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Purpose To assess a radiomic machine learning (ML) model in classifying solid adrenal lesions (ALs) without fat signal drop on chemical shift (CS) as benign or malignant. Method 55 indeterminate ALs (21 lipid poor adenomas, 15 benign pheocromocytomas, 1 oncocytoma, 12 metastases, 6 primary tumors) showing no fat signal drop on CS were retrospectively included. Manual 3D segmentation on T2-weighted and CS images was performed for subsequent radiomic feature extraction. After feature stability testing and an 80–20% train-test split, the train set was balanced via oversampling. Following a multi-step feature selection, an Extra Trees model was tuned with 5-fold stratified cross-validation in the train set and then tested on the hold-out test set. Results A total of 3396 features were extracted from each AL, of which 133 resulted unstable while none had low variance (< 0.01). Highly correlated (r > 0.8) features were also excluded, leaving 440 parameters. Among these, Support Vector Machine 5-fold stratified cross-validated recursive feature elimination selected a subset of 6 features. ML obtained a cross-validation accuracy of 0.94 on the train and 0.91 on the test sets. Precision, recall and F1 score were respectively 0.92, 0.91 and 0.91. Conclusions Our MRI handcrafted radiomics and ML pipeline proved useful to characterize benign and malignant solid indeterminate adrenal lesions.

The nature of endometrial morular metaplasia (MorM) is still unknown. The nuclear β-catenin accumulation and the not rare ghost cell keratinization suggest a similarity with hard keratin-producing odontogenic and hair matrix tumors rather than with squamous differentiation. We aimed to compare MorM to hard keratin-producing tumors. Forty-one hard keratin-producing tumors, including 26 hair matrix tumors (20 pilomatrixomas and 6 pilomatrix carcinomas) and 15 odontogenic tumors (adamantinomatous craniopharyngiomas), were compared to 15 endometrioid carcinomas with MorM with or without squamous/keratinizing features. Immunohistochemistry for β-catenin, CD10, CDX2, ki67, p63, CK5/6, CK7, CK8/18, CK19, and pan-hard keratin was performed; 10 cases of endometrioid carcinomas with conventional squamous differentiation were used as controls. In adamantinomatous craniopharyngiomas, the β-catenin-accumulating cell clusters (whorl-like structures) were morphologically similar to MorM (round syncytial aggregates of bland cells with round-to-spindled nuclei and profuse cytoplasm), with overlapping squamous/keratinizing features (clear cells with prominent membrane, rounded squamous formations, ghost cells). Both MorM and whorl-like structures consistently showed positivity for CD10 and CDX2, with low ki67; cytokeratins pattern was also overlapping, although more variable. Hard keratin was focally/multifocally positive in 8 MorM cases and focally in one conventional squamous differentiation case. Hair matrix tumors showed no morphological or immunophenotypical overlap with MorM. MorM shows wide morphological and immunophenotypical overlap with the whorl-like structures of adamantinomatous craniopharyngiomas, which are analogous to enamel knots of tooth development. This suggests that MorM might be an aberrant mimic of odontogenic differentiation. Supplementary Information The online version contains supplementary material available at 10.1007/s00428-021-03060-2.

In 2010, serrated polyps (SP) of the colon have been included in the WHO classification of digestive tumors. Since then a large corpus of evidence focusing on these lesions are available in the literature. This review aims to analyze the present data on the epidemiological and molecular aspects of SP. Hyperplastic polyps (HPs) are the most common subtype of SP (70–90%), with a minimal or null risk of malignant transformation, contrarily to sessile serrated lesions (SSLs) and traditional serrated adenomas (TSAs), which represent 10–20% and 1% of adenomas, respectively. The malignant transformation, when occurs, is supported by a specific genetic pathway, known as the serrated-neoplasia pathway. The time needed for malignant transformation is not known, but it may occur rapidly in some lesions. Current evidence suggests that a detection rate of SP ≥15% should be expected in a population undergoing screening colonoscopy. There are no differences between primary colonoscopies and those carried out after positive occult fecal blood tests, as this screening test fails to identify SP, which rarely bleed. Genetic similarities between SP and interval cancers suggest that these cancers could arise from missed SP. Hence, the detection rate of serrated-lesions should be evaluated as a quality indicator of colonoscopy. There is a lack of high-quality longitudinal studies analyzing the long-term risk of developing colorectal cancer (CRC), as well as the cancer risk factors and molecular tissue biomarkers. Further studies are needed to define an evidence-based surveillance program after the removal of SP, which is currently suggested based on experts’ opinions.

Pituitary adenomas are among the most frequent intracranial tumors. They may exhibit clinically aggressive behavior, with recurrent disease and resistance to multimodal therapy. The ki-67 labeling index represents a proliferative marker which correlates with pituitary adenoma aggressiveness. Aim of our study was to assess the accuracy of machine learning analysis of texture-derived parameters from pituitary adenomas preoperative MRI for the prediction of ki-67 proliferation index class. A total of 89 patients who underwent an endoscopic endonasal procedure for pituitary adenoma removal with available ki-67 labeling index were included. From T2w MR images, 1128 quantitative imaging features were extracted. To select the most informative features, different supervised feature selection methods were employed. Subsequently, a k-nearest neighbors (k-NN) classifier was employed to predict macroadenoma high or low proliferation index. Algorithm validation was performed with a train-test approach. Of the 12 subsets derived from feature selection, the best performing one was constituted by the 4 highest correlating parameters at Pearson’s test. These all showed very good (ICC ≥ 0.85) inter-observer reproducibility. The overall accuracy of the k-NN in the test group was of 91.67% (33/36) of correctly classified patients. Machine learning analysis of texture-derived parameters from preoperative T2 MRI has proven to be effective for the prediction of pituitary macroadenomas ki-67 proliferation index class. This might aid the surgical strategy making a more accurate preoperative lesion classification and allow for a more focused and cost-effective follow-up and long-term management.

Pituitary tumors are a heterogeneous group of lesions (usually benign) and proper understanding of the anatomy, physiology, and pathology of the hypothalamic/pituitary region is essential to make an accurate diagnosis and define the essential treatment options (i.e., surgery, medical therapies, and radiotherapy, alone or in combination). Surgery is the primary treatment for acromegaly, Cushing disease, thyroid-stimulating hormone-secreting adenomas, resistant prolactinomas, and nonfunctioning pituitary adenomas causing mass effect. Medical and radiation therapy are reserved in cases in which surgery is not possible or does not provide a complete cure. In the last decades, tremendous innovations (i.e., targeted drugs and refined surgical tools and techniques) have expanded the treatment strategies for pituitary adenomas. We herein report the current indications for and depiction of the surgical techniques in pituitary surgery, review current medical treatments, and provide a glimpse of future possibilities.

