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BACKGROUND: Lugol solution is often administered to patients with Graves' disease before surgery. The aim is to reduce thyroid vascularization and surgical morbidity, but its real effectiveness remains controversial. The present study was designed to evaluate the effects of preoperative Lugol solution on thyroid vascularization and surgical morbidity in patients with Graves' disease undergoing total thyroidectomy. METHODS: Fifty-six patients undergoing total thyroidectomy for Graves' disease were randomly assigned to receive 7 days of Lugol treatment (Lugol+ group, 29) or no Lugol treatment (LS- group, 27) before surgery in this single-centre and single-blinded trial. Preoperative hormone and colour Doppler ultrasonographic data for assessing thyroid vascularization were collected 8 days before surgery (T0) and on the day of surgery (T1). The primary outcome was intraoperative and postoperative blood loss. Secondary outcomes included duration of surgery, thyroid function, morbidity, vascularization, and microvessel density at final pathology. RESULTS: No differences in demographic, preoperative hormone or ultrasonographic data were found between LS+ and LS- groups at T0. At T1, free tri-iodothyronine (FT3) and free thyroxine (FT4) levels were significantly reduced compared with T0 values in the LS+ group, whereas no such variation was observed in the LS- group. No differences between T0 and T1 were found for ultrasonographic vascularization in either group, nor did the histological findings differ. There were no significant differences between the LS+ and LS- groups concerning intraoperative/postoperative blood loss (median 80.5 versus 94 ml respectively), duration of surgery (75 min in both groups) or postoperative morbidity. CONCLUSION: Lugol solution significantly reduces FT3 and FT4 levels in patients undergoing surgery for Graves' disease, but does not decrease intraoperative/postoperative blood loss, thyroid vascularization, duration of surgery or postoperative morbidity. REGISTRATION NUMBER: NCT05784792 (https://www.clinicaltrials.gov).

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Background: Lung cancer is still the main cause of cancer death. In the last decades, significant innovations were introduced in non-small cell lung cancer (NSCLC) treatment and management improving patient outcomes. The discovery of immune checkpoint inhibitors and the detection of an increasing list of actionable genetic alterations are enabling a tailored approach. Herein, we assessed in a pragmatic retrospective study the rate of biomarker tests within a large pulmonary pathology-based unit (PPU) network of the Veneto region (Northern Italy). Methods: Each PPU of 7 hubs and spoke centers implemented a biomarker database with pathologic and clinical data of patients with NSCLC diagnosis over 24 months. Results: Out of 1,817 NSCLC cases, 51% were advanced and 49% early stage, with 72% being adenocarcinomas. Programmed death ligand 1 expression and epidermal growth factor receptor mutations were available in most samples, 91% and 78%, respectively. Only 36% of advanced stages received all 5 biomarker tests with an increased rate over time. Co-occurring molecular alterations were detected in 42 cases (2%): the prevalence was (n=17) 41% and (n=25) 59% in early and late-stage adenocarcinomas, respectively. Conclusions: In this real-world study, while most patients received at least one biomarker test, less than 50% had all 5 biomarkers. The screening appeared to increase over time especially with the progressive use of next generation sequencing. Our results confirm the importance of systematic biomarker testing including all NSCLCs based on the evidence of several genomic alterations also in early-stage disease whose analysis may become relevant as neo-adjuvant targeted therapies are available. Keywords: Non-small cell lung cancer (NSCLC); biomarkers; actionable targets; lung cancer.

