Pathobiology最新文献

Introduction: Triple-negative breast cancer (TNBC) is associated with alterations in the retinoblastoma pathway. As a consequence of retinoblastoma protein (pRB) loss, compensatory upregulation of p16 occurs due to the loss of phosphorylated pRB-mediated negative feedback on p16 expression. The aim of this study is to investigate the clinicopathologic and genomic characteristics associated with the diffuse pattern of p16 immunohistochemistry (IHC) in TNBC.

Methods: The study analyzed surgically resected TNBC for whole-exome sequencing in 113 cases and for cDNA microarray in 144 cases. The p16 IHC results were classified into two patterns: diffuse and negative/mosaic.

Results: In the entire cohort (n = 257), the diffuse pattern of p16 IHC was observed in 123 (47.9%) patients and the negative/mosaic pattern in 134 (52.1%). Bi-allelic RB1 inactivation was observed in 14.3% of patients with the diffuse pattern. The diffuse pattern of p16 IHC showed more frequent RB1 alterations and cell cycle progression signatures, a higher Ki-67 labeling index, more frequent chromosome segment copy number changes, a higher frequency of homologous recombination deficiency high, and immune-related signatures. PIK3CA mutations were more frequent in the negative/mosaic pattern. CCND1 amplification was identified in five cases, all with the negative/mosaic pattern Conclusion: In TNBC, the diffuse p16 pattern shows clinical and genomic similarities to pRB-deficient tumors, suggesting shared characteristics. This suggests that p16 IHC testing may provide new therapeutic approaches, underscoring its potential clinical importance.

Introduction: Artificial intelligence image recognition has applications in clinical practice. The purpose of this study was to develop an automated image classification model for lung cancer cytology using a deep learning convolutional neural network (DCNN).

Methods: Liquid-based cytology samples from 8 normal parenchymal (N), 22 adenocarcinoma (ADC), and 15 squamous cell carcinoma (SQCC) surgical specimens were prepared, and 45 Papanicolaou-stained slides were scanned using whole-slide imaging. The final dataset of 9,141 patches consisted of 2,737 N, 4756 ADC, and 1648 SQCC samples. Densenet-121 was used as the DCNN to classify N versus malignant (ADC+SQCC) and ADC versus SQCC images. AdamW optimizer and 5-fold cross-validation were used in the training.

Results: For malignancy prediction, the sensitivity, specificity, and accuracy were 0.97, 0.85, and 0.94, respectively, in the patch-level classification, and 0.92, 0.88, and 0.91, respectively, in the case-level classification. For SQCC prediction, the sensitivity, specificity, and accuracy were 0.86, 0.91, and 0.90, respectively, in the patch-level classification and 0.73, 0.82, and 0.78, respectively, in the case-level classification.

Conclusion: The DCNN model performed excellently in predicting malignancy and histological types of lung cancer. This model may be useful for predicting cytopathological diagnosis in clinical situations by reinforcing training.

Introduction: Minichromosome maintenance complex component 7 (MCM7) plays an essential role in proliferation and DNA replication of cancer cells. However, the expression and prognostic significance of MCM7 in breast cancer (BC) remain to be defined. In this study, we aimed to evaluate the role of MCM7 in BC.

Methods: We conducted immunohistochemistry staining of MCM7 in 1,156 operable early-stage BC samples and assessed MCM7 at the transcriptomic levels using publicly available cohorts (n = 13,430). MCM7 expression was evaluated and correlated with clinicopathological parameters including Ki67 labelling index and patient outcome.

Results: At the transcriptomic level, there was a significant association between high MCM7 mRNA levels and shorter patient survival in the whole cohort and in luminal BC class but not in the basal-like molecular subtype. High MCM7 protein expression was detected in 43% of patients and was significantly associated with parameters characteristic of aggressive tumour behaviour. MCM7 was independently associated with shorter survival, particularly in oestrogen receptor-positive (luminal) BC. MCM7 stratified luminal tumours with aggressive clinicopathological features into distinct prognostic groups. In endocrine therapy-treated BC patients, high MCM7 was associated with poor outcome, but such association disappeared with administration of adjuvant chemotherapy. Patients with high expression of Ki67 and MCM7 showed worst survival, while patients with double low expression BC showed the best outcome compared with single expression groups.

