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Background: In the transplant setting, the definition of the risk of neoplastic transmission from donor to recipient often requires intraoperative pathological evaluation on frozen sections. Although most lesions can be easily classified into acceptable or unacceptable risk according to the Italian National Guidelines, there are cases in which unusual histologic features cannot be further investigated because of the lack of ancillary techniques on frozen sections., Case Presentation: Here we present a case of a liver lesion in a 51-year-old male donor, subjected to histopathological on-call examination. The frozen sections showed a well-demarcated lesion consisting of epithelioid cells disposed in laminar structures and intermingled with a dense lymphocytic population: this led to organ discard with interruption of the donation process. The definitive histological analysis required an extensive immunohistochemical (IHC) investigation: the final diagnosis was "bile duct adenoma with oncocytic features", eventually confirmed by a strongly positive anti-mitochondrial IHC. Finally, an NGS panel analysis was performed, which revealed NRAS mutation., Discussion: To the best of our knowledge, this is the first case of oncocytic bile duct adenoma confirmed by anti-mitochondrial IHC and with NRAS mutation. The most challenging aspect of this case was represented by the transplant setting. In fact, the oncocytic features and the dense lymphocytic infiltrate represented concomitant unusual histological features that led to the halt of the organ donation procedures., Competing Interests: Declaration of Competing Interest I, DEBORAH MALVI, on behalf of all Authors, declare that there are no conflicts of interest to be disclosed concerning the manuscript “NRAS-Mutated oncocytic benign liver lesion in an organ donor: pitfalls and troubles in frozen section diagnosis and risk assessment”., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen responsible for pandemic coronavirus disease 2019 (COVID-19). It is a highly contagious virus which primarily affects the respiratory tract, nevertheless, the lungs are not the only target organs of the virus. The intestinal tract could represent an additional tropism site for SARS-CoV-2. Several observations have collectively suggested that enteric infections can occur in COVID-19 patients. However, the detection of viral RNA in gastrointestinal (GI) tissue samples has not been adequately investigated and results are conflicting., Aim: To detect the presence of SARS-CoV-2 RNA in intestinal mucosa samples and to evaluate histological features., Methods: The COVID-19 patients hospitalized at an Italian tertiary hospital from April 2020 to March 2021 were evaluated for enrollment in an observational, monocentric trial. The study population was composed of two groups of adult patients. In the first group (biopsy group, 30 patients), patients were eligible for inclusion if they had mild to moderate disease and if they agreed to have a rectal biopsy; in the second group (surgical specimen group, 6 patients), patients were eligible for inclusion if they underwent intestinal resection during index hospitalization. Fifty-nine intestinal mucosal samples were analyzed., Results: Viral RNA was not detectable in any of the rectal biopsies performed (0/53). Histological examination showed no enterocyte damage, but slight edema of the lamina propria with mild inflammatory lymphoplasmacytic infiltration. There was no difference in inflammatory infiltrates in patients with and without GI symptoms. SARS-CoV-2 RNA was detected in fecal samples in 6 cases out of 14 cases examined (42.9%). In the surgical specimen group, all patients underwent emergency intestinal resection. Viral RNA was detected in 2 surgical specimens of the 6 examined, both of which were from patients with active neoplastic disease. Histological examination also pointed out abundant macrophages, granulocytes and plasma cells infiltrating the muscular layer and adipose tissue, and focal vasculitis., Conclusion: Mild-moderate COVID-19 may not be associated with rectal infection by the virus. More comprehensive autopsies or surgical specimens are needed to provide histological evidence of intestinal infection., Competing Interests: Conflict-of-interest statement: All the authors report having no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: The combination of BRAF and MEK inhibitors has deeply changed the treatment of BRAF V600-mutant non-small cell lung cancer patients. These agents demonstrated high antitumor activity as well as safe and manageable toxicity profile. Hypertension, pyrexia and increased liver enzymes are the most common adverse events. Gastrointestinal toxicities are rare, and mainly consist of mild grade vomiting and diarrhea., Case Report: We report the case of 70-year-old man affected by BRAF V600-mutant NSCLC with bilateral lung and bone metastases. First-line treatment with encorafenib (450 mg once daily) and binimetinib (45 mg twice daily) was administered within a clinical trial. At the first radiological assessment, computed tomography (CT) scan showed a partial response and signs of intestinal inflammation were reported. The investigational treatment was timely withheld. The subsequent colonoscopy demonstrated the presence of ulcerative lesions at the caecal tract, and the histological diagnosis suggested a drug-induced colitis. No specific treatment was given as the patient did not report abdominal disturbances. Forty-five days after treatment interruption a new CT scan showed the resolution of bowel inflammation and investigational treatment was resumed at the same doses. The patient is still alive and free of toxicity recurrence after 11 months from treatment initiation. Conclusion. Severe gastrointestinal toxicities are uncommon with BRAF and MEK inhibitors, although cases of colitis and intestinal perforation have already been reported in literature. The pathogenesis seems to be related to the MAPK pathway inhibition performed by MEK inhibitors. These adverse events should be accounted given the potential to evolve into life-threatening conditions., (© 2021. The Author(s).)

