Feasibility of intraoperative pathologic examination for sentinel lymph nodes during sentinel node navigation surgery in early gastric cancer: results of pathologic protocol for SENORITA trial.

BACKGROUND: During sentinel node navigation surgery in patients with gastric cancer, intraoperative pathologic examination of sentinel nodes is crucial in determining the extent of surgery. In this study, we evaluated the feasibility and accuracy of intraoperative pathologic protocols using data from a prospective, multicenter, randomized trial. METHODS: A retrospective analysis was conducted using data from the SEntinel Node ORIented Tailored Approach trials from 2013 to 2016. All sentinel lymph nodes were evaluated during surgery with hematoxylin-eosin (HE) staining using a representative section at the largest plane for lymph nodes. For permanent histologic evaluation, sentinel basin nodes were stained with HE and cytokeratin immunohistochemistry in formalin-fixed, paraffin-embedded (FFPE) sections and examined with HE for three deeper-step sections at 200-µm intervals. The failure rate of identification by frozen section and the metastasis rate in non-sentinel basins were investigated. RESULTS: Of the 237 patients who underwent sentinel node basin dissection, 30 had lymph node metastases on permanent pathology. Thirteen patients had macrometastasis confirmed in frozen sections as well as FFPE sections (failure rate: 0%). Patients with negative sentinel nodes in frozen sections but micrometastasis in FFPE sections had no lymph node recurrence during the follow-up period (0%, 0/6). However, in cases with tumor-positive nodes in frozen sections, metastases in non-sentinel basins were detected in the paraffin blocks (8.3%, 2/24). CONCLUSIONS: The single-section HE staining method is sufficient for detecting macrometastasis via intraoperative pathological examination. If a negative frozen-section result is confirmed, sentinel basin dissection can be performed safely. Otherwise, standard surgery is required.

Metastasis of Sublingual Gland Adenoid Cystic Carcinoma to the Upper Gingiva.

Adenoid cystic carcinoma (ACC) of the sublingual gland is rare. There are no previous reports of the metastasis of sublingual gland ACC to the upper gingiva. Herein, we report the first case of a patient with metastasis of sublingual gland ACC to the upper gingiva. It should be recognized that although metastasis of sublingual gland ACC to the upper gingiva is very rare, it can occur.

Metastasis of parotid adenocarcinoma to the external auditory canal.

Metastatic carcinoma of the external auditory canal (EAC) is extremely rare. Herein, we report the first case of a patient with metastasis of parotid adenocarcinoma to the EAC. Clinicians should include it in the differential diagnosis of tumors of the EAC. In patients with parotid carcinoma, a physical examination of the entire head and neck, including the EAC, should be performed before surgery.

Carcinoma ex pleomorphic adenoma of the parotid gland.

INTRODUCTION: Carcinoma ex pleomorphic adenoma (CXPA) is a rare malignant tumor of the parotid gland. We analyzed the clinical characteristics and treatment outcomes of CXPA of the parotid gland in patients managed for 11 years at this hospital. METHODS: The study included 17 cases of CXPA of the parotid gland from January 2010 to December 2020. RESULTS: Over 11 years, CXPA was the fourth most common parotid carcinoma, accounting for 9.4% of the 180 cases finally diagnosed as parotid carcinoma. Of the 17 cases of CXPA of the parotid gland, 12 lesions were removed by superficial parotidectomy, four lesions by total parotidectomy, and one lesion by radical parotidectomy. Four patients underwent neck dissection. The most common histopathology type was salivary duct carcinoma (n = 13, 76.5%). Postoperative radiation therapy (RT) was performed in 15 patients. Two patients (11.8%) experienced CXPA recurrence 14 and 19 months after surgery. CONCLUSION: CXPA of the parotid gland was treated without recurrence in about 90% of the patients through surgery and postoperative RT. In the case of frankly invasive or adverse factors in the histopathological examination, more attention is required because CXPA recurrence may occur more frequently.

Sellar plasmacytoma with massive bleeding during surgery.

Plasmacytoma in the sellar region is an extremely rare occurrence. Sellar plasmacytoma is often difficult to differentiate from pituitary tumors both clinically and radiologically. The occurrence of cranial nerve palsy, the preservation of pituitary hormone function, the presence of sellar floor destruction, and better contrast enhancement are regarded as the differentiating factors between sellar plasmacytoma and pituitary tumors. We recommend adding the massive bleeding properties of sellar plasmacytoma as another characteristic which differentiates it from a pituitary tumor.

