molecular typing impedes the implementation of targeted therapy for hepatocellular carcinoma (HCC). High-throughput sequencing techniques represented by next-generation sequencing (NGS) are tools for detecting targetable genes. The objective of this study is to explore the genetic alterations associated with clinicopathological features and the risk of recurrence/metastasis in HCC. NGS analysis was conducted on formalin-fixed paraffin-embedded tissues from 164 resected liver samples obtained from Chinese patients. Morphologic subtypes were reviewed based on hematoxylin-eosin and immunohistochemistry staining, Correlation to the acquired molecular features were analyzed with clinicopathological information. We also retrieved follow-up information of the 123 transplanted cases from 2017 to 2019 to screen recurrence/metastasis-associated factors by univariate analysis. Generally, the most frequently mutated genes include TP53 and CTNNB1 which showed a trend of mutually exclusive mutation. Copy-number variant with the highest frequency was detected in TAF1 and CCND1 in 11q13.3 loci. Correlation analysis showed that various genetic alterations were associated with morphologic subtypes and other pathologic features. While gene signatures of proliferation/nonproliferation class were correlated with differentiation, satellite foci and other invasive morphological features. Macrotrabecular-massive subtype, TSC2 (tuberous sclerosis complex 2) mutation, Ki-67 expression, and other six factors were found to be associated with recurrence/metastasis after liver transplantation. Genetic alterations detected by NGS show correlation with not only pathological and clinical features, but also with recurrence/metastasis after liver transplantation. Further gene-level molecular typing will be practical for targeted therapy and individual recurrence risk assessment in HCC patients.

Impact of masticatory activity and rehabilitation on astrocyte morphology across the molecular layer of the dentate gyrus: Insights from the outer, medial, and inner sublayers and their relationship with spatial learning and memory

The dentate gyrus plays a crucial role in learning and spatial memory, particularly in its middle third molecular layer, which receives the primary afferent input via the medial perforant path. Interestingly, changes in masticatory activity are described to affect this region with visible astrogliosis, release of pro-inflammatory cytokines and oxidative stress, affecting synaptic physiology, and cognition. This study aimed to investigate the impact of altered masticatory activity on spatial memory in young Swiss albino mice, correlating these effects with morphological changes in astrocytes. The mice were divided into three groups: Hard diet with pellets (HD), hard diet/soft diet (HD/SD, reduced masticatory activity), and HD/SD/HD (rehabilitated). The Morris water maze test was used to measure escape latency, while three-dimensional microscopic reconstruction methods provided morphometric data on the astrocytes. Hierarchical clustering analysis validated the existence of four morphological subtypes with decreasing complexity (AST1, AST2, AST3, and AST4), in the outer, middle, and inner thirds of the dentate gyrus molecular layer. Changes in masticatory activity affected the number and distribution of astrocytes subtypes excepting AST3 in the middle third layer. Canonical discriminant function analysis indicated that complexity was the variable most influencing cluster formation. Correlation tests between complexity and escape latency for each animal group showed a significant correlation with a large effect size of 60 % [Pearson’s R: 0.605, p < 0.001] in the HD group in the middle third, which was disrupted by altered masticatory activity. AST3 morphotype in the middle third showed a linear correlation with learning and spatial memory functions in the HD group [Pearson’s R: 0.624, p < 0.001] that disappeared with a reduction in masticatory activity, and nor restored by diet rehabilitation. This finding was not observed for inner and outer layers, supporting the contribution of middle third AST3 to learning and spatial memory. Group comparison tests also revealed that diet differentially impacts astrocyte subpopulations on each third of the dentate gyrus molecular layer. Data validate the influence of the masticatory activity on astrocyte complexity and suggest the existence of AST3 association with spatial memory and learning tasks in young female mice. Further research on the underlying mechanisms of these relationships is essential to identify potential therapeutic targets for cognitive disorders and to develop effective interventions to preserve cognitive function.