While somatic disruptive mitochondrial DNA (mtDNA) mutations that severely affect the respiratory chain are counter-selected in most human neoplasms, they are the genetic hallmark of indolent oncocytomas, where they appear to contribute to reduce tumorigenic potential. A correlation between mtDNA mutation type and load, and the clinical outcome of a tumor, corroborated by functional studies, is currently lacking. Recurrent familial oncocytomas are extremely rare entities, and they offer the chance to investigate the determinants of oncocytic transformation and the role of both germline and somatic mtDNA mutations in cancer. We here report the first family with Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome showing the inherited predisposition of four individuals to develop parathyroid oncocytic tumors. MtDNA sequencing revealed a rare ribosomal RNA mutation in the germline of all HPT-JT affected individuals whose pathogenicity was functionally evaluated via cybridization technique, and which was counter-selected in the most aggressive infiltrating carcinoma, but positively selected in adenomas. In all tumors different somatic mutations accumulated on this genetic background, with an inverse clear-cut correlation between the load of pathogenic mtDNA mutations and the indolent behavior of neoplasms, highlighting the importance of the former both as modifiers of cancer fate and as prognostic markers.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE. In this study, we investigated the enteric submucosal microvasculature and the effect of hypoxia on fibrosis and enteric neurons density in jejunal full-thickness biopsies collected from patients with MNGIE. Orcein staining was used to count blood vessels based on their size. Fibrosis was assessed using the Sirius Red and Fast Green method. Hypoxia and neoangiogenesis were determined via hypoxia-inducible-factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron-specific enolase was used to label enteric neurons. Compared with controls, patients with MNGIE showed a decreased area of vascular tissue, but a twofold increase of submucosal vessels/mm 2 with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index, and HIF-1α protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased interganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of patients with MNGIE. Neoangiogenetic changes, as detected by the abundance of small size vessels in the jejunal submucosa, along with hypoxia provide a morphological basis to explain neuromuscular alterations, vasculature breakdown, and ischemic abnormalities in MNGIE. NEW & NOTEWORTHY Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by a genetically driven defect of thymidine phosphorylase, a multitask enzyme playing a role also in angiogenesis. Indeed, major gastrointestinal bleedings are life-threatening complications of MNGIE. Thus, we focused on jejunal submucosal vasculature and showed intestinal microangiopathy as a novel feature occurring in this disease. Notably, vascular changes were associated with neuromuscular abnormalities, which may explain gut dysfunction and help to develop future therapeutic approaches in MNGIE.

Introduction: Amyloidosis is an uncommon disease caused by the deposition of amyloid fibrils in tissues. This disease does not usually require surgical intervention, which could be warranted in the presence of complications such as bleeding, obstruction, or perforation. We present a case of primary amyloidosis of the colon in a patient affected by polymyositis who underwent Hartmann's procedure after a spontaneous colonic perforation. After 2 months of well-being, the patient underwent two consecutive surgical procedures for stenosis of the ostomy orifice., Areas Covered: A review of the literature has been performed, gathering case reports highlighting the distribution of this disease by age, gender, location, and treatment when available., Expert Commentary: Gastrointestinal amyloid disease is a rare condition, and it could be considered among the rare causes of intestinal perforation. Timely surgical management is often necessary.

