Loss of ATRX and DAXX in pancreatic neuroendocrine tumors: Association with recurrence risk, cellular phenotype, and heterogeneity.

Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of neoplasms in terms of biological behavior. This study aims to develop a practical algorithm based on emerging biomarkers, including chromatin-remodeling molecules DAXX/ATRX/H3K36me3, in conjunction with established prognostic factors, such as WHO grade and size. In immunohistochemical analyses, 18 of the 111 (16.2%) primary PanNETs showed DAXX or ATRX loss in a mutually exclusive manner. DAXX/ATRX loss was significantly correlated with higher recurrence risk and better predicted postoperative recurrence than WHO grade. We proposed a novel algorithm for stratifying patients with resectable PanNET into three groups according to recurrence risk: (A) WHO Grade 1 and ≤2 cm (very low-risk); for the others, (B) retained DAXX/ATRX (low-risk) and (C) DAXX/ATRX complete/heterogeneous loss (high-risk). Furthermore, we elucidated the intratumoral heterogeneities of PanNETs. Among cases with DAXX or ATRX loss, nine cases demonstrated heterogeneous loss of expression of DAXX/ATRX/H3K36me3. The majority of cases with DAXX/ATRX loss, either homogeneous or heterogeneous loss, showed uniform α-cell-like phenotype (ARX1+/PDX1-). In cases of metastatic or recurrent tumors, the expression pattern was identical to that observed in at least part of the primary tumor. In some instances, the expression pattern differed among different metastatic or recurrent tumors of the same patient. In summary, we propose a clinically useful and practical algorithm for postoperative recurrence risk stratification in PanNETs, by combining DAXX/ATRX status with WHO grade and size. Moreover, our findings highlighted the frequent spatiotemporal heterogeneity of chromatin-remodeling molecule expression in PanNETs with an α-cell phenotype, offering insights into tumorigenesis.

Intrasellar chordoma masquerading as a pituitary neuroendocrine tumor: Illustrative case.

Background: Chordomas are rare, locally aggressive neoplasms recognized as derivatives of the notochord vestiges. These tumors typically involve the midline axial skeleton, and intracranial chordomas exhibit proclivity for the spheno-occipital region. However, purely intrasellar occurrences are extremely rare. We report a case of intrasellar chordoma, which masqueraded as a pituitary neuroendocrine tumor. Case Description: An 87-year-old female presented with an acutely altered mental state after a few-week course of headaches and decreased left vision. Adrenal insufficiency was evident, and magnetic resonance imaging revealed an intrasellar lesion with heterogeneous contrast enhancement and marked T2 hyperintensity. Central adrenal insufficiency due to an intrasellar lesion was suspected. Cortisol replacement was initiated, and transsphenoidal surgery was performed. Anterosuperior displacement of the normal pituitary gland and the absence of the bony dorsum sellae were notable during the procedure. Histological examination led to a diagnosis of conventional chordoma, and upfront adjuvant stereotactic radiosurgery was executed. She has been free from tumor progression for 12 months. Conclusion: This case and literature review suggested that the pathognomonic features of intrasellar chordoma were heterogeneous contrast enhancement, marked T2 hyperintensity, osteolytic destruction of the dorsum sellae, and anterosuperior displacement of the pituitary gland. Clinical outcomes seemed slightly worse than those of all skull base chordomas, which were the rationale for upfront radiosurgery in our case. Neurosurgeons should include intrasellar chordomas in the differential diagnosis of intrasellar lesions, carefully dissect them from the adjacent critical anatomical structures, and consider upfront radiosurgery to achieve optimal patient outcomes.

Brain Metastasis Mimicking Glioma on Imaging Appearance During Tyrosine Kinase Inhibitor Administration: A Case Series and Literature Review.

OBJECTIVE: Preoperative imaging diagnosis is critical to planning treatment strategies; however, it is occasionally challenging and sometimes misleading. The effects of molecularly targeted therapies on imaging appearances remain uncharted. We investigated the imaging characteristics of brain metastasis during tyrosine kinase inhibitor (TKI) administration. METHODS: We analyzed the 12 cases of brain metastasis from lung cancer in our institute, including a case of a 49-year-old woman under gefitinib. Additionally, we reviewed the cases of brain metastasis from lung cancer with gefitinib treatment in the literature. RESULTS: A woman during five-year gefitinib treatment for postoperative recurrence of lung adenocarcinoma was found to have a cerebellar tumoral lesion incidentally on magnetic resonance imaging (MRI). This lesion did not harbor any peritumoral edema, along with appearing hypometabolic on fluorodeoxyglucose (FDG) positron emission tomography (PET). This appearance was inconsistent with a typical metastatic appearance, and high-grade glioma was instead highly suspected, leading to a decision to proceed to gross total tumor resection. The pathological diagnosis, however, was brain metastasis from lung cancer. The other 11 cases without TKI treatment showed peritumoral edema on MRI and higher accumulation of FDG on PET. The two cases of brain metastasis with gefitinib in the literature showed no peritumoral edema on MRI. CONCLUSION: TKIs like gefitinib can affect tumor biology, leading to a loss of typical imaging findings such as peritumoral brain edema and hyper-metabolism. As preoperative imaging diagnosis guides us in surgical planning, including biopsy or resection, ongoing treatment information should be fully integrated into imaging interpretation.