Muscle-invasive and metastatic urothelial carcinoma from a pathological point of view

Muscle-invasive and metastatic urothelial carcinoma is a heterogeneous disease with a broad morphological and molecular spectrum. The amendment of the WHO classification has resulted in some changes in the nomenclature and classification of muscle-invasive and metastatic urothelial carcinomas. Due to the increasing individualisation of therapeutic options, the correct diagnosis of morphological variants of urothelial carcinoma, which are associated with specific molecular alterations, is becoming more and more important. The morphological variants also correlate with molecular subtypes of urothelial carcinoma. In addition, both morphological and molecular subtypes are associated with immunological and other molecular characteristics that could be relevant for modern immunotherapies or antibody-drug conjugates, e.g. in the form of PD-L1 and NECTIN-4 status. With the pending approval of erdafitinib (FGFR3 inhibitor), molecular tumour boards for patients with metastatic urothelial carcinoma will also become more important in the future.

Myxoid Solitary Fibrous Tumor of the Nasal Vestibule: An Unusual Histological Subtype in the Head and Neck Region.

Solitary fibrous tumors (SFTs) are mesenchymal neoplasms associated with the characteristic NAB2::STAT6 gene fusion. They frequently occur in extra-thoracic sites and are not uncommon in the head and neck (HN) region. Myxoid SFT is a rare morphological subtype of SFT, the features of which overlap with those of other myxoid-appearing tumors, making the diagnosis challenging. We describe the distinctive histopathological and immunohistochemical features of myxoid SFT that occurred in a 32-year-old man with a recurrent swelling in the nasal vestibule. Histological examination showed a nodular tumor composed of short spindle-shaped cells in an abundant myxoid stroma. Nuclei were ovoid, with minimal pleomorphism. Occasional intervening slender vascular channels were present; staghorn vasculature was absent. Tumor cells were diffusely immunopositive for STAT6, CD34, and BCL2, while S100, SOX10, EMA, ER, and CD10 were negative, confirming the diagnosis of myxoid SFT. Thus, myxoid SFTs are unusual in the HN, with potential for misdiagnosis. Due to their propensity for local recurrence if incompletely excised, a high index of suspicion is required to include them in differential diagnosis of myxoid mesenchymal neoplasms occurring at this location. STAT6 is a reliable immunohistochemical marker that aids in diagnosis, reducing the necessity for molecular testing.

P63 Expression in Ductal Carcinoma In Situ (DCIS) of the Breast and Its Correlation with Histopathological Grading and Morphological Variants

Background: Ductal carcinoma in situ (DCIS) is a non-invasive breast cancer with varying potential for progression to invasive carcinoma. Myoepithelial cells (MECs) play a role in preventing this progression, and their absence is a hallmark of invasive disease. The p63 protein is a myoepithelial marker that can be assessed by immunohistochemistry (IHC). This study aimed to evaluate the relationship between p63 expression in MECs, the grade of DCIS, and the morphological subtype of DCIS. Methods: A cross-sectional study was conducted on 35 cases of DCIS diagnosed at the Anatomical Pathology Laboratory of Dr. M. Djamil General Hospital Padang. Paraffin blocks were collected, and Hematoxylin and Eosin (H&amp;E) slides were reviewed to confirm the diagnosis and determine the histopathological grading (low, intermediate, and high) and morphological variants (comedo and non-comedo) of DCIS. Paraffin blocks were re-cut for p63 immunohistochemical staining. The extent of p63 expression was classified as complete or incomplete. Results: The majority of DCIS cases were high grade (54.3%) and of the non-comedo subtype (68.4%). All cases with complete p63 expression were of low histologic grade, while all cases with incomplete p63 expression were of high histologic grade. The results of the Chi-square test showed a statistically significant relationship between p63 expression and histopathological grading (p&lt;0.001). There was no statistically significant relationship between p63 expression and morphological variant. Conclusion: The absence of p63 expression in DCIS is associated with high histologic grade. This finding suggests that p63 IHC may be a useful adjunct in evaluating DCIS.

LW-MorphCNN: a lightweight morphological attention-based subtype classification network for lung cancer

Abstract Lung cancer is generally considered one of the most deadly cancers globally. If it can be identified early and diagnosed correctly, the survival probability of patients can be significantly improved. In this process, histopathological examination is a commonly used method for diagnosing and detecting lung cancer. It is crucial to accurately identify lung cancer subtypes from histopathological images, as this helps doctors formulate effective treatment plans. However, the visual inspection in histopathological diagnosis requires a large amount of time and also depends on the subjective perception of clinicians. Therefore, this paper proposes a lightweight lung cancer subtype classification network based on morphological attention (LW-MorphCNN), which is used to automatically classify the histopathological images of benign lung tumors, ADC (adenocarcinoma), and SCC (squamous cell carcinoma) provided in the public dataset LC25000 (Lung and Colon). This paper takes histopathological images as input and conducts a comparative analysis with classic networks such as VGG16, VGG19, DenseNet121, and ResNet50, as well as existing classification methods proposed in the same work. The network proposed in this paper is superior to other networks in terms of parameter quantity and performance, with an accuracy rate and F1 - score reaching 99.47% and 99.44% respectively. Clinicians can install the provided LW-MorphCNN in the hospital to confirm the diagnosis results.