Purpose: A retrospective longitudinal study was conducted to identify the cutoff value of infiltration depth for predicting the risk of lymph node metastasis of the neck in a well-defined population of surgically treated patients affected by stage T1 to T2 oral squamous cell carcinoma of the tongue., Patients and Methods: Sixty-seven patients were enrolled in this study. Forty-four patients (65.5%) had pN0 status and 23 (34.5%) had pN(+) status. Thirty-five positive lymph nodes were analyzed. The median follow-up for these patients was 51.4 months., Results: The mean infiltration depth of the N-negative group was 2.4 mm; this was substantially different from the mean value observed in the N-positive group at 5.5 mm. A meaningful cutoff was identified at an infiltration depth value of 4 mm., Conclusion: Infiltration depth was identified as an important predictor for neck nodal status. In this specific population, mortality was associated with increasing tumor infiltration depth., (Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Ghost cell odontogenic carcinomas are rare neoplasms that arise in the maxillary bones either from a calcifying odontogenic cyst or de novo. They are aggressive locally and can metastasize. We report herein a case of a ghost cell odontogenic carcinoma arising in the mandible of a Caucasian male 86 years of age. We have described the clinical and radiographic features, histological characteristics, immunohistochemistry findings, and surgical treatment. We especially focused on how Ki-67 expression guides the treatment choice. Finally, we reviewed 32 cases described in the literature and compared them with the cases described up until 2014 to help clinicians identify the diagnostic characteristics of and select appropriate treatment modalities for ghost cell odontogenic carcinomas.

Objective: Perineural invasion (PNI) is frequent in oral squamous cell carcinoma (OSCC) and could play an important role in treatment decisions., Study Design: This retrospective study used multivariate analysis to evaluate the impact of PNI on locoregional recurrence, neck metastases, and survival in 236 consecutive patients with oral cancer., Results: There were significant differences in the local (P = .007) and regional (P = .041) failure rates in the PNI-positive group compared with the PNI-negative group. Univariate analysis demonstrated that PNI-positive patients had significantly worse locoregional control (P = .011), disease-specific survival (P = .023), and overall survival (P = .046) compared with PNI-negative patients., Conclusion: PNI was an independent predictor of local and regional failure in a well-defined, homogeneous population with OSCC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Preoperative chemoradiotherapy has been widely adopted as the standard of care for stage II-III rectal cancers. However, patients with T3N0 lesions had been shown to have a better prognosis than other categories of locally advanced tumor. Thus, neoadjuvant chemoradiation is likely to be overtreatment in this subgroup of patients. Nevertheless, the low accuracy rate of preoperative staging techniques for detection of node-negative tumors does not allow to check this hypothesis. We analyzed a group of patients with cT3N0 low rectal cancer who underwent neoadjuvant chemoradiotherapy with the purpose of evaluating the incidence of metastatic nodes in the resected specimens., Methods: Between January 2002 and February 2008, 100 patients with low rectal cancer underwent clinical staging by means of endorectal ultrasound, computed tomography, positron emission tomography, and magnetic resonance imaging. All patients received preoperative 5-fluorouracil-based chemoradiotherapy and surgical resection with curative aim., Results: Of 100 patients with locally advanced rectal cancer, 32 were clinically staged as T3N0M0. Pathological analysis showed the presence of lymph node metastases in nine patients (28%) (node-positive group). In the remaining 23 cases, clinical N stage was confirmed at pathology (node-negative group). Node-positive and node-negative groups differ only in the number of ypT3 tumors (P < .01)., Conclusions: Our results indicate that immediate surgery for patients with cT3N0 rectal cancer represents an undertreatment risk in at least 28% of cases, making necessary the use of postoperative chemoradiotherapy. Preoperative chemoradiotherapy should be the therapy of choice on the grounds of the principle that overtreatment is less hazardous than undertreatment for cT3N0 rectal cancers.

