Genotype and phenotype characteristics of primary colorectal carcinomas and matched metastatic lesions

Primary colorectal adenocarcinomas tend to exhibit shared genomic alterations with their corresponding metastases. However, a comprehensive understanding of morphologic parameters that are potentially reflective of underlying genotypes is currently lacking. Next generation sequencing (NGS) is currently widely used in translational research in order to explore the molecular landscape of tumors and correlate the findings with various clinicopathologic variables. We examined phenotype (histologic examination) and genotype (NGS) associations in matched pairs of primary and metastatic colorectal adenocarcinomas originating from 75 patients, 44% of which had synchronous and 56% metachronous metastases. The morphologic findings included in the analysis were tumor budding, micronecrosis and tumor infiltrating lymphocytes. Micronecrosis in primary tumors correlated with higher nodal status (p=0.0054) and micronecrosis in metastases (p=0.0216), particularly metachronous ones (p=0.0033). We identified one or more mutations in 64 cases (85.3%) by using an NGS panel of 57 genes. Tumor infiltrating lymphocytes in metastases were associated with mutation burden (p=0.0058) and EGF mutations (p=0.0325), as well as RAS family genes (p=0.0043) and MMR genes (p=0.0069). Increased number of micronecrosis correlated with mutations in APC (p=0.0004) and MSH6 (p=0.0385). Genotypic changes were shared in 90.1% of paired primary and metastatic lesions. However the same mutation was clonal in only 57.1% of these pairs. Metachronous metastases had more private clonal mutations (p=0.0029) than synchronous metastases and in this group, clonal changes correlated with dense tumor infiltrating lymphocytes (p=0.0334) and increased number of micronecrosis (p=0.0133). Dense tumor infiltrating lymphocytes in metachronous lesions were prognostic of more favorable overall survival (log-rank p=0.044). The findings of this study are in line with the clonal evolution model of metastatic progression in colorectal adenocarcinomas, accompanied by a brisk host anti-tumor immune response. This study demonstrates that micronecrosis and tumor infiltrating lymphocytes assessed in metastatic colorectal adenocarcinomas can be of prognostic value and can infer useful information regarding the underlying genomic status of the tumors. If validated in larger case series, these findings can be useful in everyday clinical practice of surgical pathology.Παρόλο που τα πρωτοπαθή καρκινώματα του παχέος εντέρου συχνά εμφανίζουν κοινές γενωμικές αλλοιώσεις με τις μεταστάσεις τους, οι μορφολογικές παράμετροι που μπορεί να υποδηλώνουν τον υποκείμενο γονότυπο στην κάθε θέση ανάπτυξης του όγκου δεν είναι απόλυτα γνωστές. Η αλληλούχιση νέας γενιάς (NGS) χρησιμοποιείται ευρέως πλέον στη μεταφραστική έρευνα προκειμένου να εξερευνηθεί το μοριακό τοπίο των όγκων και να συσχετιστούν τα ευρήματα με διάφορες κλινικοπαθολογοανατομικές παραμέτρους. Εξετάσαμε τις συσχετίσεις φαινοτύπου (ιστολογική εξέταση) και γονοτύπου (αλληλούχιση επόμενης γενιάς, NGS) σε ζεύγη πρωτοπαθών και μεταστατικών αδενοκαρκινωμάτων του παχέος εντέρου από 75 ασθενείς. Τριάντα τρεις (44%) μεταστάσεις ήταν σύγχρονες και σαράντα δύο (56%) μετάχρονες. Συγκρίναμε τα γονοτυπικά χαρακτηριστικά που προέκυψαν από αναλύσεις NGS με τις διηθητικές μικροεκβλαστήσεις του όγκου, τις μικρονεκρώσεις και τις λεμφοκυτταρικές διηθήσεις του όγκου. Οι μικρονεκρώσεις στους πρωτοπαθείς όγκους σχετίστηκαν σημαντικά με το στάδιο μεταστατικής προσβολής των λεμφαδένων (p=0.0054) και τις μικρονεκρώσεις στις μεταστατικές εστίες (p=0.0216), ιδιαίτερα στις μετάχρονες μεταστάσεις (p=0.0033). Χρησιμοποιώντας ένα πάνελ 57 γονιδίων ανιχνεύσαμε μία ή περισσότερες μεταλλάξεις σε 64 περιστατικά (85,3%). Στις μεταστάσεις, πυκνές λεμφοκυτταρικές διηθήσεις συσχετίστηκαν με το συνολικό φορτίο μεταλλάξεων (p=0.0058) και με μεταλλάξεις του EGF (p=0.0325), των γονιδίων RAS (p=0.0043), των γονιδίων MMR (p=0.0069), ενώ αυξημένος αριθμός μικρονεκρώσεων συσχετίστηκε με μεταλλάξεις στα APC (p=0.0004) και MSH6 (p=0.0385). Οι γενωμικές αλλοιώσεις ήταν κοινές στο 90,1% των ζευγών πρωτοπαθούς και μεταστατικού όγκου, ωστόσο η κλωνικότητα της ίδιας μετάλλαξης ήταν κοινή μόνο στο 57,1% των ζευγών αυτών. Σε σύγκριση με τις σύγχρονες μεταστάσεις, οι μετάχρονες είχαν περισσότερες ιδιωτικές κλωνικές αλλαγές (p=0.0291) και στην ομάδα αυτή οι κλωνικές αλλαγές συσχετίστηκαν με πυκνές λεμφοκυτταρικές διηθήσεις του όγκου (p=0.0334) και υψηλό αριθμό μικρονεκρώσεων (p=0.0133). Οι πυκνές λεμφοκυτταρικές διηθήσεις στις μεταστατικές εστίες ήταν προγνωστικές καλύτερης συνολικής επιβίωσης (log-rank p=0.044). Οι παρατηρηθείσες συσχετίσεις φαινοτύπου και γονοτύπου υποστηρίζουν το μοντέλο της κλωνικής εξέλιξης των μεταστάσεων στα αδενοκαρκινώματα του παχέος εντέρου, οι οποίες φαίνεται ότι συνοδεύονται από ισχυρή ανοσιακή απάντηση έναντι του όγκου. Αν ο ρόλος αυτός των μικρονεκρώσεων και των πυκνών λεμφοκυτταρικών διηθήσεων επιβεβαιωθεί σε μελέτες με μεγαλύτερο αριθμό περιστατικών, οι ιστολογικές αυτές παράμετροι θα ήταν σημαντικό να προστεθούν στην φαρέτρα εργαλείων του παθολογοανατόμου για την εκτίμηση των μεταστάσεων από καρκινώματα του παχέος εντέρου