Radon Exposure Is Associated with Breast Cancer Risk: A Long-Term Population-Based Study from Finland

Abstract Background Radon is a common environmental carcinogen. It is not known whether radon exposure and breast cancer risk are associated at the population level. Methods Women continuously living in Finland during the 1987-2016 period were linked to municipality-level indoor radon data annually to estimate their cumulative radon exposure over 30 years. Breast cancer incidence was observed over five years from 2017 onwards. Association between radon exposure and breast cancer incidence was assessed using conditional Cox models adjusted for family history of breast cancer, reproductive history, and socio-demographic covariates. Population attributable fractions (PAF) of breast cancer due to radon exposure were estimated. Robustness analyses were conducted in the population who lived only in houses. Results Among 1,335,947 women, 20,067 breast cancer cases were observed during a median follow-up period of 4.9 years. Among women who were exposed to high levels of radon (&amp;gt;100 Bq/m3), overall breast cancer incidence was 10% higher (Hazard ratio 1·10 [95% CI 1·05-1·16]), duct carcinoma incidence was 6% higher (1·06 [1·00-1·13]), lobular carcinoma incidence was 8% higher (1·08 [0·94-1·23]), and the incidence of other morphological sub-types was 34% higher (1·34 [1·17-1·53]) than among other women. Robust associations with overall breast cancer incidence (1·12 [1·05-1·20]) and the incidence of morphological sub-types in the house sample. Correspondingly, suggestive dose-response associations were observed. Conclusions High radon exposure is associated with elevated breast cancer risk at the population level, and this relationship is independent of well-established risk factors. Key messages • This study investigates the association between long-term radon exposure and breast cancer incidence based on national register data. • High radon exposure is robustly associated with breast cancer risk in general Finnish population.

Morphologic Characterization of Pancreatic Ductal Adenocarcinoma following Post-neoadjuvant Pancreatectomy and Clinical value of Intratumor Heterogeneity.

To evaluate the morphologic landscape of pancreatic ductal adenocarcinoma (PDAC), intratumor spatial heterogeneity, and the resulting clinical impact following post-neoadjuvant pancreatectomy. The clinical value of PDAC morphologic subtypes and intratumor spatial heterogeneity post-treatment remains an open issue. The study cohort included patients who underwent post-neoadjuvant pancreatectomy for PDAC at the University of Verona Hospital Trust between 2013 and 2019. All hematoxylin and eosin-stained slides were reviewed to assess PDAC histomorphology and intratumor heterogeneity. The relationship with other clinicopathological variables, overall survival (OS), and recurrence-free (RFS) survival was evaluated using standard statistics. The study cohort included 400 patients. Histological revision identified ten different morphologic subtypes. Gland-forming PDAC with a conventional pattern was the most frequently identified subtype (41.8%). Overall, 247 tumors (61.7%) showed only one histological pattern and were classified as homogeneous, whereas 153 (38.3%) showed different morphologies and were classified as heterogeneous tumors. The median post-resection survival was 30.1 months (95%CI 26.6-33.5). There was a substantial survival variability according to the morphologic subtype, ranging from 19.1 months in the gyriform subtype to 47.0 months in the papillary subtype. Tumors with a heterogeneous morphology displayed a higher rate of nodal metastases, worse tumor regression metrics, and worse oncologic outcomes relative to spatially homogeneous tumors. This paper provided a morphological taxonomy of residual tumors following post-neoadjuvant pancreatectomy for PDAC. The morphologic subtype and intratumor spatial heterogeneity have relevant prognostic implications and could be included in the pathology report to complement regression metrics.