FGF23-related hypophosphatemia in a patient with small cell lung cancer: a case report and literature review.

Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.

COVID-19 Analysis in Tissue Samples Acquired by Minimally Invasive Autopsy in Out-of-Hospital Deaths with Postmortem Degeneration.

Minimally invasive autopsy (MIA) is an alternative to a full autopsy for the collection of tissue samples from patients' bodies using instruments such as a biopsy needle. MIA has been conducted in many cases of coronavirus disease 2019 (COVID-19) and has contributed to the elucidation of the disease pathogenesis. However, most cases analyzed are hospital deaths, and there are few reports on the application of MIA in out-of-hospital deaths with varying extents of post-mortem changes. In this study, MIA and autopsies were performed in 15 patients with COVID-19 2-30 days after death, including 11 out-of-hospital deaths. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome detection by reverse transcriptase quantitative polymerase chain reaction using MIA samples was mostly consistent with autopsy samples, particularly lung tissue, even in out-of-hospital cases. MIA had high sensitivity and specificity (> 0.80). Histological examination of lung tissue obtained by MIA showed characteristics of COVID-19 pneumonia, with 91% agreement with autopsy samples, whereas localization of SARS-CoV-2 protein in lung tissue was indicated by immunohistochemistry, with 75% agreement. In conclusion, these results suggest that MIA is applicable to out-of-hospital deaths due to COVID-19 with various postmortem changes, especially when autopsies are not available.

Multiple ulcers and perforation of small intestine with everolimus use in a patient with rectal neuroendocrine tumor: A case report.

INTRODUCTION: Everolimus is an orally administered inhibitor of the mammalian target of rapamycin, which is a serine/threonine protein kinase. It is used for the treatment of pancreatic and gastrointestinal neuroendocrine tumors (NETs). Gastrointestinal perforations in patients being treated with everolimus is extremely rare, with only five reported cases. CASE PRESENTATION: A 62-year-old woman, who had previously undergone surgery for rectal NET, presented to our hospital with fever and abdominal pain. Abdominal computed tomography revealed perforation of the lower gastrointestinal tract, and we performed emergency surgery. There were multiple ulcers 150 cm distal from the ligament of Treitz to the terminal ileum; an ulcer at the anastomosis of stoma closure, 35 cm from the terminal ileum, was transmural. We subsequently performed a partial intestinal resection. CLINICAL DISCUSSION: The diagnosis of NETs is increasing worldwide, owing to recent improvements in diagnostic techniques. Although the use of everolimus has increased, gastrointestinal ulcer perforations caused by everolimus treatment have rarely been reported. The mechanism may be due to the inhibition of angiogenesis by mTOR inhibitors, as well as vascular endothelial growth factor inhibitors. In this case, It was considered that everolimus use most likely caused perforation. CONCLUSION: It is necessary to recognize that drug-induced gastrointestinal ulcers and perforations may occur with the use of mTOR inhibitors, and careful follow-up should be performed during administration.

High titers of infectious SARS-CoV-2 in corpses of patients with COVID-19.

OBJECTIVES: The prolonged presence of infectious SARS-CoV-2 in deceased patients with COVID-19 has been reported. However, infectious virus titers have not been determined. Such information is important for public health, death investigation, and handling corpses. The aim of this study was to assess the level of SARS-CoV-2 infectivity in the corpses of patients with COVID-19. METHODS: We collected 11 nasopharyngeal swabs and 19 lung tissue specimens from 11 autopsy cases with COVID-19 in 2021. We then investigated the viral genomic copy number by real-time reverse transcription-polymerase chain reaction and infectious titers by cell culture and virus isolation. RESULTS: Infectious virus was present in six of 11 (55%) cases, four of 11 (36%) nasopharyngeal swabs, and nine of 19 (47%) lung specimens. The virus titers ranged from 6.00E + 01 plaque-forming units/ml to 2.09E + 06 plaque-forming units/g. In all cases in which an infectious virus was found, the time from death to discovery was within 1 day and the longest postmortem interval was 13 days. CONCLUSION: The corpses of patients with COVID-19 may have high titers of infectious virus after a long postmortem interval (up to 13 days). Therefore, appropriate infection control measures must be taken when handling corpses.