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This report describes the case of a 46-year-old non-smoker housewife. She presented to our attention having a diagnosis of "difficult asthma" from another center in the previous two years. She had no allergies and had not been exposed to an excessive amount of noxious stimuli. Her chronic respiratory symptoms (dyspnea on exertion with wheezing) remained uncontrolled despite maximal anti-asthmatic inhaled therapy. An HRCT scan was performed to further investigate other pulmonary diseases that mimic asthma. It revealed a pedunculated endotracheal lesion with regular borders that obstructed 90% of the tracheal lumen. The lesion was removed via rigid bronchoscopy with laser endobronchial; histological examination revealed the presence of atypical carcinoid. Atypical carcinoids are a rare subtype of neuroendocrine lung tumor that accounts for 2% of all thoracic malignancies. They frequently arise from the central airways and cause obstructive symptoms such as coughing, wheezing, chest pain, or recurrent obstructing pneumonia, which is caused by central airway obstruction. Clinical onset is gradual and characterized by non-specific symptoms, which frequently result in misdiagnosis. As a result, in a young patient with progressive dyspnea, chronic cough, and wheezing that is not responding to anti-asthmatic treatment, second-level investigations are required and may lead to a definite diagnosis, allowing the appropriate course of treatment to begin.

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OBJECTIVE: Autoimmune gastritis (AIG) is an immunomediated disease targeting parietal cells, eventually resulting in oxyntic-restricted atrophy. This long-term follow-up study aimed at elucidating the natural history, histological phenotype(s), and associated cancer risk of patients with AIG consistently tested H. pylori-negative (naïve H. pylori-negative subjects). DESIGN: Two-hundred eleven naïve H. pylori-negative patients (tested by serology, histology, molecular biology) with AIG (F:M=3.15:1; p<0.001) were prospectively followed up with paired biopsies (T1 vs T2; mean follow-up years:7.5 (SD:4.4); median:7). Histology distinguished non-atrophic versus atrophic AIG. Atrophy was further subtyped/scored as non-metaplastic versus metaplastic (pseudopyloric (PPM) and intestinal (IM)). Enterochromaffin-like-cell (ECL) status was categorised as diffuse versus adenomatoid hyperplasia/dysplasia, and type 1 neuroendocrine tumours (Type1-NETs). RESULTS: Over the long-term histological follow-up, AIG consistently featured oxyntic-predominant-mononuclear inflammation. At T1, PPM-score was greater than IM (200/211 vs 160/211, respectively); IM scores increased from T1 to T2 (160/211 to 179/211), with no changes in the PPM prevalence (T1=200/211; T2=201/211). At both T1/T2, the prevalence of OLGA-III-stage was <5%; no Operative Link on Gastritis Assessment (OLGA)-IV-stage occurred. ECL-cell-status progressed from diffuse to adenomatoid hyperplasia/dysplasia (T1=167/14 vs T2=151/25). Type1-NETs (T1=10; T2=11) always coexisted with extensive oxyntic-atrophy, and ECL adenomatoid-hyperplasia/dysplasia. No excess risk of gastric or other malignancies was found over a cumulative follow-up time of 10 541 person years, except for (marginally significant) thyroid cancer (SIR=3.09; 95% CI 1.001 to 7.20). CONCLUSIONS: Oxyntic-restricted inflammation, PPM (more than IM), and ECL-cell hyperplasia/neoplasia are the histological AIG hallmarks. Compared with the general population, corpus-restricted inflammation/atrophy does not increase the GC risk. The excess of GC risk reported in patients with AIG could plausibly result from unrecognised previous/current H. pylori comorbidity.