MNGA-02 MENINGIOMA WITH CONTROLATERAL SUB-DURAL HEMATOMA: CASE REPORT AND LITERATURE REVIEW

Abstract BACKGROUND Meningiomas account for around 20% of primary intracranial tumors. It is the most common benign brain tumor. The association of meningiomas with subdural hematoma is rare, and very few cases have been reported in the literature. The pathophysiological mechanisms are not yet fully understood. We therefore report a case of chronic subdural haematoma associated with a meningioma and review the relevant literature. CASE PRESENTATION A 72-year-old patient with known hypertension and a right basifrontal lesion discovered a few months previously. He was brought to emergency by his daughter for multiple comitial seizures and confusion. On clinical examination, the patient was conscious but confused, with anosmia and no sensory or motor deficits. A brain scan and MRI revealed a right parasagittal basifrontal meningioma associated with a chronic left subdural hematoma. The patient had no coagulation disorders. He underwent removal of the meningioma using a bifrontal approach, cranialisation of the sinuses, and drainage of the hematoma using an external subdural shunt. The postoperative course was favorable. Post-operative imaging showed satisfactory Simpson 1 resection and good drainage. The anatomopathological examination concluded that the meningioma had a meningothelial morphological subtype of doubtful invasiveness, suggesting a grade 2 invasive meningioma or a grade 1 meningothelial meningioma. No additional treatment was required. CONCLUSION The presence of a meningioma should always be suspected in the presence of an acute non-traumatic subdural hematoma. To obtain a more comprehensive pathophysiological explanation of the association, a meta-analysis involving a larger number of cases and a larger series would be necessary.

Is Chinese Dyslexia Similar Across Chinese Societies? Evidence from Hong Kong, Beijing, and Taipei

AbstractWhile previous research has documented the unique aspects of Chinese dyslexia as compared to dyslexia in alphabetic scripts, it remains unclear whether the difference in Chinese literacy experiences influences the manifestation of Chinese dyslexia. The present article first reviews the characteristics of Chinese languages and scripts, including important cognitive‐linguistic correlates (rapid automatized naming, phonological, orthographic, and morphological awareness) of Chinese reading development and impairment. The diversity in Chinese literacy experiences of scripts, languages, and instructional practices, and consequently their impact on Chinese literacy acquisition across different Chinese societies are also reviewed. Using an equivalent Chinese assessment battery administered to 91 children with dyslexia from Hong Kong, Beijing, and Taipei, we examined the subtypes of Chinese dyslexia across these three societies concurrently. With the four cognitive‐linguistic skills included as the clustering variable, the hierarchical cluster analysis revealed four cognitive subtypes of dyslexia: 38% mild orthographic deficit subtype (OD), 33% phonological deficit subtype (PD), 18% morphological deficit subtype (MD), and 11% global deficit subtype (GD)—each with their own set of cognitive‐linguistic deficit profiles. Interestingly, all four subtypes of dyslexia manifested poorer orthographic skills as compared to the control group. Bayesian Analysis of Contingency Table further showed that the distribution of dyslexia subtypes remains similar across the three Chinese societies, suggesting invariance of the Chinese dyslexia construct. Findings highlight the importance of assessment in orthographic processing, rapid automatized naming, phonological awareness, and morphological awareness in order to understand Chinese dyslexia, both in a within and cross‐cultural Chinese perspective.

Cell-type-specific origins of locomotor rhythmicity at different speeds in larval zebrafish

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

Cell-type-specific origins of locomotor rhythmicity at different speeds in larval zebrafish.

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

Abstract B076: Morphological diversity predicts functional traits in pancreatic cancer