Development and multi-institutional validation of an artificial intelligence-based diagnostic system for gastric biopsy.

To overcome the increasing burden on pathologists in diagnosing gastric biopsies, we developed an artificial intelligence-based system for the pathological diagnosis of gastric biopsies (AI-G), which is expected to work well in daily clinical practice in multiple institutes. The multistage semantic segmentation for pathology (MSP) method utilizes the distribution of feature values extracted from patches of whole-slide images (WSI) like pathologists' "low-power view" information of microscopy. The training dataset included WSIs of 4511 gastric biopsy tissues from 984 patients. In tissue-level validation, MSP AI-G showed better accuracy (91.0%) than that of conventional patch-based AI-G (PB AI-G) (89.8%). Importantly, MSP AI-G unanimously achieved higher accuracy rates (0.946 ± 0.023) than PB AI-G (0.861 ± 0.078) in tissue-level analysis, when applied to the cohorts of 10 different institutes (3450 samples of 1772 patients in all institutes, 198-555 samples of 143-206 patients in each institute). MSP AI-G had high diagnostic accuracy and robustness in multi-institutions. When pathologists selectively review specimens in which pathologist's diagnosis and AI prediction are discordant, the requirement of a secondary review process is significantly less compared with reviewing all specimens by another pathologist.

High-grade transformation of pancreatic neuroendocrine tumor associated with TP53 mutations: A diagnostic pitfall mimicking neuroendocrine carcinoma.

Among pancreatic neuroendocrine neoplasms, mutations in ATRX, DAXX, and MEN1 are specific to neuroendocrine tumors (NETs), whereas TP53 and RB1 mutations are characteristic of neuroendocrine carcinomas (NECs). We report a case of pancreatic NET that underwent high-grade transformation associated with acquisition of TP53 mutations. The primary pancreatic tumor consisted of conventional grade 2 NET with loss of alpha-thalassemia/mental retardation, X-linked expression and wild-type TP53, with a small focus exhibiting significant pleomorphism and increased mitotic activity of the neoplastic cells with two pathogenic TP53 mutations. Two years later, multiple liver metastases developed and were surgically resected. The metastatic tumors showed marked pleomorphism with increased mitotic activity (17/2 mm2 ) and TP53 mutations identical to the small area with TP53 mutations in the primary tumor. Liver metastases with a single TP53 mutation were also noted. Notably, hormonal phenotype has changed during progression with decreased glucagon and increased insulin expression in the metastases. Our observations suggest that TP53 mutation can occur in pancreatic NETs during progression and can be associated with phenotypic transformation. Importantly, increased pleomorphism, mitotic activity, as well as TP53 mutations could be diagnostic pitfalls leading to an overdiagnosis of NEC.

Histological growth patterns of colorectal cancer liver metastases: a strong prognostic marker associated with invasive patterns of the primary tumor and p53 alteration.

The histological growth pattern of liver metastases (desmoplastic, pushing, and replacement patterns) at the tumor-liver parenchymal interface is a prognostic factor in patients with colorectal cancer. However, data regarding its association with the primary tumor characteristics and molecular alterations are limited. This study evaluated the histological growth pattern in 136 cases of colorectal cancer liver metastases without preoperative treatment, comparing it with the clinicopathological features of the primary tumor. Liver metastasis exhibiting predominantly non-desmoplastic pattern (<50%), observed in 74 cases (54%), was associated with hepatic vein invasion (P = 0.025), worse recurrence-free survival (P < 0.001) and overall survival (P = 0.008). In multivariate analyses, multiple tumors (P < 0.001) and non-desmoplastic patterns (P = 0.009) were associated with worse recurrence-free survival, and tumor size (P = 0.025) and non-desmoplastic pattern (P = 0.025) were associated with worse overall survival. In 88 patients with available primary tumor tissue slides, non-desmoplastic pattern in the liver metastasis was associated with high-grade tumor budding (P = 0.002), high-grade poorly differentiated cluster (P = 0.021), absence of mucinous histology (P = 0.016), and aberrant p53 expression (complete loss or overexpression; P  0.001) of the primary colorectal cancer. In conclusion, the histological growth pattern in liver metastasis was a strong and independent prognostic factor for colorectal cancer. Our observations highlight the significant associations between histological growth patterns in liver metastases and histopathological features of the primary tumor, especially invasive front morphology and p53 aberration.

Atypical Neurofibromatous Neoplasm with Uncertain Biologic Potential in the Posterior Mediastinum of a Young Patient with Neurofibromatosis Type 1: A Case Report.