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Objectives: Intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis and often demonstrates an anti-apoptotic landscape, which is a key step to chemotherapy resistance. Isocitrate dehydrogenase 1 or 2 (IDH1-2)-mutated ICCs have been described and associated with better prognosis. Ferroptosis is a regulated iron-mediated cell death induced by glutathione peroxidase 4 (GPX4) inhibition, and may be triggered pharmacologically. GPX4 is overexpressed in aggressive cancers, while its expression is inhibited by IDH1 R132C mutation in cell lines. We investigated tissue expression of ferroptosis activation markers in ICC and its correlation with clinical-pathological features and IDH1-2 status. Materials and Methods: We enrolled 112 patients who underwent hepatic resection or diagnostic liver biopsy for ICC. Immunostaining for transferrin-receptor 1 and GPX4, and Pearls' stain for iron deposits were performed to evaluate ferroptosis activation. Immunostaining for STAT3 was performed to study pro-inflammatory and anti-apoptotic landscape. Main IDH1-2 mutations were investigated in 90 cases by real-time polymerase chain reaction. Results: GPX4 overexpression was seen in 79.5% of cases and related to poor histological prognostic factors (grading and perineural and vascular invasion; p < 0.005 for all) and worse prognosis (OS p = 0.03; DFS p = 0.01). STAT3 was expressed in 95.5% of cases, confirming the inflammation-related anti-apoptotic milieu in ICC, and directly related to GPX4 expression (p < 0.0001). A high STAT3 expression correlated to a worse prognosis (OS p = 0.02; DFS p = 0.001). Nearly 12% of cases showed IDH1 105GGT single nucleotide polymorphism, which was never described in ICC up to now, and was related to lower tumor grade (p < 0.0001), longer overall survival (p = 0.04), and lower GPX4 levels (p = 0.001). Conclusion: Our study demonstrates for the first time that in most inflammatory ICCs ferroptosis is not active, and its triggering is related to IDH1-2 status. This supports the possible therapeutic role of ferroptosis-inducer drugs in ICC patients, especially in drug-resistant cases.

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AIMS: This study aimed to identify any microscopic features associated with abnormal (membranous/velamentous or marginal) placental cord insertions and to analyse their adverse neonatal outcomes. METHODS: We retrospectively analysed the records-including pathological findings, clinical information and pregnancy outcomes-for 1060 singleton pregnancies, involving newborn delivered after 24 weeks of gestation. RESULTS: Marginal cord insertions were identified in 26.60% of cases and membranous cord insertions in 2.64%. Subchorionic vessel thrombus was more prevalent in marginal or membranous insertions (0.97%) than in normal cord insertions (0.27%) (p=0.129). Intervillous thrombi (13.73% vs 8.41%, p<0.05) and chorioamnionitis (8.53% vs 5.48%, p=0.089) were more prevalent in normal cord insertions. Premature rupture of membranes was significantly more commonly associated with abnormal (marginal 15.25% and membranous 17.86%) than with normal (9.87%) insertions (p<0.05). Pre-eclampsia was more common in the group with membranous cord insertions (7.14%) than in the other groups (marginal 0.35%; normal 0.80%) (p<0.05). Marginal and membranous placental cord insertions were associated with earlier gestational age at delivery and smaller fetuses than in the group with normal insertions. Intrauterine fetal demise, cardiac malformations and pregestational diabetes were also more common among cases of abnormal cord insertions. CONCLUSIONS: Subchorionic vessel thrombus and adverse pregnancy-related outcomes were more prevalent in cases of marginal/membranous cord insertion than for normal insertions.

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Autoimmune hepatitis (AIH) is a relatively rare non-resolving chronic liver disease, which mainly affects women. It is characterized by hypergammaglobulinemia, circulating autoantibodies, interface hepatitis on liver histology and a favourable response to immunosuppression. The putative mechanism for the development of autoimmune hepatitis is thought to be the interaction between genetic predisposition, environmental triggers and failure of the native immune system.AIH still remains a major diagnostic and therapeutic challenge, mainly because it is a very heterogeneous disease. Prompt and timely diagnosis is crucial since, if left untreated, AIH has a high mortality rate. Histological demonstration of hepatitis is required for the diagnosis of AIH and, therefore, liver biopsy is mandatory in the initial diagnostic work-up, before treatment. In this review, we summarize the histological features of AIH with the main aim of highlighting the most important clinical-pathological hallmarks useful in the routine diagnostic practice.