Abstract Cell morphologies represent a phenotypic integration of intrinsic cellular processes, changes in cell state, and interactions with neighboring cells. While analyses of large cell line collections such as the Cancer Dependency Map (DepMap) have greatly enhanced discovery of novel molecular biomarkers and therapeutic targets, morphological analysis of these models has not yet been performed. Hence, there is a rich opportunity to discover novel regulators and functional properties of cell morphologies by linking image-based profiling to -omics based assays. Here, we studied the transcriptional and functional properties of 16 human pancreatic cancer cell lines, associations with distinct cell morphologies, and treatment-induced remodeling. At baseline, we observed extensive morphological heterogeneity across and within cell lines, as well as differences in multicellular organization. We categorized cell line morphologies into epithelial, mesenchymal, and spheroid, and organizational patterns into tightly aggregated, multilayered, and dispersed. We performed differential expression analysis across morphological subtypes utilizing DepMap transcriptomics data and queried functional correlates including CRISPR dependency, drug sensitivity, and proclivity for metastasis. For example, we discovered that the mesenchymal morphology and multilayered organizational pattern [WH3] were associated with metastatic potential, while expressing reduced levels of tight junction and cell adhesion genes. We then explored treatment associated morphological changes and their potential as cost-effective biomarkers for cell-intrinsic resistance to chemotherapy (e.g., 5-FU and gemcitabine) and KRAS inhibitors (e.g., MRTX1133 and RMC- 6236). Cells were treated continuously and monitored with live cell imaging (Incucyte SX5) followed by Cell Painting at the three-day endpoint. We observed conserved morphological responses to therapy across cell lines including a shift towards spindle-like cell shapes with neurite-like projections in chemotherapy-treated conditions, and a cell bloating phenomena characterized by an increase in cell area in KRAS inhibitor treated conditions. To directly link transcriptional state to morphology, we performed 1000-plex spatial molecular imaging (Nanostring CosMx) at subcellular resolution to pools of cell lines, demonstrating that morphological diversity within cell lines corresponded to distinct transcriptional states. In conclusion, this study highlights the potential of harnessing cell morphological information in a rapid, cost-effective phenotyping assay to aid precision oncology efforts leveraging patient- derived in vitro models. Citation Format: Dennis Gong, William L Hwang. Morphological diversity predicts functional traits in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B076.

Multifocality in gallbladder cancer: An imaging-based study.

Gallbladder cancer (GBC) lesions are usually solitary. The presence of multifocal disease can alter resectability and management. There are no systematic imaging-based studies evaluating multifocality in GBC. Thus, we aimed to evaluate multifocality in GBC based on cross-sectional imaging studies. This retrospective study screened cross-sectional imaging (contrast-enhanced computed tomography [CT] or magnetic resonance imaging [MRI]) of consecutive patients with histopathological or cytological diagnoses of GBC. The CT/MRI images of patients with multifocal disease (defined as the presence of two or more foci of abnormal wall thickening, intraluminal polypoidal lesions or masses in the gallbladder, cystic duct, or the extrahepatic bile ducts with the intervening area of normal gallbladder/extrahepatic bile ducts) were evaluated by two radiologists independently for various imaging findings. Of the 324 patients, 17 (5.2%; 13 females; mean age, 54 ±11 years) had multifocal disease with two sites of involvement in all cases. The most common sites of involvement were the gallbladder fundus and neck region (58.8% of cases), followed by the gallbladder fundus and common bile duct (29.4%). Wall thickening type of GBC was the most common morphological subtype (85.3%), followed by mass forming type (14.7%). The majority (70.6%) of cases showed the same morphology at both sites, while 29.4% showed different morphology. Most (70.6%) of the patients with multifocal GBC were unresectable at the time of diagnosis. Although rare, imaging-based diagnosis of multifocal GBC may allow appropriate management.

The different subtypes of cam morphology as defined by statistical shape modeling and their relationship with the development of hip osteoarthritis: A nationwide prospective cohort study (CHECK) with 10 years follow-up

ObjectiveTo determine if subtypes of cam morphology on anteroposterior (AP) radiographs exist using statistical shape modelling (SSM), and to assess their association with incident radiographic hip osteoarthritis (RHOA) within 10 years. DesignThe nationwide prospective Cohort Hip and Cohort Knee (CHECK) study included 1,002 participants aged 45-65 years with 10-year follow-up. Subtypes of cam morphology were defined as SSM-based shape variations of femoral head-neck junction that are associated with baseline cam morphology (alpha angle ≥60°). The association between each subtype in hips free of osteoarthritis at baseline (Kellgren & Lawrence (KL) grade <2) and incident RHOA (KL grade≥2, or a total hip replacement) was estimated using logistic regression at 10-year follow-up and stratified by sex. ResultsIn sex-combined group, but also for males and females separately, cam morphology subtypes were captured in modes 1, 3, 4, and 5 with odds ratios (ORs) ranging from 0.39(0.27-0.58) to 2.25(1.64-3.10). For sex-combined group, only mode 3, a flattened head-neck junction, was associated with incident RHOA (OR:1.14, 1.02-1.27). Males’ modes 1 and 3 and females’ modes 3 and 4 were associated with RHOA. Notably, the female mode 4, a slightly flattened neck but with subtle curvature, was significantly protective for RHOA (OR:0.88, 0.80-0.98). ConclusionsWe identified four distinct morphological subtypes of cam morphology defined by alpha angle. Only some subtypes were found acting as risk factors for RHOA at 10-year follow-up, which differed between males and females. This highlights the need to study cam morphology beyond the alpha angle alone.

