Lessons from autopsy: Topographical variability of atherosclerosis plaques.

Atherosclerosis is a complex disease characterized by the accumulation of plaques in arterial walls. Understanding its pathogenesis remains incomplete, with factors like inflammation, oxidative stress, and hypertension playing critical roles. The disease exhibits preferential localization of plaques, with variability observed even within the same individual. Genetic, environmental, and lifestyle factors contribute to its heterogeneity. Histological plaque phenotypes vary widely, prompting classification schemes focusing on systemic and local factors deteriorating fibrous caps. Recent research highlights differences in plaque histology among arterial systems, suggesting unique pathophysiological mechanisms. This study reports on multiple atherosclerotic plaques detected at autopsy in various vascular sites of a single subject, emphasizing their histological diversity and underscoring the systemic nature of atherosclerosis.

Mismatch Repair system protein deficiency as a resistance factor for locally advanced rectal adenocarcinoma patients receiving neoadjuvant chemo-radiotherapy.

BACKGROUND: Available data on Mismatch Repair system (MMR) deficiency are conflicting and derived from small studies. Our study aimed to evaluate the therapeutic implications of MMR status in patients with locally advanced rectal cancer (LARC). METHODS: We retrospectively collected data from 318 patients affected by LARC treated in Italy at the Medical Oncology Units of the University Hospital of Cagliari, Istituto Nazionale dei Tumori Milan, and AOU Ospedali Riuniti Ancona. All patients underwent neoadjuvant chemoradiotherapy. The primary objective was major TRG while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). RESULTS: One hundred sixty patients (148 pMMR and 12 dMMR) were included in the exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in the validation cohort. A major TRG has been shown in 42.6% and 43.1% patients with pMMR in exploratory and validation cohort, respectively; while no major TRG have been shown in dMMR patients in both cohorts. Exploratory and validation cohorts showed a statistically significant higher mDFS in pMMR patients compared to dMMR: NR vs. 14 months and NR vs. 17 months, respectively. CONCLUSION: Our results indicated an association between dMMR and poor response to preoperative chemoradiotherapy and they represent a hypothesis-generating data for new neoadjuvant strategies.

Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma.

Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E-cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)-positive/HER2-negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)-stained sections. In set B (62 cases), participants were provided with HE-stained sections and E-cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non-lobular BC versus mixed BC versus ILC. Pairwise inter-observer agreement and agreement with a pre-defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E-cadherin mutation status. Thirty-five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter-observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48-0.66) and substantial in set B (median κ = 0.75, IQR: 0.56-0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57-0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73-0.93, p < 0.001). The median frequency of CDH1/E-cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56-72%) and 73% in set B (IQR: 65-75%, p < 0.001). Cases with variable subtype calls included E-cadherin-positive ILCs harboring CDH1 missense mutations, and E-cadherin-negative ILCs with tubular elements and focal P-cadherin expression. ILCs with trabecular growth pattern were often misclassified as non-lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre-defined reference standard, if assessment is supported by E-cadherin IHC. CDH1 missense mutations associated with preserved E-cadherin protein expression, E- to P-cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification.

Zinc as a Drug for Wilson's Disease, Non-Alcoholic Liver Disease and COVID-19-Related Liver Injury.

Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson's disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson's disease. On the basis of the similarities, at histological level, between Wilson's disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.

Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study.

High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.

Metabolomic analysis of plasma from breast tumour patients. A pilot study.