Spitz Melanocytic Tumors: A Fascinating 75-Year Journey

Over the last 75 years, our understanding of Spitz lesions has undergone substantial evolution. Initially considered a specific type of melanoma, the perception has shifted towards recognizing Spitz lesions as a spectrum comprising Spitz nevi, Spitz melanocytomas, and Spitz melanomas. Spitz lesions are known for posing a significant diagnostic challenge regarding the distinction between benign neoplasms displaying atypical traits and melanomas. A comprehensive understanding of their molecular basis and genomic aberrations has significantly improved precision in classifying and diagnosing these challenging lesions. The primary aim of this review is to encapsulate the current understanding of the molecular pathogenesis and distinct clinicopathologic characteristics defining this intriguing set of tumors

Tunica Vaginalis Thickening, Hemorrhagic Infiltration and Inflammatory Changes in 8 Children with Primary Hydrocele; Reactive Mesothelial Hyperplasia? A Prospective Clinical Study

The aim of this study is to describe an entity of primary hydrocele accompanied with fibrosis, thickening and hemorrhagic infiltration of parietal layer of tunica vaginalis (PLTV). During a 4-year period (2011–2014), 94 boys (2.5–14 years old) underwent primary hydrocele repair. Hydrocele was right sided in 55 (58.5 %), left sided in 26 (28.7%) and bilateral in 12 patients (13.8%). Eighty three out of 94 patients (88.30%) had communicating hydrocele and the rest eleven patients (11.7%) had non-communicating. Our case group consists of 8 patients (8.51%) based on operative findings consistent with PLTV induration, thickening and hemorrhagic infiltration. Preoperative ultrasonography did not reveal any pathology of the intrascrotal structures besides hydrocele. There weren’t hyperechoic reflections or septa within the fluid. Evaluation of thickness of the PLTV was not feasible. Presence of lymph or exudate was excluded after fluid biochemical analysis. Tunica vaginalis histological examination confirmed thickening, hemorrhagic infiltration and inflammation, while there was absence of mesothelial cells. Immunochemistry for desmin was positive, excluding malignant mesothelioma. One patient underwent high ligation of the patent processus vaginalis and PLTV sheath fenestration, but one year later, he faced a recurrence. An elective second surgery was conducted via scrotal incision and Jaboulay operation was performed. The latter methodology was our treatment choice in other 7 out of 8 patients. During a 2-year postoperative follow-up, no other patient had any recurrence. We conclude that in primary hydrocele with macroscopic features indicative of tunica vaginalis inflammation, reversion of the tunica should be a part of operative strategy instead of sheath fenestration, in order to minimize the recurrence

Ceruminous Adenoma of the External Auditory Canal: A Case Report with Imaging and Pathologic Findings

Ceruminous adenomas are benign tumors that are rare in humans and present with a nonspecific symptomatology. The treatment of choice is surgical excision. We present an 87-year-old woman who presented with a reddish, tender, round, soft mass of the outer third of the inferior wall of the left external auditory canal, discharging a yellowish fluid upon pressure. Coincidentally, due to her poor general condition, this patient also showed symptoms consistent with chronic otitis media, parotitis, and cervical lymphadenopathy, such as otorrhea, through a ruptured tympanic membrane and swelling of the parotid gland and cervical lymph nodes. The external auditory canal lesion was surgically excised under general anesthesia, utilizing a transmeatal approach. The pathological diagnosis was ceruminous gland adenoma. The tumor was made of tubular and cystic structures and embedded in a fibrous, focally hyalinized stroma. Immunohistochemistry confirmed the presence of two distinct cell populations. The luminal cells expressed keratin 7, while peripheral (basal) cells expressed keratins 5/6, S100 protein, and p63. The apocrine gland-related antigen GCDFP-15 was focally expressed by tumor cells. The postoperative course was uneventful and at the 2-year follow-up no recurrence of the ceruminous adenoma was noted