Frequency and Prognostic Value of IDH Mutations in Korean Patients With Cholangiocarcinoma.

The molecular profile of cholangiocarcinoma (CC) remains elusive. The prognostic value of isocitrate dehydrogenase (IDH) mutations in CC is controversial, and there have been few relevant studies in Asian populations. In the present study, we investigated the frequency and prognostic significance of IDH mutations in Korean patients with CC. CC specimens were collected from patients who underwent surgical liver resection between 2004 and 2019. Clinical and pathological data were retrospectively reviewed from medical records. Mutational IDH profiling was performed by peptide nucleic acid-mediated PCR clamping in 206 surgical specimens; IDH-mutant samples were confirmed by next-generation sequencing (NGS). Of the 195 patients with CC, six (3.13%) were found to exhibit IDH1 (n = 5) or IDH2 (n = 1) mutations. Among patients with IDH1 mutations, four had R132C (c.394C>T) and one had R132G (c.394C>G) mutations. One patient had R172W (c.514A>T) mutations in IDH2. All IDH-mutant samples were of intrahepatic origin, and patients with IDH mutations had physiological to low serum levels of carbohydrate antigen 19-9 (CA19-9). No association between IDH mutation status and long-term survival outcomes was observed. The frequency of IDH mutations was considerably lower than the 10-20% reported in previous studies. The frequency and pattern of IDH mutations in CC are likely to vary among patients with different ethnicities. These findings suggest that characterization of the oncogenic mutation profile in different populations is of high clinical importance.

Fibroblast growth factor receptor 4 increases epidermal growth factor receptor (EGFR) signaling by inducing amphiregulin expression and attenuates response to EGFR inhibitors in colon cancer.

Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross-talk between FGFR4 and EGFR, and the effect of anti-EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab-induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti-EGFR therapy in colon cancer.

Recurrent KRAS mutations identified in papillary renal neoplasm with reverse polarity-a comparative study with papillary renal cell carcinoma.

Comprehensive molecular analyses revealed that papillary renal cell carcinoma (PRCC) is a heterogenous entity. Papillary renal neoplasm with reverse polarity (PRNRP) is a subset of PRCC with characteristic histomorphologies such as low-grade nuclear features, inverted nuclear location, eosinophilic cytoplasm, and indolent clinical behavior. We tried to define the molecular, clinicopathological, histologic, and immunohistochemical features of PRNRP by comparing them with type 1 PRCC (PRCC1) and type 2 PRCC (PRCC2). A cohort of 30 PRNRP, 23 PRCC1, and 26 PRCC2 cases was used. Targeted sequencing of 90 cancer-related genes including KRAS was performed in 26 PRNRP tumor samples. PNA-mediated clamping PCR of KRAS was performed using paired normal and tumor DNA from 30 PRNRP, 23 PRCC1, and 26 PRCC2 cases. Tissue microarray slides were made in three cores per tumor, which were stained with cytokeratin 7 (CK7), alpha-methylacyl-CoA racemase (AMACR), epithelial membrane antigen (EMA), E-cadherin, vimentin, and CD10. Recurrent mutations in KRAS were detected in 28 of the 30 PRNRPs. However, there were no KRAS mutations in any PRCC1 or PRCC2 cases. PRNRP exhibited distinct clinicopathological features: small tumor size, lower pathologic T stage, and no disease-specific death during the follow-up period. Histologically, peritumoral lymphoid aggregation, prominent papillary architecture (>80% of tumor), hyalinized papillae, inverted nuclear location, and lower nuclear grade were observed. PRNRP was usually positive for CK7, AMACR, EMA, and E-cadherin, and negative for CD10. The findings suggest that PRNRP is a subtype of papillary renal neoplasm that is different from PRCC1 or PRCC2 in terms of molecular, clinicopathological, histological, and immunohistochemical features.

Metastatic small cell neuroendocrine carcinoma of the submandibular gland from the lung: A case report.

RATIONALE: Small cell neuroendocrine carcinoma of the salivary gland is an extremely rare condition. To the best of our knowledge, metastasis of small cell neuroendocrine lung cancer to the submandibular gland has not been reported in the literature. PATIENT CONCERN: An 87-year-old female complained of a left neck mass that enlarged from one month ago. DIAGNOSIS: The final diagnosis was diagnosed as a metastatic small cell neuroendocrine carcinoma of the submandibular gland from lung by an immunohistochemistry. INTERVENTIONS: Left submandibular resection was performed under general anesthesia. OUTCOMES: We recommended further evaluation and treatment, but the patient and patient family support team rejected further treatment of her condition. It was confirmed that 3 months after this conclusive diagnosis, the patient died as a result of this condition and disease. LESSONS: Small cell neuroendocrine carcinoma of the salivary gland is an extremely rare condition. We report a case of metastatic small cell neuroendocrine carcinoma of the submandibular gland from the lung.

Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study.

PURPOSE: The most recent 2017 World Health Organization (WHO) classification of pancreatic neuroendocrine neoplasms (PanNENs) has refined the three-tiered 2010 scheme by separating grade 3 pancreatic neuroendocrine tumors (G3 PanNETs) from poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). However, differentiating between G3 Pan- NETs and PanNECs is difficult in clinical practice. MATERIALS AND METHODS: Eighty-two surgically resected PanNENs were collected from 16 institutions and reclassified according to the 2017 WHO classification based on the histological features and proliferation index (mitosis and Ki-67). Immunohistochemical stains for ATRX, DAXX, retinoblastoma, p53, Smad4, p16, and MUC1 were performed for 15 high-grade PanNENs. RESULTS: Re-classification resulted in 20 G1 PanNETs (24%), 47 G2 PanNETs (57%), eight G3 well-differentiated PanNETs (10%), and seven poorly differentiated PanNECs (9%). PanNECs showed more frequent diffuse nuclear atypia, solid growth patterns and apoptosis, less frequent organoid growth and regular vascular patterns, and absence of low-grade PanNET components than PanNETs. The Ki-67 index was significantly higher in PanNEC (58.2%± 15.1%) compared to G3 PanNET (22.6%±6.1%, p < 0.001). Abnormal expression of any two of p53, p16, MUC1, and Smad4 could discriminate PanNECs from G3 PanNETs with 100% specificity and 87.5% sensitivity. CONCLUSION: Histological features supporting the diagnosis of PanNECs over G3 PanNETs were the absence of a low-grade PanNET component in the tumor, the presence of diffuse marked nuclear atypia, solid growth pattern, frequent apoptosis and markedly increased proliferative activity with homogeneous Ki-67 labeling. Immunohistochemical stains for p53, p16, MUC1, and Smad4 may be helpful in distinguishing PanNECs from G3 PanNETs in histologically ambiguous cases, especially in diagnostic practice when only small biopsied tissues are available.

Recurrent Glioma With Lineage Conversion From Oligodendroglioma to Astrocytoma in Two Cases.

Following the introduction of the molecular classification of gliomas by the WHO in 2016, molecularly-proven lineage conversion during glioma recurrence has never been reported. The reported two cases were initially diagnosed as oligodendroglioma with 1p/19q-codeletion and mutation of isocitrate dehydrogenase 1 (IDH1)-R132H. The recurrent tumors showed loss of alpha-thalassemia/mental retardation X-linked (ATRX) expression, strong P53 positivity, and 1p/19q-nondeletion. Next generation sequencing analysis performed on the first case confirmed the transition of molecular traits from oligodendroglioma to astrocytoma. An IDH mutation of R132H was preserved in the episodes of recurrence, but ATRX and TP53 mutations were newly acquired and TERT promoter mutation C228T was lost at the most recent recurrence. The issue in question for the presented cases is whether the original tumors were pure oligodendrogliomas that then transdifferentiated into astrocytomas, or whether the original tumor was an oligoastrocytoma having oligodendroglioma cells that outnumbered the astrocytoma cells and where the astrocytoma cells becoming more dominant over the episodes of recurrence. With the recognition of the possibility of lineage conversion, our study suggests that molecular examination should be performed to adjust therapeutic strategies in recurrent gliomas. Indeed, our observation of lineage conversion in glioma recurrence calls into question the current distinction drawn between oligodendroglioma, astrocytoma and oligoastrocytoma, rather than simply bidding "farewell to oligoastrocytoma."

Anthracofibrotic Lymph Node of Neck Mimicking Metastatic Malignant Melanoma in a Patient With Gastric Cancer.

Extrathoracic anthracofibrosis in head and neck region is of extremely rare occurrence and can be confused with malignancy. In this article, we report an unusual case of an anthracofibrotic lymph node of neck that was mistaken for metastatic malignant melanoma in a gastric cancer patient. Because the incidence of an anthracofibrotic lymph node of the neck is very low, it is important to distinguish it from other diseases, including malignancy or metastasis, especially in patients with a cancer history. Thus, pathological diagnosis of anthracofibrosis is necessary to make an accurate diagnosis and find appropriate treatment.