Muscle-invasive and metastatic urothelial carcinoma of the urinary bladder : Current state of histopathologic, molecular, and immunologic prognostic and predictive factors

Muscle-invasive and metastatic urothelial carcinoma (UC) represents aheterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes. This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC. Muscle-invasive and metastatic UC exhibits awide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.

Radiological Features of Primary Pulmonary Invasive Mucinous Adenocarcinoma Based on 312 Consecutive Patients.

The aim of this study is to investigate the radiological features of primary pulmonary invasive mucinous adenocarcinoma (IMA) in a relatively large population to help improve its further understanding and its accuracy of initial diagnosis. This retrospective study included consecutive patients with pathologically confirmed primary pulmonary IMA from January 2019 to December 2021. According to tumor morphology, IMAs were divided into regular nodule/mass, irregular, and large consolidative types. According to tumor density, IMAs were divided into solid, halo, part-solid, pure ground-glass, and cystic types. ANOVA, chi-square, or Fisher exact tests were used to analyze the differences in radiological and clinicopathological characteristics of IMA according to morphological and density subtypes. We analyzed 312 patients. Pulmonary IMA tended to occur in the elderly, with a slightly higher number of women than men. IMA showed a predominance in the lower lobe and adjacent to pleura. IMA of regular nodule/mass, irregular, and large consolidative types accounted for 80.8% (252/312), 13.8% (43/312), and 5.4% (17/312), respectively. Solid, halo, part-solid, pure ground-glass, and cystic IMAs accounted for 55.8% (174/312), 28.2% (88/312), 11.2% (35/312), 1.3% (4/312), and 3.5% (11/312), respectively. The lobulated (76.9%), spiculated (63.5%), and air bronchogram (56.7%) signs were common in IMA. Dead branch sign (88.2%), angiogram sign (88.2%), and satellite nodules/skipping lesions (47.1%) were common in large-consolidative-type IMA. Kirsten rat sarcoma viral oncogene mutations were common (56.1%), whereas epidermal growth factor receptor mutations were relatively rare (2.3%). Pulmonary IMA of regular nodule/mass type and solid type were the most common at the initial diagnosis. Detailed radiological features can aid in the differential diagnosis of IMA.

Pediatric Quadricuspid Aortic Valve: Morphology, Characteristics, Clinical Outcomes, and Literature Review.

Quadricuspid aortic valve (QAV) is an exceedingly rare congenital heart defect (CHD) which has not been well-defined in a pediatric population. The Mayo Clinic echocardiography database was retrospectively analyzed to identify patients ≤18 years diagnosed with QAV from January 1990 to December 2023. Patients with truncus arteriosus were excluded. All images were independently reviewed to define morphology of the QAV by using the Hurwitz and Roberts classification. Fourteen patients with QAV were identified with a median age at time of diagnosis being 10.5 years (interquartile range [IQR] 6-14 years). Male-to-female ratio was 3:1. Associated CHDs were present in 50% (n = 7) patients. The most common morphological subtypes of QAV were Type D in 43% (n = 6) and Type B in 29% (n = 4). Aortic regurgitation was the most frequently associated valvular abnormality affecting 86% (n = 12) cases, with greater than moderate regurgitation in only two patients. Aortic valve stenosis was observed in 14% (n = 2) patients. Ascending aortic dilatation was present in 21% (3/14) of the cohort, but only 14% (1/7) of isolated QAV patients. At a mean follow up of 11 ± 6.6 years and a median follow-up age of 22 years (IQR 14-27 years), survival was 100% with no primary interventions on the aortic valve or aorta. However, four patients required surgical interventions for associated CHDs. Among children with QAV, almost half of the patients had additional CHD. Aortic regurgitation was the predominant hemodynamic abnormality. Long-term survival was excellent with minimal progression during childhood and adolescence.