Aims: The presence of ground glass hepatocytes in a liver biopsy may be related to different conditions, including fibrinogen storage disease. Three types of fibrinogen storage disease have been described, namely types I, II and III. Type I is an hereditary hypofibrinogenaemia genetically characterized by a mutant variant of the fibrinogen molecule designated as fibrinogen Brescia, consistent with a gamma284 Gly-->Arg mutation. Only rare cases of types II and III fibrinogen storage disease have been described. The purpose of the present paper is to describe two cases of fibrinogen storage disease without associated hypofibrinogenaemia, which appeared during acute infectious diseases., Methods and Results: Both patients were female, aged 77 and 73 years, who developed high transaminases during an infectious disease. In each case blood coagulation tests were within the normal range, and despite clinical and laboratory investigations no possible cause for liver disease could be found. Liver biopsies were performed; in both cases weakly eosinophilic cytoplasmic inclusions were observed. Using immunohistochemistry the inclusions were found to be due to fibrinogen accumulation. At ultrastructural level features corresponding to type II inclusions were observed. Molecular studies, performed in case 2, excluded the mutation typical of type I fibrinogen storage disease. Both patients also presented features of chronic hepatitis. In case 1, giant cell granulomas were additionally present. No close relatives of the patients presented any clinical or laboratory features of liver disease. In both patients altered liver function test values gradually, spontaneously, returned to within normal ranges after infectious disease was resolved., Conclusions: These cases suggest that, on rare occasions, hepatocytes may accumulate fibrinogen during an infectious disease.

The immunohistochemical expression and distribution of epidermal growth factor receptor (EGFr) in mammary myoepithelial cells (MECs) in normal tissue, benign epithelial proliferative lesions, and in situ carcinoma was performed. Results of the current study demonstrated that MECs stained constantly and strongly for EGFr, creating an outer continuous ring surrounding the epithelium of ducts and acini in healthy, in proliferative epithelial lesions, and in in situ carcinoma, both of ductal and lobular type. Foci of microinvasion were easily appreciated for the complete loss of EGFr immunostaining. Epidermal growth factor receptor expression in normal epithelia ranged from negative to weakly positive; it was positive in hyperplasia, whereas it was not constantly negative in in situ carcinoma. In conclusion, immunohistochemical staining for EGFr is diagnostically useful for MEC identification. The specific EGFr in MECs leads the authors to suggest that its expression may be related to the recently recognized high-specialized paracrine function by which the MECs exert the natural mechanical and functional role in the juxtaposition between epithelium and stoma.

A case of hyperkeratosis follicularis et parafollicularis in cutem penetrans Kyrle's disease in a 41-year-old woman is described. It was a recurrence of a lesion surgically removed and originally diagnosed as invasive squamous cell carcinoma. Kyrle's disease is a rare dermatosis and should not be confused with neoplastic conditions i.e. squamous cell carcinoma. Pathologists should be aware of such conditions in order to avoid misdiagnosis, which can imply over treatment for the patient.

Here we describe a case of gastrointestinal autonomic nerve tumor (GANT) arosen in a patient with von Recklinghausen's disease. To the best of our knowledge, only four other similar cases have been previously reported in the literature. Histologically, the tumour was composed of spindle shaped cells arranged in short bundles. The neoplastic cells had pleomorphic nuclei and numerous mitoses. Immunohistochemical investigation displayed evidence of neural differentiation. Neoplastic cells were diffusely anti-synaptophysin, anti-neuron specific enolase and anti-vimentin positive. The clinicopathological features of the present case are described and discussed together with those of the other previously reported cases.

We have studied 25 thymomas by both immunohistochemistry and in situ hybridization for the presence of growth hormone (GH)-producing cells. Our results indicate that 1) GH-immunoreactive cells were present in 13 of 17 thymomas of cortical and predominantly cortical type but not in medullary (spindled) thymomas (n = 3) or low- to high-grade thymic carcinomas (n = 5), 2) GH-positive cells were mainly located at the periphery of the neoplastic lobules, at the periphery of the perivascular spaces and in the areas of medullary differentiation, 3) cells containing GH mRNA appeared at locations similar to those of GH-immunoreactive cells, and 4) GH-immunoreactive material was present only in the epithelial cell component as revealed by immunoelectron microscopy. In conclusion, this paper demonstrates the occurrence of GH-producing cells in noncarcinoid thymic tumors. The relevance of GH in thymoma cell biology requires additional investigations.