Meningioangiomatosis is a rare congenital hamartomatous malformation of the leptomeninges that can also involve the adjacent cerebral tissue, sometime arising in association with neurofibromatosis. Here we report the case of a 55-year-old man with neuroradiological evidence of meningioangiomatosis, known to be a well-defined malformative-dysplastic lesion, preceding the onset of central nervous system B-cell lymphoma. We describe for the first time this unusual association, highlighting how meningioangiomatosis could accompany different pathologies more frequently than thought. Keywords: Meningioangiomatosis, Neurofibromatosis, Lymphoma, Magnetic resonance imaging

During the 5th NIKE (Neuroendocrine tumors Innovation in Knowledge and Education) meeting, held in Naples, Italy, in May 2019, discussions centered on the understanding of pathology reports of gastroenetropancreactic neuroendocrine neoplasms. In particular, the main problem concerned the difficulty that clinicians experience in extrapolating relevant information from neuroendocrine tumor pathology reports. During the meeting, participants were asked to identify and rate issues which they have encountered, for which the input of an expert pathologist would have been appreciated. This article is a collection of the most rated questions and relative answers, focusing on three main topics: 1) morphology and classification; 2) Ki67 and grading; 3) immunohistochemistry. Patient management should be based on multidisciplinary decisions, taking into account clinical and pathology-related features with clear comprehension between all health care professionals. Indeed, pathologists require clinical details and laboratory findings when relevant, while clinicians require concise and standardized reports. In keeping with this last statement, the minimum requirements in pathology datasets are provided in this paper and should be a baseline for all neuroendocrine tumor professionals.

Meningiomas recur with a rate of 10–32% at ten years. Several features influence the risk of recurrence. Our aim is to define the pathological and surgical features at risk of diffuse-multicentric versus local-peripheral recurrence. Thirty-three cases of multicentric-diffuse recurrence of intracranial meningiomas were retrospectively analyzed and compared with 50 cases who experienced local-peripheral recurrence. The analyzed factors included age and sex, tumor location and shape, brain-tumor interface, entity of resection, WHO grade, Ki67 MIB1, progesterone receptor (PR) expression, number of reoperations, progression of WHO grade, and outcome. The multicentric-diffuse recurrences were mainly related to flat-shaped and Ki67 Li greater than 4% features at first surgery. Among patients with multicentric-diffuse recurrences, 25 underwent one to three reoperations; among them, 17 are alive with local tumor control or slow progression 2 to 25 years after the initial surgery versus only 2 out of 8 who did not undergo surgery. We conclude that flat-shaped meningiomas and those with Ki67 Li greater than 4% are at higher risk to recur in multicentric-diffuse pattern. Even multiple reoperations over a period of several years may obtain rather long survivals in selected patients with prevalent intradural not anaplastic tumors and not too extensive dural infiltration.

Growing evidence supports the pivotal role played by periprostatic adipose tissue (PPAT) in prostate cancer (PCa) microenvironment. We investigated whether PPAT can affect response to Docetaxel (DCTX) and the mechanisms associated. Conditioned medium was collected from the in vitro differentiated adipocytes isolated from PPAT which was isolated from PCa patients, during radical prostatectomy. Drug efficacy was studied by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide citotoxicity assay. Culture with CM of human PPAT (AdipoCM) promotes DCTX resistance in two different human prostate cancer cell lines (DU145 and PC3) and upregulated the expression of BCL‐xL, BCL‐2, and TUBB2B. AG1024, a well‐known IGF‐1 receptor inhibitor, counteracts the decreased response to DCTX observed in presence of AdipoCM and decreased TUBB2B expression, suggesting that a paracrine secretion of IGF‐1 by PPAT affect DCTX response of PCa cell. Collectively, our study showed that factors secreted by PPAT elicits DCTX resistance through antiapoptotic proteins and TUBB2B upregulation in androgen independent PCa cell lines. These findings reveal the potential of novel therapeutic strategies targeting adipocyte‐released factors and IGF‐1 axis to overcome DCTX resistance in patients with PCa.

BackgroundThe progesterone receptor (PR) is variably expressed in most meningiomas and was found to have prognostic significance. However, the correlation with patient age, tumor location, time to recurrence, and pattern of regrowth has scarcely been discussed.MethodsA surgical series of 300 patients with meningiomas is reviewed. The PR expression was classified as: 0. absent; 1. low (versus multicentric diffuse), and time to recurrence.ResultsThe PR expression has shown lower rate of high expression in the elderly group (p = 0.032) and no sex difference (including premenopausal versus postmenopausal women), higher expression in medial skull base and spinal versus other locations (p = 0.0036), inverse correlation with WHO grade and Ki67-MIB1 (p < 0.0001). Meningiomas which recurred showed at initial surgery higher rates of low or moderately low PR expression than the non-recurrent ones (p = 0.0004), whereas the pattern of regrowth was not significant. Higher rates of PR values ≥80% were found in cases with time to recurrence >5 years (p = 0.036).ConclusionThe higher PR expression in medial skull base meningiomas, the significant correlation with the time to recurrence, the lack of difference of PR expression between premenopausal and postmenopausal women and between local-peripheral versus multicentric-diffuse recurrences are the most relevant unreported findings of this study. The rate of PR expression must be included in the routine pathological diagnosis of meningiomas because of its prognostic significance.

Malignant intraventricular meningiomas (IVMs) are very rare with only a few reported cases. A midline search up to December 2020 selected 40 articles for a total of 65 patients. The inclusion criteria were series and case reports in English language, as well as papers written in other languages, but with abstracts written in English. Malignant IVMs at the first diagnosis (group A, 50 patients) and those with anaplastic transformation from previous WHO grades I and II tumors (group B, 15 patients) were separately analyzed. The unique personal case among 1285 meningiomas (0.078%) is also added. Malignant IVMs mainly occur in women (61%) with a median age of 45 years and are mainly located in the lateral ventricle (93%) and trigonal region (74%), with no cases in the fourth ventricle. Irregular borders (80%), heterogeneous enhancement (83%), and perilesional edema (76%) are the most frequent radiological findings. The histology was mainly pure anaplastic (85%), whereas papillary (7%), rhabdoid (5%), and mixed forms (3%) are very rare. The CSF spread was found in 60% of the cases. The prognosis is very dismal, with an overall median survival of 17.5 months after surgery for the anaplastic forms. Malignant IVMs at initial diagnosis (group A) show better overall survival (25 months) than those occurring from anaplastic transformation of lower grade tumors (group B) (10.1 months).

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host’s metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host’s immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.