The Combined Immunohistochemical Expression of GLI1 and BCOR in Synovial Sarcomas for the Identification of Three Risk Groups and Their Prognostic Outcomes: A Study of 52 Patients.

Synovial sarcoma (SS) is a rare soft-tissue tumor characterized by a monomorphic blue spindle cell histology and variable epithelial differentiation. Morphologically, SSs may be confused with other sarcomas. Systemic treatment is more effective for patients with high-risk SSs, patients with advanced disease, and younger patients. However, further studies are required to find new prognostic biomarkers. Herein, we describe the morphological, molecular, and clinical findings, using a wide immunohistochemical panel, of a series of SS cases. We studied 52 cases confirmed as SSs by morphological diagnosis and/or molecular studies. Clinical data (gender, age, tumor size, tumor location, resection margins, adjuvant treatment, recurrences, metastasis, and survival) were also retrieved for each patient. All the available H&E slides were examined by four pathologists. Three tissue microarrays (TMAs) were constructed for each of the tumors, and a wide immunohistochemical panel was performed. For time-to-event variables, survival analysis was performed using Kaplan-Meier curves and log-rank testing, or Cox regression. Statistical significance was considered at p < 0.05. The mean age of our patients was 40.33, and the median was 40.5 years. We found a predominance of males versus females (1.7:1). The most frequent morphological subtype was monophasic. TRPS1, SS18-SSX, and SSX-C-terminus were positive in 96% of cases. GLI1 expression was strong in six and focal (cytoplasmic) in twenty patients. Moreover, BCOR was expressed in more than half of SSs. Positive expression of both proteins, BCOR and GLI1, was correlated with a worse prognosis. Multivariate analysis was also performed, but only BCOR expression appeared to be significant. The combination of GLI1 and BCOR antibodies can be used to group SSs into three risk groups (low, intermediate, and high risk). We hypothesize that these findings could identify which patients would benefit from receiving adjuvant treatment and which would not. Moreover, these markers could represent therapeutic targets in advanced stages. However, further, larger series of SSs and molecular studies are necessary to corroborate our present findings.

COL10A1 expression distinguishes a subset of cancer-associated fibroblasts present in the stroma of high-risk basal cell carcinoma.

Basal cell carcinoma (BCC) is the most frequently diagnosed skin cancer and the most common malignancy in humans. Different morphological subtypes of BCC are associated with a low or high risk of recurrence and aggressiveness, but the underlying biology of how the individual subtypes arise remains largely unknown. As the majority of BCCs appear to arise from mutations in the same pathway, we hypothesized that BCC development, growth and invasive potential is also influenced by the tumour microenvironment and, in particular, by cancer-associated fibroblasts (CAFs) and the factors they secrete. To characterize the stroma of the different BCC subtypes with a focus on CAF populations. To investigate the stromal features of the different BCC subtypes, we used laser capture microdissection (LCM) followed by RNA sequencing (RNA-Seq). Fifteen BCC samples from five different 'pure' subtypes (i.e. superficial, nodular, micronodular, sclerosing and basosquamous; n = 3 each) were selected and included in the analysis. Healthy skin was used as a control (n = 6). The results were confirmed by immunohistochemistry (IHC). We validated our findings in two independent public single-cell RNA-Seq (scRNA-Seq) datasets and by RNAscope. The stroma of the different BCC subtypes were found to have distinct gene expression signatures. Nodular and micronodular appeared to have the most similar signatures, while superficial and sclerosing the most different. By comparing low- and high-risk BCC subtypes, we found that COL10A1 is overexpressed in the stroma of sclerosing/infiltrative and basosquamous but not in micronodular high-risk subtypes. Those findings were confirmed by IHC in 93 different BCC and 13 healthy skin samples. Moreover, scRNA-Seq analysis of BCCs from two independent datasets found that the COL10A1-expressing population of cells is associated with the stroma adjacent to infiltrative BCC and shows extracellular matrix remodelling features. We identified COL10A1 as a marker of high-risk BCC, in particular of the sclerosing/infiltrative and basosquamous subtypes. We demonstrated at the single-cell level that COL10A1 is expressed by a specific CAF population associated with the stroma of infiltrative BCC. This opens up new, tailored treatment options, and suggests COL10A1 as a new prognostic biomarker for BCC progression.