Cystic Lymphangioma of the Chest Wall in a 5-Year-Old Male Patient: A Rare and Atypical Localization—A Case Report and Comprehensive Review of the Literature

Lymphangioma is a benign congenital malformation. The extremely rare and atypical localization of a lymphangioma in the chest wall was the real motive for the present case study. A 5-year-old boy was admitted to the Emergency Department of the 1st Department of Pediatric Surgery, Aristotle University of Thessaloniki, due to the presence of a mildly painful swelling in the left lateral chest wall, which was first noticed three months ago, after a blunt injury during sport. Physical examination revealed the presence of a palpable, spherical, painful, nut-sized subcutaneous lesion in the left lateral chest wall, respectively, with the anterior axillary line, at the height of the 6th to 7th intercostal space. Presence of ecchymosis on the overlying skin was also noticed. During palpation, we did not notice fluctuation, while transillumination was not feasible. Performance of ultrasonography, including Doppler color flow imaging, followed, depicting a subcutaneous cystic lesion, 2.1⁎3.2 cm in dimensions, without extension to the thoracic cavity. Scheduled surgical excision of the lesion was decided. Histopathological examination documented the diagnosis of cystic lymphangioma. Patient is still followed up on a 6-month basis. He remains asymptomatic, after 2 years, without indication of relapse

Mismatch repair deficiency and aberrations in the Notch and Hedgehog pathways are of prognostic value in patients with endometrial cancer.

The aim of this study was to investigate the prognostic value of the Hedgehog (Gli, Patched-1, Shh, Smo) and Notch (Jag1, Notch2, Notch3) pathway members, in comparison to a panel of proteins (ER, PgR, HER2/neu, Ki67, p53, p16, PTEN and MMR) previously suggested to be involved in the pathogenesis of endometrial cancer, in association with clinical outcome and standard clinicopathological characteristics. A total of 204 patients with histological diagnosis of endometrial cancer treated from 2004 to 2013 were included. The evaluation of protein expression was assessed by immunohistochemistry. Univariate analysis showed that higher Ki67 labeling, expression of PTEN, p16, Notch2 and Notch3 proteins, as well as MMR proficiency were associated with increased relapse and mortality rate. Additionally, Patched-1 protein expression was associated with worse DFS, while p53 overexpression was associated with worse OS. In multivariate analyses, patients with MMR proficient tumors had more than double risk for death than patients with MMR deficient (MMRd) tumors (adjusted HR = 2.19, 95% CI 1.05-4.58, p = 0.036). Jag1 positivity conferred reduced mortality risk (HR = 0.48, 95% CI 0.23-0.97, p = 0.042). However, as shown by hierarchical clustering, patients fared better when their tumors expressed high Jag1 protein in the absence of Notch2 and Notch3, while they fared worse when all three proteins were highly expressed. Patched-1 positivity conferred higher risk for relapse (HR = 2.04, 95% CI 1.05-3.96, p = 0.036). Aberrant expression of key components of the Notch and Hedgehog signaling pathways, as well as MMRd may serve as independent prognostic factors for recurrence and survival in patients with endometrial cancer

Clinical Significance of Major Angiogenesis-Related Effectors in Patients with Metastatic Breast Cancer Treated with Trastuzumab-based Regimens.

PURPOSE: Angiogenesis is a crucial phenomenon in the development and progression of breast cancer (BC), but the clinical significance of angiogenesis-related proteins in metastatic BC remains unknown. This study investigates the prognostic value of vascular endothelial growth factor receptors 1, 2, 3 (VEGFR1, VEGFR2, VEGFR3) as well as vascular endothelial growth factors A and C (VEGFA and VEGFC) in metastatic BC patients treated with trastuzumab-based regimens. MATERIALS AND METHOD: Two hundred female patients were included. Protein and mRNA expression of the studied angiogenesis-related factors were evaluated by immunohistochemistry and quantitative Polymerase Chain Reaction (qPCR), respectively. RESULTS: High expression of VEGFA, VEGFC, VEGFR1, VEGFR2 and VEGFR3 in the tumor cells was observed in 43.5%, 24.2%, 36%, 29.5% and 43%, respectively. Stromal elements expressed high levels of VEGFA, VEGFC, VEGFR1, VEGFR2, VEGFR3 in 78.9%, 93.3%, 90.7%, 90.2 %,74.8% of tumors with available data. High tumor cell expression of VEGFR1 was a favorable prognosticator for survival among patients with HER2-positive tumors (HR=0.55, p=0.013). A trend towards longer progression free survival (PFS) was detected univariately for patients with HER2-negative tumors and high expression of VEGFR2, (HR=0.60, p=0.059). CONCLUSION: VEGFR1 and VEGFR2 seem to have significant prognostic value in BC patients with metastatic disease treated with trastuzumab-based regimens