BACKGROUND: Patients at risk of breast cancer are submitted to mammography, resulting in a classification of the lesions following the Breast Imaging Reporting and Data System (BI-RADS®). Due to BI-RADS 3 classification problems and the great uncertainty of the possible evolution of this kind of tumours, the integration of mammographic imaging with other techniques and markers of pathology, as metabolic information, may be advisable. DESIGN AND METHODS: Our study aims to evaluate the possibility to quantify by gas chromatography-mass spectrometry (GC-MS) specific metabolites in the plasma of patients with mammograms classified from BI-RADS 3 to BI-RADS 5, to find similarities or differences in their metabolome. Samples from BI-RADS 3 to 5 patients were compared with samples from a healthy control group. This pilot project aimed at establishing the sensitivity of the metabolomic classification of blood samples of patients undergoing breast radiological analysis and to support a better classification of mammographic cases. RESULTS: Metabolomic analysis revealed a panel of metabolites more abundant in healthy controls, as 3-aminoisobutyric acid, cholesterol, cysteine, stearic, linoleic and palmitic fatty acids. The comparison between samples from BI-RADS 3 and BI-RADS 5 patients, revealed the importance of 4-hydroxyproline, found in higher amount in BI-RADS 3 subjects. CONCLUSION: Although the low sample number did not allow the attainment of high validated statistical models, some interesting data were obtained, revealing the potential of metabolomics for an improvement in the classification of different mammographic lesions.

Interobserver variability in upfront dichotomous histopathological assessment of ductal carcinoma in situ of the breast: the DCISion study.

Histopathological assessment of ductal carcinoma in situ, a nonobligate precursor of invasive breast cancer, is characterized by considerable interobserver variability. Previously, post hoc dichotomization of multicategorical variables was used to determine the "ideal" cutoffs for dichotomous assessment. The present international multicenter study evaluated interobserver variability among 39 pathologists who performed upfront dichotomous evaluation of 149 consecutive ductal carcinomas in situ. All pathologists independently assessed nuclear atypia, necrosis, solid ductal carcinoma in situ architecture, calcifications, stromal architecture, and lobular cancerization in one digital slide per lesion. Stromal inflammation was assessed semiquantitatively. Tumor-infiltrating lymphocytes were quantified as percentages and dichotomously assessed with a cutoff at 50%. Krippendorff's alpha (KA), Cohen's kappa and intraclass correlation coefficient were calculated for the appropriate variables. Lobular cancerization (KA = 0.396), nuclear atypia (KA = 0.422), and stromal architecture (KA = 0.450) showed the highest interobserver variability. Stromal inflammation (KA = 0.564), dichotomously assessed tumor-infiltrating lymphocytes (KA = 0.520), and comedonecrosis (KA = 0.539) showed slightly lower interobserver disagreement. Solid ductal carcinoma in situ architecture (KA = 0.602) and calcifications (KA = 0.676) presented with the lowest interobserver variability. Semiquantitative assessment of stromal inflammation resulted in a slightly higher interobserver concordance than upfront dichotomous tumor-infiltrating lymphocytes assessment (KA = 0.564 versus KA = 0.520). High stromal inflammation corresponded best with dichotomously assessed tumor-infiltrating lymphocytes when the cutoff was set at 10% (kappa = 0.881). Nevertheless, a post hoc tumor-infiltrating lymphocytes cutoff set at 20% resulted in the highest interobserver agreement (KA = 0.669). Despite upfront dichotomous evaluation, the interobserver variability remains considerable and is at most acceptable, although it varies among the different histopathological features. Future studies should investigate its impact on ductal carcinoma in situ prognostication. Forthcoming machine learning algorithms may be useful to tackle this substantial diagnostic challenge.

The role of neuropathological markers in the interpretation of neuropsychiatric disorders: Focus on fetal and perinatal programming.

The study of neuropathological markers in patients affected by mental/psychiatric disorders is relevant for the comprehension of the pathogenesis and the correlation with the clinical symptomatology. The neuropathology of Alzheimer's disease (AD) recognizes intraneuronal and extracellular neurofibrillary formation responsible for neuronal degeneration. Immunohistochemical studies discovered many interesting results for a better interpretation of the AD pathogenesis, while the "metal hypothesis" supports that metal ions might differentially influence the formation of amyloid aggregates. The most relevant pathological findings reported in schizophrenia originate from computer assisted tomography (CT), Magnetic Resonance Imaging (MRI) studies and Diffusion Tensor Imaging (DTI), suggesting the brain abnormalities involved in the pathophysiology of schizophrenia. The theory of fetal programming illustrates the epigenetic factors that may act during the intrauterine life on brain development, with relevant consequences on the susceptibility to develop AD or schizophrenia later in life. The neuropathological interpretation of AD and schizophrenia shows that the presence of severe neuropathological changes is not always associated with severe cognitive impairment. A better dialogue between psychiatrics and pathologists might help to halt insurgence and progression of neurodegenerative diseases.