Coronaviridae family includes pathogen viruses for humans, that lead to clinical conditions with main respiratory involvement; many of these viruses have notoriously a neuroinvasive potential, as demonstrated by published data on SARS-CoV and MERS-CoV epidemics, as well by results obtained in experimental models. During pandemic of coronavirus disease 2019 (COVID-19), it is noticed that the central nervous system involvement represented a truly significant moment in the history of some COVID-19 patients; indeed, clinical and radiological features published in literature regarding COVID-19 disease are consistent with a neurological involvement. It is also known that histopathological data related to SARS-CoV2 infection have been published with considerable delay, which was even greater for neuropathological information. Moreover, many published data are incomplete, and often the lesions described are not directly related to the action of the virus. In this review, we collected the available radiological and neuropathological information, in order to delineate a more complete picture of the relationship between SARS-Cov2 and brain, focusing our attention on the two most important neuroinvasion routes for the virus. We also highlighted what we consider methodological mistakes both in the autopsy procedures and brain study in COVID-19 deaths. We emphasize the need for a complete study of all the organs in case of autopsy. It is important that through this experience, we no longer do the mistake of neglecting the brain.

Extraovarian germ cell tumors are very rare and their occurrence during pregnancy is exceptional. In this case report an abdominal mass was shown by ultrasonography, during a routine monitoring of a 26-year-old pregnant woman. The patient was left under radiological control in the following months in order to bring the pregnancy to term. A few months after the delivery, the patient underwent surgery and a diagnosis of extraovarian (abdominal) dysgerminoma was made. To the best of our knowledge, there are only 3 other case reports describing an extra-gonadal dysgerminoma occurring during pregnancy. The aim of this study was to report an extremely rare tumor, whose management can be challenging first because this neoplasm has some differences from its ovarian and testicular counterparts. Furthermore, the occurrence during pregnancy makes the multidisciplinary approach mandatory since 3 distinct but not independent entities are involved (tumor, mother and fetus).

The first step leading to metastasis, or for the acquisition of local invasiveness, involves changes in the phenotype of neoplastic cells in the primary tumor. The epithelial&ndash, mesenchymal transition (EMT) is a process that determines the acquisition of a form and a transcriptional program that are characteristic of mesenchymal cells, in epithelial cells. The factors involved in this process are E-cadherin and N-cadherin adhesion proteins and some transcription factors such as Slug and Twist. EMT is a site-specific mechanism that is also active in embryogenesis&mdash, embryonic cells are affected if invested in certain points, probably due to the signals emanating from the cells or groups of surrounding cells. It is known that neuroendocrine neoplasms have a biological behavior that differs in grading, staging, and site. The aim of our study was to investigate the immunohistochemical expression of EMT factors (Twist, Slug, and E-cadherin) in the neuroendocrine neoplasms of the gastrointestinal tract, the pancreas, and lungs, in 65 cases retrieved from the archives of the Department of Pathology, of three hospitals. The immunoscores were compared in each site and correlated with the clinico-pathological parameters. Statistical evaluation revealed an association between the higher Twist immunoscore and higher grading (p value &lt, 0.0001) and staging (p value = 0.0055). Slug was detected only in pancreatic cases where its reduced expression was associated with a higher grading (p value = 0.0033). This data could be of diagnostic utility in the case of metastases from neuroendocrine neoplasm, to define the site of the primitive tumor when the traditional immunohistochemical panel is not sufficient. In summary, our results indicated, first that the EMT is also an active process in neuroendocrine neoplasms. To the best of our knowledge, this was the first study that evaluated the expression of EMT factors in neuroendocrine neoplasms of different districts.

Background: Meningiomas recur with a rate of 10–32% at 10 years. Several features influence the risk of recurrence. Objective: To define the pathological and surgical features at risk of multicentric-diffuse versus local–peripheral recurrence. Methods: Thirty-three patients operated on for intracranial meningiomas who experienced multicentric-diffuse recurrence were retrospectively analyzed. The data of these patients were compared to those of 50 patients who experienced local–peripheral recurrence. The analyzed factors included age and sex, tumor location and shape, brain-tumor interface, entity of resection, WHO grade, Ki67 MIB1, progesterone receptor (PR) expression, number of reoperations, progression of WHO grade, and outcome. Results: Meningiomas which recurred in multicentric-diffuse pattern showed at initial surgery a significantly higher rate of flat-shaped tumors (p =.0008) and of cases with Ki67 Li ≥ 4% (p =.037) than those which recurred in localized-peripheral pattern, whereas other factors did not significantly differ. Among patients with multicentric-diffuse recurrences, 25 underwent one to three reoperations; 17 among them (66%) are alive with local tumor control or slow progression 2–25 years after the initial surgery versus only 2 out of 8 who did not undergo surgery. Conclusions: Flat-shaped meningiomas and those with Ki67 Li ≥ 4% are at higher risk of multicentric-diffuse recurrence. Multiple reoperations over a period of several years may obtain rather long survivals in selected patients with prevalent intradural, not anaplastic tumors and not too extensive dural infiltration.

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10–100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium-stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or

Neuroendocrine neoplasms (NENs) are a group of tumors originating from the neuroendocrine system. They mainly occur in the digestive system and the respiratory tract. It is well-know a strict interaction between neuroendocrine system and inflammation, which can play an important role in NEN carcinogenesis. Inflammatory mediators, which are produced by the tumor microenvironment, can favor cancer induction and progression, and can promote immune editing. On the other hand, a balanced immune system represents a relevant step in cancer prevention through the elimination of dysplastic and cancer cells. Therefore, an inflammatory response may be both pro- and anti-tumorigenic. In this review, we provide an overview concerning the complex interplay between inflammation and gastroenteropancreatic NENs, focusing on the tumorigenesis and clinical implications in these tumors.

Background: Endocrine neoplasms are generally slow-growing tumors that can show hormonal activity and give metastases. In most cases they are benign and clearly malignant forms are easy to diagnose. However, borderline forms may occur and be, for the pathologists, very difficult to classify. In these cases, there is a strong need to identify factors that may aid. Official classification systems for endocrine neoplasms are based on the evaluation of proliferation and, in most cases, they rely on mitotic count. In support, the study of Ki67 is carried out which, however, has not yet been included in any official classification system, except for neuroendocrine neoplasms of the gastro-entero-pancreatic tract. Purpose: The aim of the present study was to investigate the proven or unproven role of Ki67 in endocrine neoplasms, in different districts, in order to bring to light the substantial differences, in terms of proliferation, existing between neoplasms so similar, but at the same time, so different. Methods: A thorough search of English language literature was performed, looking for articles concerning Ki67 in five endocrine neoplasms (pituitary adenomas, thyroid neoplasms, adrenocortical neoplasms, pheochromocytomas and paragangliomas). Results: From 2170, 236 articles were selected and it was seen that the endocrine neoplasm in which Ki67 was most studied was the pituitary, where it still shows a controversial role. In other neoplasms different roles were identified. Conclusion: The pathologist should be aware of the contribution that this proliferative marker can give to the diagnosis and, sometimes, to the therapy selection, for the clinician.