Conclusion: The current findings indicate that MCM7 expression has a prognostic value in BC and can be used to identify luminal BC patients who can benefit from adjuvant chemotherapy.

Introduction: Defining the origin of metastatic cancer is crucial for establishing an optimal treatment strategy, especially when obtaining sufficient tissue from secondary malignancies is limited. While cytological examination is often used in this diagnostic setting, morphologic analysis alone often fails to differentiate metastases derived from the breast from other primaries. The hormone receptor, human epidermal growth factor receptor-2 (HER2), gross cystic disease fluid protein 15 (GCDFP-15), and mammaglobin immunohistochemistry are often used to diagnose metastatic breast cancer. But their effectiveness decreases in estrogen-receptor (ER)-negative breast cancers, including the triple-negative breast cancer (TNBC) subtype.

Methods: We conducted a comprehensive evaluation of GATA-binding protein 3 (GATA-3), trichorhinophalangeal syndrome type 1 (TRPS-1), and Matrix Gla Protein (MGP) immunochemistry across 140 effusion cytology specimens with metastatic adenocarcinoma derived from various primaries, including the breast, colon, pancreaticobiliary, lung, ovary, and stomach.

Results: The expression rates of these immunomarkers were significantly higher in metastatic cancers originating from the breast than in other primaries. In TNBC, TRPS-1 (80.00%) and MGP (65.00%) exhibited higher positivity rates compared to GATA-3 (40.00%). Additionally, our data suggests that an immunohistochemical panel comprising MGP, GATA-3, and TRPS-1 significantly enhances the detection of metastatic breast cancer in effusion cytology specimens, including TNBC in particular. When considering dual-marker positivity, the diagnostic accuracy was calculated to be 89.29% across all breast cancer subtypes and 92.93% for TNBC.

Conclusions: MGP appears to be a robust marker for identifying metastatic breast cancer in malignant effusions, especially TNBC. MGP notably enhances diagnostic accuracy when incorporated together with GATA-3 and TRPS-1 in an immunohistochemical panel.

Introduction: Although urothelial papilloma (UP) is an indolent papillary neoplasm that can mimic the morphology of low-grade papillary urothelial carcinoma (PUC), there is no immunomarker to differentiate reliably these two entities. In addition, the molecular characteristics of UP are not fully understood.

Methods: We conducted an in-depth proteomic analysis of papillary urothelial lesions (n = 31), including UP and PUC along with normal urothelium. Protein markers distinguishing UP and PUC were selected with machine learning analysis, followed by internal and external validation using immunohistochemistry.

Results: In the proteomic analysis, UP and PUC showed overlapping proteomic profiles. We identified EHD4 and KRT18 as candidate diagnostic biomarkers of UP. Through immunohistochemical validation in two independent cohorts (n = 120), KRT18 was suggested as a novel UP diagnostic marker, able to differentiate UP from low-grade PUC. We also found that 3.5% of patients with UP developed urothelial carcinoma in subsequent resections, supporting the malignant potential of UP. KRT18 downregulation was significantly associated with UPs subsequently progressing to urothelial carcinoma, following their initial diagnosis.

Conclusion: This is the first study that successfully revealed UPs comprehensive proteomic landscape, while it also identified KRT18 as a potential diagnostic biomarker of UP.

Introduction: Many mouse models for autoimmune diseases also have lesions in non-target organs, which may make it difficult to determine whether the target organ lesion is primary or secondary. Hyposalivation has conventionally been studied using genetically modified mouse models for Sjogren's syndrome as well as spontaneous autoimmune mice with systemic lesions, none of which has salivary gland-specific injury.