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Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of different conditions which are characterized by hepatic steatosis in the absence of secondary causes. It is currently the most common chronic liver disease worldwide, and its estimated prevalence is about 1.5-6.5%. The only histological finding of steatosis ("simple" steatosis) represents the uncomplicated form of NAFLD, while non-alcoholic steatohepatitis (NASH) is its inflammatory subtype associated with disease progression to cirrhosis and hepatocellular carcinoma (HCC), and represents the major indication for liver transplantation. NASH is still a diagnostic and therapeutic challenge for clinicians and liver biopsy is currently the only accepted method to reliably distinguish NASH from "simple" steatosis. From the histological perspectives, NAFLD and NASH continue to be an area of active interest for pathologists, with a specific focus on better methods of evaluation, morphologic clues to pathogenesis, and predictors of fibrosis progression. This review focuses on histopathology of NAFLD in adults, with the aim to provide a practical diagnostic approach useful in the clinical routine.

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HCC incidence rates have been rising in the past 3 decades and by 2025 > 1 million individuals will be affected annually. High-throughput sequencing technologies led to the identification of several molecular HCC subclasses that can be broadly grouped into 2 major subgroups, each characterized by specific morphological and phenotypical features. It is likely that this increasing knowledge and a more appropriate characterization of HCC at the pathological level will impact HCC patient management.

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Benign biliary tumor are common lesions that are often an incidental finding in subjects who undergo medical imaging tests for other conditions. Most are true neoplasms while few result from reactive or malformative proliferation. Benign tumors have no clinical consequences, although the premalignant nature or potential for malignant transformation is of concern in some cases. The main practical problem for pathologists is the need to differentiate them from malignant biliary tumours, which is not always straightforward.Premalignant lesions of the bile duct have been described, although their incidence has been poorly characterized. These lesions include biliary mucinous cystic neoplasms, intraductal papillary neoplasms of the bile duct, and biliary intraepithelial neoplasia. In this article, histopathology of benign biliary tumors and biliary tumor precursors is discussed, with a focus on the main diagnostic criteria.

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Liver cancer represents the third leading cause of cancer-related death worldwide. Cholangiocarcinoma (CCA) is the second most common type of liver cancer after hepatocellular carcinoma, accounting for 10-15% of all primary liver malignancies. Both the incidence and mortality of CCA have been steadily increasing during the last decade. Moreover, most CCAs are diagnosed at an advanced stage, when therapeutic options are very limited.CCA may arise from any tract of the biliary system and it is classified into intrahepatic, perihilar, and distal CCA, according to the anatomical site of origin. This topographical classification also reflects distinct genetic and histological features, risk factors, and clinical outcomes. This review focuses on histopathology of CCA, its differential diagnoses, and its diagnostic pitfalls.

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Autoimmune cholestatic liver diseases are rare hepato-biliary disorders characterized by a progressive, inflammatory destruction of bile ducts. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. Both may evolve into secondary biliary cirrhosis and its complications. Therapeutic options are limited and liver transplantation remains the only definitive treatment for PBC and PSC.Most PBC and PSC patients have a typical presentation, which does not require liver biopsy. However, in routine clinical practice, important variants or specific subgroups that benefit from liver biopsy for proper management may be observed. Herein, we provide a general overview of clinical and pathological characteristic of PBC and PSC, highlighting the most important features for routine diagnostic practice.

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Desmoplastic neurotropic melanoma (DNM) is a rare melanoma subtype that shows tropism for the nerves, perineural invasion correlates to higher rate of local recurrence, poorer prognosis and worse morbidity. Given the paucity of typical melanoma features, both clinical and pathological, this confusing skin cancer may act as a pretender, thus leading clinician to misdiagnosis and subsequent inappropriate conservative treatment. Sarcomatoid-like cells rearrangement and absence of pigmentation can lead towards sarcoma diagnosis, so specific skills are required to pathologist to properly recognize this melanoma subtype. In this case report, we present an example of how challenging can be the diagnosis, and how it can affect clinical outcome.