The prognosis of neuroendocrine neoplasms (NENs) is widely variable and has been shown to associate with several tissue- and blood-based biomarkers in different settings. The identification of prognostic factors predicting NEN outcome is of paramount importance to select the best clinical management for these patients. Prognostic markers have been intensively investigated, also taking advantage of the most modern techniques, in the perspective of personalized medicine and appropriate resource utilization. This review summarizes the available data on the possible role of circulating tumor cells and microRNAs as prognostic markers in NENs.

Objective To investigate the diagnostic accuracy of endometrial biopsy performed with hysteroscopic direct visualization using the “grasp technique” for the detection of endometrial carcinoma (EC) histology type and tumor grade. Methods A cross-sectional study including the clinical and pathology records of patients with confirmed EC who underwent definitive surgery at University of Naples was performed. The preoperative diagnosis of endometrial tumor type and grade obtained using the hysteroscopy grasp technique was correlated with the final pathology specimens. Those results were compared to the diagnostic accuracy of the biopsies collected in a cohort of patients who underwent preoperative diagnostic hysteroscopy followed by blind endometrial biopsy using the Novak curette with subsequent surgical definitive treatment at University of Pisa. Statistical analysis was based on frequency data and diagnostic agreement of the pathology results. Results A total of 129 patients were included in the final analysis. An agreement rate of 104/106 (98.1%) for endometrioid type and 15/23 (65.2%) for non-endometrioid type was obtained between preoperative hysteroscopic grasp endometrial biopsy specimens and the final pathology with a coefficient k for G1, G2 and G3 tumors of 0.928, 0.925 and 0.974, respectively. When compared to 121 patients undergoing preoperative blind Novak endometrial biopsy, the hysteroscopic grasp technique was superior in agreement rates for tumor histotype [diagnostic accuracy (0.922 vs 0.890); K value (0.705 vs 0.642)] and grade when in presence of endometrioid type EC (K Cohen 0.354 for G1, 0.263 for G2 and 0.488 for G3). Conclusions Preoperative hysteroscopic guided “grasp” endometrial biopsy provides a more accurate diagnosis of EC histology type and tumor grade when in presence of endometrioid type tumor compared to blind endometrial biopsy obtained using the Novak curette.

BackgroundMachine learning assisted MRI radiomics, which combines MRI techniques with machine learning methodology, is rapidly gaining attention as a promising method for staging of brain gliomas. This study assesses the diagnostic value of such framework applied to dynamic susceptibility contrast (DSC)-MRI in classifying treatment-naïve gliomas from a multi-center patient pool into WHO grades II-IV and across their isocitrate dehydrogenase (IDH) mutation status.Methods333 patients from 6 tertiary centres, diagnosed histologically and molecularly with primary gliomas (IDH-mutant=151 or IDH-wildtype=182) were retrospectively identified. Raw DSC-MRI data was post-processed for normalised leakage-corrected relative cerebral blood volume (rCBV) maps. Shape, intensity distribution (histogram) and rotational invariant Haralick texture features over the tumour mask were extracted. Differences in extracted features between IDH-wildtype and IDH-mutant gliomas and across three glioma grades were tested using the Wilcoxon two-sample test. A random forest algorithm was employed (2-fold cross-validation, 250 repeats) to predict grades or mutation status using the extracted features.ResultsFeatures from all types (shape, distribution, texture) showed significant differences across mutation status. WHO grade II-III differentiation was mostly driven by shape features while texture and intensity feature were more relevant for the III-IV separation. Increased number of features became significant when differentiating grades further apart from one another. Gliomas were correctly stratified by IDH mutation status in 71% of the cases and by grade in 53% of the cases. In addition, 87% of the gliomas grades predicted with an error distance up to 1.ConclusionDespite large heterogeneity in the multi-center dataset, machine learning assisted DSC-MRI radiomics hold potential to address the inherent variability and presents a promising approach for non-invasive glioma molecular subtyping and grading.Key points-On highly heterogenous, multi-centre data, machine learning on DSC-MRI features can correctly predict glioma IDH subtyping in 71% of cases and glioma grade II-IV in 53% of the cases (87% -Shape features distinguish best grade II from grade III gliomas.-Texture and distribution features distinguish best grade III from grade IV tumours.Importance of studyThis work illustrates the diagnostic value of combining machine learning and dynamic susceptibility contrast-enhanced MRI (DSC-MRI) radiomics in classifying gliomas into WHO grades II-IV as well as across their isocitrate dehydrogenase (IDH) mutation status. Despite the data heterogeneity inherent to the multi-centre design of the studied cohort (333 subjects, 6 centres) that greatly increases the theoretical challenges of machine learning frameworks, good classification performance (accuracy of 53% across grades (87% With its strong generalisability property, its ability to further incorporate participating centres and its possible use to identify borderline cases, the proposed machine learning framework has the potential to contribute to the clinical translation of machine-learning assisted diagnostic tools in neuro-oncology.

Ovarian borderline tumors (OBT) are tumors with an intermediate grade of malignancy whose diagnosis is purely based on morphological criteria. They usually occur in young women (under 40 years) and are characterized by a cellular proliferation with slight nuclear atypia and lacking stromal invasion with a destructive pattern. Aim of this study was to explore the immunohistochemical expression of Ki67 proliferative index in OBT and to correlate it with known clinicopathologic prognostic factors in patients older than 40 years.Twenty cases of OBTdiagnosed in the period ranging from 2016 to 2018 were retrieved. Each specimen was taken from hysterectomy or adnexectomy surgery. Immunohistochemical studies were performed on the most representative sample of the tumor. Positive signal was nuclear and it was evaluated by three independent pathologists.Ki67 Labelling Index (L.I.) value ranged from 2% to 40%, with an average value of 14% and a median of 10%. Higher Ki67 L.I. was observed in patients older than 40 years (pvalue = 0.0194) and in those with tumors with a maximum diameter ≥ 10 cm (pvalue = 0.0547). Furthermore, a direct correlation was evident between tumor size value and Ki67 L.I. (p value0.0001, r = 0.7745). Hitherto no known prognostic factor correlated with high Ki67 L.I.Overall, OBT are tumors with greater risk of evolution at a more advanced age and when they are greater in size. The assessment of Ki67 could be a valid support in the diagnosis of a more aggressive tumor. Further studies are needed to assess possible correlation with data concerning recurrences rate, that in our cases were not available.

Oncocytomas are in most cases benign tumors, usually arising in kidneys as well as thyroid, parathyroid, salivary or pituitary glands (1,2). This kind of tumor is extremely rare in adrenals and it is usually discovered as incidental finding because is nonfunctional; however, in about 20% of cases features suggestive for malignancy and/or adrenal hypersecretion have been reported (3). Tumor size criterion often allows to differentiate a benign from a malignant adrenal mass, but in oncocytic neoplasm neither size lesion nor imaging findings are useful for this purpose; indeed, usually oncocytomas present as large adrenal masses and surgical excision is often required (4,5). Therefore, a careful diagnostic evaluation is recommended for lesion characterization as well as for the assessment of potential malignancy. We aimed to describe imaging features of adrenal oncocytoma and to highlight the diagnostic pitfalls that can be encountered in the interpretation of images obtained from different modalities reporting a case of a female patient evaluated in our institution.