Pap-tests with non-hyperchromatic dyskariosis are often associated with squamous intraepithelial lesions of the cervix uteri with eosinophilic features.

BACKGROUND: Squamous intraepithelial lesions of the cervix uteri with eosinophilic features (eosinophilic dysplasia, ED) are a peculiar type of dysplasia with metaplastic phenotype which was described in histological specimens. The cytological features of these lesions have not been studied yet. METHODS: Histological samples from 66 women with features of ED and positive p16(INK4a) staining were included in the study. Within the previous year, all women had at least one pap-test, whose features were recorded and compared with 31 control samples with high-grade dysplasia of usual type. RESULTS: The previous pap-test showed high-grade dysplastic cells with non-hyperchromatic nuclei in 56/66 (84.8%) cases and metaplastic features in 60/66 (90.9%) cases. Conversely, the dysplastic cells of the usual lesions showed non-hyperchromatic nuclei in 6/31 (19.4%) and metaplastic features in 4/31 (12.9%) cases. Statistical analysis showed significant differences in distribution of the non-hyperchromatic nuclei (P < 0.001), metaplastic features (P < 0.001), presence of both non-hyperchromatic nuclei and metaplastic features (P < 0.001) and usual dysplastic features (P < 0.001) among the study and control groups. CONCLUSIONS: A high-grade squamous intraepithelial lesion with non-hyperchromatic nuclei or metaplastic features is often found in the pap-test previous to the histological diagnosis of ED and may represent the cytologic correlate of this particular type of dysplasia. Diagn. Cytopathol. 2016;44:783-786. © 2016 Wiley Periodicals, Inc.

CINtec PLUS immunocytochemistry as a tool for the cytologic diagnosis of glandular lesions of the cervix uteri.

Cytologic findings of glandular lesions of the cervix uteri are often difficult to evaluate. We studied the usefulness of CINtec PLUS p16/Ki-67 double stain (mtm laboratories, Heidelberg, Germany) for the diagnosis of glandular lesions. The study included 47 abnormal results on liquid-based cytologic tests with a subsequent histologic diagnosis of adenocarcinoma in situ or with early invasion, and 16 samples with negative results on follow-up. All samples were stained with CINtec PLUS p16/Ki-67 double stain. Of the neoplastic samples, 7 were excluded because of insufficient residual cellularity or loss of neoplastic cells. Of the samples that were adequate, 92.5% were stained with CINtec PLUS, whereas 7.5% were judged inconclusive. All inconclusive cases were at least 3 years old. Of the 16 negative samples, 15 (93.8%) stained negative and only 1 (6.2%) showed several positive clusters of cells. Our study shows that CINtec PLUS is a robust and useful tool for the diagnosis of glandular lesions of the cervix uteri.

Hepatocyte Paraffin 1 Immunoreactivity in Early Colon Carcinogenesis.