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BACKGROUND: The histological spectrum of oxyntic mucosal atrophy (a major determinant of gastric cancer risk) includes pseudopyloric metaplasia (PPM), which histological assessment has been regarded as unreliable. PPM consistently expresses Trefoil-Factor 2 (TFF2), which is histochemically detecteble (TFF2-IHC). AIMS: Intra- and inter-observer consistency in assessing PPM was examined using both hematoxylin & eosin (H&E) and TFF2-IHC. MATERIALS AND METHODS: Seventy-four oxyntic biopsy samples obtained from autoimmune gastritis were considered. Two serial histological sections obtained from the paraffin-embedded tissue-samples were stained with H&E and TFF2-IHC. Three pathologists (Alpha, Beta, Gamma) independently scored PPM by both staining and the Intra- and inter-observer consistency (H&E versus TFF2-IHC) was calculated using k-statistics and/or Spearman's coefficient. RESULTS: Based on H&E-stain versus TFF2-IHC, intra-observer consistency in PPM assessement was ranked as consistently "good" (k-values: Alpha=0.79; Beta=0.78; Gamma=0.75). Based on H&E, the overall PPM inter-observer consistency among the 3 observers was ranked as "good" (k=0.77) (the inter-observer consistency for pairs of observers was as follows: Alpha versus Beta k=0.88; Alpha versus Gamma k=0.87; Beta versus Gamma k=0.80). Based on TFF2-IHC, the overall PPM inter-observer agreement was ranked as "excellent" (k=0.91) (the inter-observer consistency for pairs of observers was as follows: Alpha versus Beta k=1; Alpha versus Gamma k=0.91; Beta versus Gamma k=0.91). CONCLUSION: Relying on either H&E staining or TFF2-IHC, pathologists assess PPM consistently.

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This manuscript concerns the ethical aspects of the clinical autopsy procedure. Much of the literature on this topic addresses some of the multifaceted issues potentially involved: religious beliefs and/or cultural traditions coming to bear on the management of autopsies, relations between families and healthcare personnel (physicians and technicians) involved in conducting an autopsy, ethical implications of regulations to follow and procedures for obtaining biological samples for further diagnostics or research. All these issues have ethical implications, particularly in today's globalised cultural domain. To preserve for future generations the teaching and scientific value of the clinical autopsy, scientific societies and academic institutions should endorse educational efforts to promote the ethical management of autopsy procedures.

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[This corrects the article DOI: 10.1186/s12935-018-0634-8.].

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Since nutrition might have a significant impact on liver function, we analyzed the early effect of Western-type diet on hepatic tissue and lipid and drug metabolism in Wistar-Kyoto rats (n = 8); eight rats fed with a standard diet were used as controls. Histological analysis of liver tissue was performed, and plasma biochemical parameters were measured. Plasma concentration of six bile acids was determined by ultra-liquid chromatography-tandem mass spectrometry UHPLC-MS/MS. Hepatic gene expressions of enzymes involved in drug and lipid metabolism were assessed by means of real-time reverse transcription (qRT)-PCR. Liver of rats fed with a Western diet did not show macroscopic histological alterations, but number and diameter of lipid droplets increased, as well as DGAT1, GPAT4, SCD, FASN and SREBP2 expression. Furthermore, Western diet-fed animals showed an increase in the activation of hepatic stellate cells and macrophage number in liver tissue, as well as a significant increase in AST and bilirubin levels (p < 0.01), and in the LDL:HDL cholesterol ratio (p < 0.001). Plasma chenodeoxycholic acid concentration increased significantly, whereas cholic acid decreased (p < 0.05), and cytochrome P450 genes were generally downregulated. Significant changes in hepatic lipid and drug metabolism are early induced by the Western diet, prior to steatosis development. Such changes are associated with a peculiar alteration in circulating bile acids, which could represent an early marker of non-alcoholic fatty liver disease (NAFLD) development.

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