We report a case of primitive colonic dedifferentiated liposarcoma along with lymph node metastases. The patient’s clinical, radiologic, surgical, and histologic data were reviewed, as well as the literature on colonic dedifferentiated liposarcoma with a focus on the incidence of lymph node metastasis in gastrointestinal sarcomas and on the differential diagnosis with other spindle cell tumors in the gastrointestinal tract. A 53-year-old man was referred to our hospital with a 3 year-history of pain on the right back that was refractory to drugs. He performed an abdominal computed tomography scan which revealed a colonic wall thickening in the hepatic flexure and a few serosal nodularities. With these findings, the patient underwent an extended right hemicolectomy. On histopathologic examination, it turned out to be a colonic dedifferentiated liposarcoma with lymph node metastases. The present case was a challenging diagnosis both at presurgical and histopathological level because it strongly mimicked a colonic adenocarcinoma. This was due to non-specific clinical and radiological presentation, to the non-characteristic histologic morphology and to the misleading presence of lymph node metastases. Malignant stromal tumors of the gastrointestinal tract beyond gist are fairly rare entities. Colonic dedifferentiated liposarcoma must be kept in mind and must be considered in the differential diagnosis of gastrointestinal tumors.

The basement membrane collagen IV-degrading matrix metalloproteinases -2 and -9 (MMPs) are most often linked to the malignant phenotype of tumor cells by playing a critical role in invasion, metastasis, angiogenesis, and vasculogenesis. We verified the activity of these two MMPs in the sera of patients affected by brain tumors (20 gliomas, 28 meningiomas and 20 metastasis) by zymography. The sera of 25 healthy volunteers with no concomitant illnesses were used for controls. Zymography showed four dominant gelatinolytic bands of 240, 130, 92 (MMP-9) and 72 (MMP-2) kDa. No statistically significant variations of MMP-2 proteolytic activity between patients and healthy individuals were observed. On the contrary, MMP-9 (both monomeric and multimeric forms) lytic activities were significantly higher in tumors specimens compared to healthy controls (p < 0.001). Moreover, MMP-9 immunohistochemistry revealed: (1) a strong reactivity in neoplastic vessels of high-grade gliomas showing an inverse correlation with serum multimeric gelatinolytic activity; (2) a cytoplasmatic reactivity in meningiomas with a significantly increase in atypical meningioma compared with low-grade ones (p = 0.036); (3) a positive correlation between MMP-9 and Ki-67 (Sperman Rho coefficient r = 0.418 and p = 0.034). Our results suggest that serum and tissue MMP-9 might provide clinicians additional objective information in intracranial neoplasms. Finally, it should be possible to use MMP-9 as a target for new forms of therapy. Nevertheless, due to the small number of patients included in the study, the conclusion may not be transferable to the general population and therefore further evaluations are needed.

Granulocytic sarcoma (GS) is a rare extramedullary manifestation of acute myeloid leukemia (AML). GS may develop simultaneously to AML or as a relapse of leukemia, particularly following allogeneic hematopoietic stem cell transplant. Subperiosteal bone, lymph nodes and skin are commonly involved, whereas rhinopharyngeal involvement is less common, with only 14 cases reported in the literature. Due to its rarity, rhinopharyngeal GS may lead to diagnostic pitfalls, particularly when it is poorly differentiated or is without concomitant marrow involvement. Thus, immunohistochemical findings play a key role in diagnosis. The current report describes a case of a 53-year-old female suffering from rhinopharyngeal GS and with a history of AML treated with chemotherapy and radiotherapy, focusing on the importance of the immunohistochemical pattern to assess the right diagnosis. Recent studies have demonstrated that the immunophenotype is of utmost importance for the diagnosis of GS. The high expression of myeloperoxidase (MPO) is common in GS; however, ~30% of GSs do not contain MPO. Therefore, the presence of other markers is required to confirm the diagnosis of GS.

// Luisa Circelli 1, * , Concetta Sciammarella 2, * , Elia Guadagno 3 , Salvatore Tafuto 4 , Marialaura del Basso de Caro 3 , Giovanni Botti 1 , Luciano Pezzullo 5 , Massimo Aria 6 , Valeria Ramundo 2 , Fabiana Tatangelo 7 , Nunzia Simona Losito 7 , Caterina Ierano 1 , Crescenzo D’Alterio 1 , Francesco Izzo 8 , Gennaro Ciliberto 9 , Annamaria Colao 2 , Antongiulio Faggiano 5 , Stefania Scala 1 1 Molecolar Immunology and Immuneregulation, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy 2 Departments of Clinical Medicine and Surgery, “Federico II” University of Naples, Italy 3 Advanced Biomedical Sciences, Division of Pathology, “Federico II” University of Naples, Italy 4 Abdominal Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy 5 Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy 6 Economics and Statistics, “Federico II” University of Naples, Naples, Italy 7 Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy 8 Abdominal Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy 9 Scientific Directorate, Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Naples “Fondazione G. Pascale”, Naples, Italy * These authors have contributed equally to this work Correspondence to: Stefania Scala, e-mail: s.scala@istitutotumori.na.it Antongiulio Faggiano, e-mail: afaggian@unina.it Keywords: chemokine, mTOR, NET, clinical outcome, grading Received: September 18, 2015 Accepted: January 06, 2016 Published: February 26, 2016 ABSTRACT Objective: To evaluate the possible crosstalk between C-X-C chemokine receptor 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12)/C-X-C chemokine receptor 7 (CXCR7) axis with the mammalian target of rapamycin (mTOR) pathway in neuroendocrine tumors (NETs). Methods: Sixty-one human NETs were included into the study. CXCR4/CXCL12/CXCR7 axis and mTOR pathway were assessed by qRT-PCR and immunohistochemistry (IHC). The effect of mTOR inhibitor, RAD001, was evaluated on CXCR4 pathway through proliferation and p-Erk and p-AKT induction. Results: CXCR4/CXCL12/CXCR7 axis and p-mTOR were found to be active and correlated with grading, Ki67 index and tumor stage. mTOR pathway activation significantly correlated with poor prognosis. In human NET cells, CXCL12 induced mTOR signalling while AMD3100 (CXCR4-antagonist) impaired it. The mTOR-antagonist, RAD001, impaired the CXCL12-dependent induction of CXCR4 downstream effectors. Combination of AMD3100 and RAD001 potentiate cell growth inhibition. Conclusions: CXCR4/CXCL12/CXCR7 axis is active in NETs and signals on mTOR. CXCR4 might be considered a prognostic factor in NETs. Combined treatment with AMD3100 and RAD001 may provide clinical benefits in NET patients with drug-resistant.