BACKGROUND: This study was aimed at evaluating the correlation between Hepatocyte paraffin 1 (Hep par 1) and colorectal cancer. METHODS: To this end, 50 intestinal biopsies were analyzed including 10 colorectal polyps with low grade dysplasia, 10 with high grade dysplasia, 10 colorectal adenocarcinomas, 10 specimens of normal ileum and 10 of normal colon mucosa. Tissue sections were immunostained for Hep par 1 utilizing a commercial antibody. Normal colonic mucosa did not express Hep par 1. RESULTS: Immunoreactivity for Hep par 1 was detected in 20% of polyps with low grade dysplasia, 50% of polyps with high grade dysplasia and 60% of colorectal carcinomas. Hep par 1 was frequently detected in the deepest areas of adenocarcinomas mainly in infiltrating tumour cells. CONCLUSIONS: Our data show that Hep par 1 immunoreactivity in human colon carcinogenesis is correlated with progression from low grade to high grade dysplasia and adenocarcinoma. In clinical practice, our data show that caution should be taken in utilizing Hep par 1 as the sole tool in differentiating hepatocellular carcinoma from a liver metastasis of colon adenocarcinoma. Our data encourage further investigations into the potential role played by Hep par 1 in gastrointestinal carcinogenesis.

Lymphoepitelioma-like hepatocellular carcinoma: a case report and a review of the literature.

Lymphoepitelioma is a particular form of undifferentiated carcinoma, characterized by a prominent lymphoid stroma, originally described in the nasopharynx. Lymphoid stroma-rich carcinomas arising in other organs have been termed lymphoepithelioma-like carcinoma (LELC). In the liver, primary LELCs are very rare, and the majority has been identified as cholangiocarcinomas. Here a rare case of lymphoepithelioma-like hepatocellular carcinoma (HCC) is described. A 47-year old woman presented with abdominal pain. Ultrasonography revealed a liver nodule, 2.2 cm in diameter, localized in the right lobe, adjacent to the gallbladder. Viral markers for hepatic B virus (HBV), hepatic C virus (HCV) and Epstein-Barr virus (EBV) were negative. The nodule was hypoechogenic. The patient underwent surgery, with resection of the nodule. Histology showed hepatocellular carcinoma, characterized by a prominent lymphoid infiltrate. At immunocytochemistry, tumor cells were reactive for Hep Par1 and glypican 3. Immunophenotyping of tumor infiltrating lymphocytes evidenced the predominance of CD8+ cytotoxic suppressor T cells. The postoperative clinical outcome was favorable and the patient was recurrence-free 15 mo after resection. This case, to the best of our knowledge, is the first reported non EBV and non cirrhosis-associated lymphoepithelioma-like hepatocellular carcinoma. The association between the lack of EBV infection, the absence of cirrhosis, a "cytotoxic profile" of the inflammatory infiltrate and a good prognosis could identify a variant of lymphoepithelioma-like HCC with a favorable clinical outcome.

Synchronous isolated splenic metastasis from colon carcinoma and concomitant splenic abscess: a case report and review of the literature.

This study aimed to describe a case in which an isolated splenic metastasis was synchronous with the colonic primary and a concomitant splenic abscess was associated. A wide review of the literature was also performed. A 54-year-old woman with abdominal pain and fever was admitted to our department. Abdominal CT revealed two low-density areas in the spleen and wall-thickening of the left colonic flexure, which was indistinguishable from the spleen parenchyma. The patient underwent emergency celiotomy, with the presumptive diagnosis of obstructing colon carcinoma of the splenic flexure, and concomitant splenic abscess. Subtotal colectomy and splenectomy were performed. Pathological findings were consistent with mucinous colonic carcinoma, synchronous isolated splenic metastasis and concomitant splenic abscess. This paper is also a review of the existing literature on the association between colorectal cancer and splenic metastasis. Only 41 cases of isolated splenic metastasis from colon carcinoma have been reported in the literature. This report is the third described case of synchronous isolated splenic metastasis from colon carcinoma. Only one case with concomitant splenic abscess has been previously reported. When obstructing left-sided colorectal cancer is suspected, careful CT examination can allow early diagnosis of splenic involvement by the tumor. The literature review suggests that there might be a significant improvement in survival following splenectomy for a metachronous isolated splenic metastasis from colon carcinoma. Prognosis for synchronous splenic metastasis seems to be related to the advanced stage of the disease. Nevertheless, no definitive conclusions can be drawn because of the small number of cases.