Methods: In this study, we established a salivary gland-specific injury mouse model using the TRECK system by gene modification with the transgene composed of the 5' untranslated region of human salivary mucin gene MUC7 (highly expressed specifically in human salivary gland) inserted at the upstream of hHB-EGF (diphtheria toxin receptor) in the TRECK vector.

Results: In this transgenic mouse model, we confirmed salivary gland-specific expression of hHB-EGF gene, and hyposalivation after treatment with diphtheria toxin. Histological assessment of the salivary gland from these mice showed granular convoluted tubule epithelial cells destruction at the same position as a positivity in TUNEL assay.

Conclusion: This transgenic mouse model may become a useful tool for elucidating the mechanisms involved in hyposalivation and for developing pharmaceuticals and tissue regenerative medical products for this condition.

Background: Perineural invasion (PNI) is a complex molecular process histologically represented by the presence of tumor cells within the peripheral nerve sheath and defined when infiltration into the 3 nerve sheath layers can be clearly identified. Several molecular pathways have been implicated in cSCC. PNI is a well-recognized risk factor in cutaneous squamous cell carcinoma (cSCC) and its accurate assessment represents a challenging field in pathology daily practice.

Summary: As a highly intricate and dynamic process, PNI involves a contingent on bidirectional signaling interactions between the tumor and various nerve components, such as Schwann cells and neurons. The current staging systems recommend the identification of PNI as a dichotomous variable (presence vs. absence) to identify a subgroup of high-risk patients. However, recent further insights revealed that the evaluation of morphological PNI-related features in cSCC may enhance the prognostic stratification of patients and may optimize the current staging guidelines for recurrence risk assessment and improvement of patient selection for postoperative adjuvant treatments. Furthermore, recent emerging biomarkers could redefine early PNI detection.

Key messages: This review provides updated insights into cSCC with PNI, focusing on molecular and cellular pathogenic processes, and aims to increase knowledge on prognostic relevant PNI-related histological features.

Introduction: The tumor microenvironment of sarcomas has not been studied in detail; in particular, little is known about cancer-associated fibroblasts (CAFs). Sarcoma cells are difficult to distinguish from CAFs, either histomorphologically or immunohistochemically.

Methods: We scored the expression of individual CAF markers (fibroblast-activating protein [FAP], CD10, and podoplanin) in the intratumoral and marginal areas of 133 sarcomas. We also examined the association between these markers, as well as the number of CD163-positive macrophages (i.e., tumor-associated macrophages), and clinical outcome.

Results: In all cases, the log-rank test revealed that those with high marker scores and macrophage counts (except for marginal CD10+ CAFs) showed significantly worse disease-free survival (DFS). Grade 2/3 cases with high CAF scores (excluding the marginal FAP and CD10 scores) showed significantly worse DFS, whereas those with high intratumoral FAP/CD10 and marginal podoplanin scores showed significantly worse metastasis-free survival (MFS), and those with high intratumoral CD10 score showed significantly worse local recurrence-free survival (LFS). Multivariate analysis identified intratumoral CD10/podoplanin scores and marginal FAP/podoplanin scores as independent prognostic factors for DFS, intratumoral FAP/CD10 and marginal FAP/podoplanin/CD163-positive macrophage scores as independent prognostic factors for MFS, and the intratumoral podoplanin score as an independent prognostic factor for LFS. There was a weak-to-moderate correlation between each score and CD163-positive macrophage counts.

Conclusion: Patients with high CAF marker expression in the intratumoral and marginal areas have a poorer outcome.

Introduction: Diagnosing low-grade adenosquamous carcinoma (LGASC) presents significant challenges due to its subtle morphology, variable immunohistochemical expression, and resemblance to benign lesions like radial scar and complex sclerosing lesions.

Case presentation: We present a case of a 53-year-old woman with a subareolar mass initially thought to be a fibroepithelial neoplasm on core biopsy. Subsequent wide excision revealed LGASC with oestrogen receptor expression (weak to moderate intensity, 40% of tumour cells).

Conclusion: These findings, rarely reported, highlight the difficulty of diagnosing LGASC on small tissue samples.