Introduction Adrenal gland neoplasms are mostly benign. The differential diagnosis between adrenocortical adenoma and carcinoma relies on nine morphologic parameters (Weiss criteria) that are mostly subjective. Although rare, carcinomas represent an aggressive disease that require short time follow-up. For this reason, the diagnosis should be accurate. Neoplasms of the medulla are mostly represented by phaeochromocytomas, all potentially metastatic. Prognostic score systems (GAPP and PASS) have been implemented but not enough objective and useful in borderline cases. More objective parameters should be introduced. Little is known in literature on the inflammatory response in these tumors. Aim of our study was the definition (type, density and distribution) of inflammation in the adrenal neoplasms. Material and methods Immunohistochemistry for CD45 (inflammatory cells), CD20 (B cells) and CD3 (T cells) antibodies was performed in 15 adrenocortical neoplasms and 17 phaeochromocytomas. A manual count of the signal was set for each marker, to establish the cellular type, their density (cells/mm2) and location within the tumor. Fisher's exact test was applied to assess the correlation between the immunoscore and clinico-pathologic parameters. Results The difference of cellular density between the three markers was statistically significant (p value = 0.0028), with highest values for CD45 and CD3. No differences were detected between the periphery and the center of the lesions. The most relevant finding was the detection of a higher immunoscore in adrenocortical adenomas, compared to carcinomas. Moreover, most of phaeochromocytomas showed high expression of inflammation, except the only metastatic case. Conclusions The present study showed that inflammation could represent a valuable diagnostic and potential prognostic parameter, useful for the correct management of these lesions.

The role of macrophages in the growth and the progression of tumors has been extensively studied in recent years. A large body of data demonstrates that macrophage polarization plays an essential role in the growth and progression of brain tumors, such as gliomas, meningiomas, and medulloblastomas. The brain neoplasm cells have the ability to influence the polarization state of the tumor associated macrophages. In turn, innate immunity cells have a decisive role through regulation of the acquired immune response, but also through humoral cross-talking with cancer cells in the tumor microenvironment. Neoangiogenesis, which is an essential element in glial tumor progression, is even regulated by the tumor associated macrophages, whose activity is linked to other factors, such as hypoxia. In addition, macrophages play a decisive role in establishing the entry into the bloodstream of cancer cells. As is well known, the latter phenomenon is also present in brain tumors, even if they only rarely metastasize. Looking ahead in the future, we can imagine that characterizing the relationships between tumor and tumor associated macrophage, as well as the study of circulating tumor cells, could give us useful tools in prognostic evaluation and therapy. More generally, the study of innate immunity in brain tumors can boost the development of new forms of immunotherapy.

Glioblastoma is one of the most malignant cancers, with a distinguishing dismal prognosis: surgery followed by chemo- and radiotherapy represents the current standard of care, and chemo- and radioresistance underlie disease recurrence and short overall survival of patients suffering from this malignancy. ATM is a kinase activated by autophosphorylation upon DNA doublestrand breaks arising from errors during replication, byproducts of metabolism, chemotherapy or ionizing radiations; TP53 is one of the most popular tumor suppressor, with a preeminent role in DNA damage response and repair. To study the effects of the immunohistochemical expression of p-ATM and p53 in glioblastoma patients, 21 cases were retrospectively examined. In normal brain tissue, p-ATM was expressed only in neurons; conversely, in tumors cells, the protein showed a variable cytoplasmic expression (score: +,++,+++), with being completely undetectable in three cases. Statistical analysis revealed that high p-ATM score (++/+++) strongly correlated to shorter survival (P = 0.022). No difference in overall survival was registered between p53 normally expressed (NE) and overexpressed (OE) glioblastoma patients (P = 0.669). Survival analysis performed on the results from combined assessment of the two proteins showed that patients with NE p53 /low pATM score had longer overall survival than the NE p53/ high pATM score counterpart. Cox-regression analysis confirmed this finding (HR = 0.025; CI 95% = 0.002-0.284; P = 0.003). Our study outlined the immunohistochemical expression of p-ATM/p53 in glioblastomas and provided data on their possible prognostic/predictive of response role. A "non-oncogene addiction" to ATM for NEp53 glioblastoma could be postulated, strengthening the rationale for development of ATM inhibiting drugs.

Grade 3 neuroendocrine tumor (NET G3) is a rare new entity that has recently been introduced in the classification of neuroendocrine neoplasms of the pancreas. It is a well-differentiated form, with a high proliferative activity (Ki67 > 20%), and it represents a category whose prognosis is intermediate between NET G2 and poorly differentiated neuroendocrine carcinoma (NEC G3). In sites other than the pancreas, this new category is by far less coded. Herein is reported a case of NET G3 of the stomach, the 13th described in literature. The patient was a 71-year-old man with a mass in the gastric fundus. Histological examination revealed a neuroendocrine tumor that was mostly composed by areas with conventional well-differentiated features and intermediate proliferative rate (< 20 mitoses/10 HPFs and 7% Ki67); part of the tumor was characterized by increased nuclear atypia, a confluent growth pattern, intermediate mitotic activity, and high Ki67 value (25%). The tumor was studied immunohistochemically and molecularly, and the only alteration that came out was MEN1 gene mutation (Lau584SerfsTer5) in both the high- and low-grade components. According to the actual classification of gastric neuroendocrine neoplasms, this case is labeled as NEC G3 but it should be named NET G3, with a much better prognosis than the former. Overall, both morphological pattern and the Ki67 value should be mentioned in the histological report in cases of high-grade neuroendocrine neoplasms because of its clinical significance in defining the prognosis and for new potential therapeutic approaches.

Background Recurrence is a common feature of craniopharyngiomas, benign tumors that origin from squamous epithelial remnants of Rathke’s pouch- arising at any segment of its whole course. There are two histotypes, showing different morphology and clinical behavior: adamantinomatous(adaCP) and papillary (papCP). An univocal strategy of management has not yet been defined, being considered the combination of surgery and radiotherapy the most effective, especially in case of incomplete resection. Therefore, the identification of factors influencing the biological and clinical behaviour is of paramount importance. β-catenin is a cell-cell adhesion protein, whose nuclear localization has been linked to the pathogenesis of adaCP: its nuclear accumulation is associated to the presence of a tumor stem cell subpopulation. The latter is made of cells capable of self-renewal, hence believed to be responsible of recurrence, metastases and resistance to therapy in all tumors. ATM is a kinase activated by autophosphorylation (p-ATM) upon DNA double-strand breaks. It is involved not only in DNA repair, but also in tumor migration and invasiveness. Its expression may have prognostic implications in many neoplastic diseases. Methods In this study, we measured the immunohistochemical expression of β-catenin, stem cell markers (CD133, CD166), Ki67 and pATMin 45 craniopharyngiomas and correlated it with clinicopathologic features. Results Statistical analysis revealed strong correlation of β-catenin with recurrence (p = 0.0039), Ki67 (p = 0.0011, r = 0.4903) and CD166 (p = 0.0002, r = 0.6218). A slight tendency to a higher expression of β-catenin was recorded for adaCP rather than papCP (p = 0.0895).Fisher’s exact test showed that CD166 was significantlyrelated with recurrence (p = 0.0040). Furthermore, cytoplasmic pATM was more expressed in adaCPs (p = 0.0470), compared to papCPs that displayed a more evident nuclear signal (p = 0.0313) instead. Conclusions Backing upon these data, we could weigh in on the need of identifying β-catenin and CD166 as prognostic markersthat could be useful in predicting thebiologicalbehavior, as recurrence risk incraniopharyngiomas. The final goal is to drew up a prognostic algorithm to be of aid in the planning of an appropriate treatment strategy. Furthermore, our findings demonstrate that pATM could be used as additional distinction-marker between the two histotypes.