Atypical neurofibromatous neoplasm with unknown biological potential (ANNUBP), proposed in a recent NIH consensus overview, is a rare precursor entity of malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) patients. Only one report on imaging findings of ANNUBP is available. Herein, we present the case of a 19-year-old female, diagnosed with a mediastinal tumor by chance, who visited to our hospital. She had café-au-lait spots on her trunk and a past history of resected neurofibroma. Her family also had café-au-lait spots; therefore, an NF1-induced tumor was strongly suspected. MRI revealed a paravertebral mass of 7.5 cm in size consisting of an inner rim with low T2 signal intensity and an outer rim with high T2 intensity, which was similar to a target sign, adjacent to the pulmonary veins; the center of the tumor was well enhanced by gadolinium, and the peripheral region was myxoid and slightly enhanced. FDG-PET showed high FDG uptake, SUVmax of 8.5, although the peripheral region represented low FDG accumulation. CT-guided needle biopsy was repeated because of the suspicion of an MPNST, which resulted in the histopathological diagnosis of ANNUBP. Marginal tumor resection was performed, and the final post-resection histopathological diagnosis was ANNUBP transformed from neurofibroma; the region of ANNUBP lost p16 immunostaining, although it was retained in the peripheral region of the neurofibroma. There has been no recurrence or metastasis 1 year after treatment. In conclusion, ANNUBP could be represented as a well-enhanced homogeneous mass on MRI and a high FDG accumulated region on FDG PET/CT, as seen in MPNST, in NF1 patients.

Tumor Budding in Intrahepatic Cholangiocarcinoma: A Predictor of Postsurgery Outcomes.

Intrahepatic cholangiocarcinoma (ICC) is an extremely aggressive carcinoma. Useful predictors for the patients' prognosis after surgery have not been fully established. From the University of Tokyo Hospital pathology archives, we reviewed 107 cases of ICC, 54 cases of perihilar cholangiocarcinoma, and 40 cases of extrahepatic cholangiocarcinoma (ECC); we also investigated the significance of tumor budding in ICC, in comparison with perihilar cholangiocarcinoma and ECC. The tumor-budding frequencies were different by tumor location: 40.2% (43/107) in ICC, 70.4% (38/54) in perihilar cholangiocarcinoma, and 60.0% (24/40) in ECC. Tumor budding in ICC was associated with many pathologic indicators associated with invasion, such as major vascular invasion (P=0.012) and Union for International Cancer Control stage (P=0.007). Univariate and multivariate Cox regression analyses revealed tumor budding as a powerful prognostic factor for both recurrence-free survival (RFS) and overall survival (OS) in ICC by univariate (RFS: hazard ratio [HR]: 2.666; 95% confidence interval [CI]: 1.517-4.683, OS: HR: 4.206; 95% CI: 2.447-7.230) and by multivariate analyses (RFS: HR: 3.038; 95% CI: 1.591-5.973, OS: HR: 4.547, 95% CI: 2.348-8.805). Tumor budding was also a significant prognostic factor of perihilar cholangiocarcinoma, but not of ECC. When ICC was divided into 2 subtypes, type 1 (hilar) and type 2 (peripheral), tumor budding was the strong prognostic factor in type 2 ICC, but not in type 1 ICC, suggesting that some differences in biological behavior exist between type 1 ICC and perihilar cholangiocarcinoma. Tumor budding is prognostically important in ICC, and its pathogenetic role in biliary tract carcinomas might be different by anatomic location.

Transformation of epidermal growth factor receptor T790M mutation-positive adenosquamous carcinoma of the lung to small cell carcinoma and large-cell neuroendocrine carcinoma following osimertinib therapy: an autopsy case report.

A 59-year-old man with relapsed epidermal growth factor receptor (EGFR) exon 19 deletion-positive stage IA adenosquamous carcinoma after lobectomy was treated with erlotinib and bevacizumab for 1 year followed by erlotinib alone for 1 year. Because of mediastinal and supraclavicular lymphadenopathy and a nodule on the left anterior chest wall, the patient underwent repeat biopsy from the supraclavicular lymph node. Pathological analysis demonstrated adenosquamous carcinoma harbouring EGFR exon 19 deletion and T790M mutation. Osimertinib treatment was therefore started. Six months later, the patient underwent a second-repeat biopsy from the mediastinal lymph nodes and liver metastases. Both specimens showed small cell lung carcinoma (SCLC). After chemotherapies for SCLC, he died from lung cancer. An autopsy demonstrated tumour heterogeneity, including histological types of adenosquamous, SCLC, and large-cell neuroendocrine carcinoma. Repeat biopsies at the time of disease progression are useful to choose subsequent treatment for patients with EGFR mutation-positive lung cancer.