Background Extramedullary plasmacytoma is a rare neoplasm characterized by monoclonal proliferation of plasma cells outside bone marrow. It accounts for 4% of all non-epithelial sinonasal tumors. According to the literature, radiotherapy is the standard therapy for extramedullary plasmacytoma. However, the conversion rate of extramedullary plasmacytoma to multiple myeloma is reported to be between 11 and 33% over 10 years. The highest risk of conversion is reported during the first 2 years after diagnosis, but conversion has been noted up to 15 years after diagnosis. Once conversion to multiple myeloma is complete, less than 10% of patients will survive 10 years. Case presentation We present three cases of sinonasal extramedullary plasmacytoma who underwent radiotherapy: a 61-year-old white man, a 60-year-old white man, and a 37-year-old white woman. We found long-term survival with stable disease in all three cases. Conclusions The management of solitary extramedullary plasmacytomas of the sinonasal tract is not well established yet. However, the possibility of recurrence and progression to multiple myeloma requires a thorough follow-up protocol. Due to the absence of a standardized protocol for these tumors, we tried to design a tailored long-term follow-up scheme.

The aim of the study was to assess incidence rate, hormonal activity, and local invasiveness and evaluate outcomes of so-diagnosed atypical pituitary adenomas that underwent endoscopic endonasal surgery at the Division of Neurosurgery of Universita degli Studi di Napoli Federico II. According to the 2004 WHO classification, atypical pituitary adenomas are defined by an invasive growth, Ki-67/MIB-1 proliferative index greater than 3 %, high p53 immunoreactivity, and increased mitotic activity. A retrospective analysis of a series of 434 pituitary adenomas that underwent endoscopic endonasal surgery at our department between March 2007 and February 2013 was performed. Fifty adenomas (11.5 %) met the criteria of diagnosis of atypical lesions; 10 (21.6 %) of the 50 patients were recurrent tumors with a previous transsphenoidal surgery. Forty-one (82 %) were macroadenomas, and 21/50 (42 %) showed a clear invasion of the cavernous sinus. Histotype of atypical adenomas figured out to be nonfunctioning in 23 cases (46 %), PRL secreting in 10 cases (20 %), ACTH secreting and GH secreting each apart in 8 patients (16 %), and in a single case a GH/PRL secreting adenoma (2 %). The Ki-67 labeling index ranged from 3.5 to 22.5 % (mean 5.6 %). Tumor recurrence was observed in six cases (12 %) after a mean time of 18 months (range 9-24 months). Mean follow-up was 36.5 months (range 2-80 months). Atypical pituitary adenomas account for ca. 10 % of all pituitary adenomas; these lesions have peculiar features. It should be considered that a strong immunopositivity of p53 and higher Ki-67 LI could predict an increased risk of tumor recurrence, but more studies and larger series are expected to confirm and enlarge the diagnostic and therapeutic management process of these lesions.

Glioblastoma (GB) is a highly aggressive brain tumor with dismal prognosis and its standard of care consists of surgery followed by radiotherapy plus adjuvant chemotherapy with temozolomide (Stupp protocol). The response to therapy is variable and may be affected by the presence, within the tumor, of a proportion of cancer stem cells, implicated in chemo- and radioresistance. The expression of the stem cell markers nestin and CD44 in GBs has been extensively investigated. The aim of our study was to compare the immunohistochemical expression of nestin and CD44 in 25 cases of GBs and evaluate their possible prognostic value in relation to overall survival time. We found that their expression was strongly correlated (p = 0.0090 e r = 0.5320) and this finding was confirmed by observation with double staining techniques. For the first time, we made a separate immunohistochemical examination of membrane and cytoplasmic nestin staining, finding that although the two signals correlated! (p = 0.0184, r =0.4678), they had different impact on survival (respectively) p = 0.0255 and p = 0.6376). Enhanced CD44 expression was associated with poor survival rates even if this finding was not statistically significant (p = 0.4481, k2 = 0.5755). Overall, membrane nestin signal was found to be a valid prognostic factor. Furthermore, the detection of CD44 in GBs could be of value also as predictive marker; hyaluronan-based nanoparticles have already shown an active targeting of this antigen in other tumors.

In the present case, we report the association of multiple ileal neuroendocrine tumors and idiopathic myointimal hyperplasia of the mesenteric veins, 2 rare conditions that could have an etiopathogenetic relationship. Idiopathic myointimal hyperplasia of mesenteric veins implies a near-total obliteration of venular vessels, which can lead to hypoxic disorders. Hypoxia in tumors is associated with increased metastatic potential and resistance to radiotherapy and chemotherapy. Herein we speculated on the existence of a relationship between hypoxia and multiple location of neuroendocrine tumors.

Somatostatin analogues (SSAs) have shown limited and variable antiproliferative effects in neuroendocrine tumours (NETs). Whether tumour control by SSAs depends on grading based on the 2010 WHO NET classification is still unclear. The aim of this study is to evaluate the efficacy of long-acting SSAs in NETs according to Ki67 index. An observational Italian multicentre study was designed to collect data in patients with gastro-entero-pancreatic or thoracic NETs under SSA treatment. Both retrospective and prospective data were included and they were analysed in line with Ki67 index, immunohistochemically evaluated in tumour samples and graded according to WHO classification (G1 = Ki67 index 0-2%, G2 = Ki67 index 3-20%, G3 = Ki67 index > 20%). Among 601 patients with NET, 140 with a histologically confirmed gastro-entero-pancreatic or thoracic NET or NET with unknown primary were treated with lanreotide autogel or octreotide LAR. An objective tumour response was observed in 11%, stability in 58% and progression in 31%. Objective response and tumour stability were not significantly different between G1 and G2 NETs. Progression free survival was longer but not significantly different in G1 than G2 NETs (median: 89 vs 43 months, p = 0.15). The median PFS was significantly longer in NETs showing Ki67 < 5% than in those showing Ki67 ≥ 5% (89 vs 35 months, p = 0.005). SSA therapy shows significant antiproliferative effects in well differentiated low/intermediate-proliferating NETs, not only G1 but also in G2 type. A Ki67 index of 5% seems to work better than 3% to select the best candidates for SSA therapy.

According to the 2007 WHO (World Health Organization) Classification, meningiomas are divided into three grades of malignancy, with different recurrence rate, based exclusively on histopathological parameters. Loss/reduction of PgR (Progesterone Receptor) expression and increased Ki67 L.I. (Labeling Index) have been proven as possible prognostic factors able to predict the relapse of the disease. However, they sometimes result unreliable, especially when discordant. p40 is the short form of the p53 homologue gene p63, also named ∆Np63, and its antibody has recently been introduced as a highly specific diagnostic marker of the squamous cell carcinoma of the lung. Nevertheless its expression has been found in many other unconventional sites (e.g. placenta, urotheluim, etc). Herein we assessed the immuno-expression of p40 protein in a series of 72 meningiomas (35 grade I and 37 grade II) and analyzed its correlation with clinicopathological parameters, overall survival and recurrence free interval. We found that a high p40 score correlated with high histological grade, presence of recurrence, increased Ki67 L.I. and loss/reduction of PgR signal. Moreover, a higher expression of p40 was shown to be a significant prognostic factor for the development of recurrences and resulted a prognostic independent variable in multivariate analysis. Overall, for the first time, we investigated the expression of p40 protein in meningiomas and explored its usefulness as prognostic marker in addition to PgR and Ki67 L.I.

Spindle cell oncocytoma (SCO) is an extremely rare neoplasm of the sellar region recognized as a distinct benign histopathological subtype of pituitary tumors in the 2007 World Health Organization classification of tumors of the central nervous system. The morphology of its neoplastic cells (spindle cells and granular eosinophilic cytoplasm) is common to several other lesions so that immunohistochemistry, together with ultrastructural examination, becomes essential in solving this differential diagnosis. Despite being labeled as benign, recurrence is described. Herein, we report a case of SCO in a 77-year-old man and discuss the diagnostic difficulties, ultrastructural aspects, and prognostic factors.

Patients suffering from Inflammatory Bowel Diseases (IBD) are at increased risk of developing cancers of the gastrointestinal tract (GI). Adenocarcinomas are the most commonly observed GI tumours in IBD, and occur through an in inflammation-driven pathway. A trend toward reduced risk of bowel cancers has been observed in IBD in recent years, presumably related to improved medical treatments. However, some cancers may be independent from active inflammation, probably originating from altered interactions between the extremely active immune system of IBD patients and environmental factors. Data concerning gastrointestinal stromal tumours (GIST) and carcinoids of the GI in IBD patients are scanty. We report our experience with these rare cancers, and provide the readers with an overview on the topic, focusing on distinguishing and peculiar features of GIST and carcinoids of the GI in IBD compared with other cancer types and with general population, and address the treatment of such challenging conditions. Available data do not support an increased risk of GIST in IBD patients, but GI carcinoids may be more commonly observed in Crohn's disease. However, the presentation of GIST and GI carcinoids is protean and does not seem to be associated with disease activity in the involved GI segment in IBD. Conversely, some evidences suggest a potential role of inflammation in sustaining GI carcinoids in IBD. Increased awareness, longer duration of disease, and improved diagnostic modalities should also be considered when evaluating the increasing trend of CaT in CD patients. Treatment of GIST and CaT is not dissimilar from that of non-IBD patients, but prompt suspicion and diagnosis are crucial to achieve optimal outcomes.

In this review, we highlight different aspects of a specialized tumor subset, neuroendocrine tumors. We discuss the terminology applied to these tumors, define their precancerous state, diagnostic criteria, immunohistochemical and molecular markers and finally the grading system that is currently applied to these subset of tumors.

The diagnosis of neuroendocrine tumours in typical sites, as gastrointestinal tract and lung, is based upon well-coded criteria that have become familiar to most of the pathologists. Much more difficult is the recognition and allocation of proper nomenclature to be referred to the same histotype in locations where these tumours have a lower incidence. The aim of our review was to provide a quick handbook of the main diagnostic pitfalls known in literature that can interpose in the histopathological examination of neuroendocrine tumours in rare sites (urinary system and male genital organs, female genital organs, head and neck and breast).

// Paolo D’Arrigo 1, * , Michele Russo 1, * , Anna Rea 1 , Martina Tufano 1 , Elia Guadagno 2 , Maria Laura Del Basso De Caro 2 , Roberto Pacelli 2 , Felix Hausch 3 , Stefania Staibano 2 , Gennaro Ilardi 2 , Silvia Parisi 1 , Maria Fiammetta Romano 1 and Simona Romano 1 1 Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Naples, Italy 2 Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy 3 Technical University Darmstadt Institute of Organic Chemistry and Biochemistry, Darmstadt, Germany * These authors have contributed equally to this work Correspondence to: Maria Fiammetta Romano, email: mariafiammetta.romano@unina.it , romano@dbbm.unina.it Keywords: PD-L1, glioblastoma multiforme, FKBP51, ionizing radiation, SAFit Received: March 10, 2017 Accepted: June 11, 2017 Published: July 17, 2017 ABSTRACT Background: FKBP51 is a co-chaperone with isomerase activity, abundantly expressed in glioma. We previously identified a spliced isoform (FKBP51s) and highlighted a role for this protein in the upregulation of Programmed Death Ligand 1 (PD-L1) expression in melanoma. Because gliomas can express PD-L1 causing a defective host anti-tumoral immunity, we investigated whether FKBP51s was expressed in glioma and played a role in PD-L1 regulation in this tumour. Methods: We used D54 and U251 glioblastoma cell lines that constitutively expressed PD-L1. FKBP51s was measured by immunoblot, flow cytometry and microscopy. In patient tumours, IHC and qPCR were used to measure protein and mRNA levels respectively. FKBP51s depletion was achieved by siRNAs, and its enzymatic function was inhibited using selective inhibitors (SAFit). We investigated protein maturation using N-glycosidase and cell fractionation approaches. Results: FKBP51s was expressed at high levels in glioma cells. Glycosylated-PD-L1 was increased and reduced by FKBP51s overexpression or silencing, respectively. Naive PD-L1 was found in the endoplasmic reticulum (ER) of glioma cells complexed with FKBP51s, whereas the glycosylated form was measured in the Golgi apparatus. SAFit reduced PD-L1 levels (constitutively expressed and ionizing radiation-induced). SAFit reduced cell death of PBMC co-cultured with glioma. Conclusions: Here we addressed the mechanism of post-translational regulation of PD-L1 protein in glioma. FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels. These findings suggest that FKBP51s is a potential target of immunomodulatory strategies for glioblastoma treatment.