Assessment of T-cell receptor repertoire and clonal expansion in peripheral T-cell lymphoma using RNA-seq data.

T-cell clonality of peripheral T-cell lymphoma (PTCL) is routinely evaluated with a PCR-based method using genomic DNA. However, there are limitations with this approach. The purpose of this study was to determine the utility of RNA-seq for assessing T-cell clonality and T-cell antigen receptor (TCR) repertoire of the neoplastic T-cells in 108 PTCL samples. TCR transcripts, including complementarity-determining region 3 (CDR3) sequences, were assessed. In normal T cells, the CDR3 sequences were extremely diverse, without any clonotype representing more than 2% of the overall TCR population. Dominant clones could be identified in 65 out of 76 PTCL cases (86%) with adequate TCR transcript expression. In monoclonal cases, the dominant clone varied between 11% and 99% of TCRß transcripts. No unique Vα or Vß usage was observed. Small T-cell clones were often observed in T- and NK-cell tumors in a percentage higher than observed in reactive conditions. γ chain expression was very low in tumors expressing TCRαß, but its expression level was high and clonality was detected in a TCRγδ expressing tumor. NK cell lymphoma (NKCL) did not express significant levels of TCR Vß or Vγ genes. RNA-seq is a useful tool for detecting and characterizing clonal TCR rearrangements in PTCL.

A Huge Ancient Schwannoma of the Epiglottis.

Ancient schwannoma of the epiglottis is extremely rare. The authors report the first case of a patient with a huge ancient schwannoma of the epiglottis. Clinicians should consider the possibility that ancient schwannoma may originate in the epiglottis mimicking the other more frequently observed lesions.

The Prognostic Significance of FGFR4 Gly388 Polymorphism in Esophageal Squamous Cell Carcinoma after Concurrent Chemoradiotherapy.

PURPOSE: The purpose of this study is to investigate the role of fibroblast growth factor receptor 4 (FGFR4) polymorphism in esophageal cancer after chemoradiotherapy (CRT). MATERIALS AND METHODS: Peripheral blood samples from 244 patients treated with CRT for esophageal squamous cell carcinoma were assessed for the role of FGFR4 genotype on treatment response and survival. RESULTS: A total of 94 patients were homozygous for the Gly388 allele, and 110 were heterozygous and 40 homozygous for the Arg388 allele. No significant association was found between the FGFR4 genotype and clinicopathological parameters. However, patients carrying the Gly388 allele showed a better overall response rate than Arg388 carriers (p=0.038). In addition, Gly388 allele patients at an earlier stage showed better overall survival (OS) and progression-free survival than Arg388 carriers. Among these, the Gly388 allele showed significantly improved OS compared to Arg388 carriers in the lymph node (LN) metastasis group (p=0.042) compared to the no LN metastasis group (p=0.125). However, similar survival outcomes were observed for advanced-stage disease regardless of genotype. CONCLUSION: This result suggests that the role of FGFR4 Gly388 in treatment outcomes differs according to esophageal cancer stage. It showed a predictive role in the response of esophageal cancer patients to CRT with a better trend for OS in Gly388 than Arg388 carriers in the early stages. In particular, LN-positive early-stage patients carrying the Gly388 allele showed improved OS compared to those carrying Arg388.

Genomic evidence of reactive oxygen species elevation in papillary thyroid carcinoma with Hashimoto thyroiditis.

Elevated levels of reactive oxygen species (ROS) have been proposed as a risk factor for the development of papillary thyroid carcinoma (PTC) in patients with Hashimoto thyroiditis (HT). However, it has yet to be proven that the total levels of ROS are sufficiently increased to contribute to carcinogenesis. We hypothesized that if the ROS levels were increased in HT, ROS-related genes would also be differently expressed in PTC with HT. To find differentially expressed genes (DEGs) we analyzed data from the Cancer Genomic Atlas, gene expression data from RNA sequencing: 33 from normal thyroid tissue, 232 from PTC without HT, and 60 from PTC with HT. We prepared 402 ROS-related genes from three gene sets by genomic database searching. We also analyzed a public microarray data to validate our results. Thirty-three ROS related genes were up-regulated in PTC with HT, whereas there were only nine genes in PTC without HT (Chi-square p-value < 0.001). Mean log2 fold changes of up-regulated genes was 0.562 in HT group and 0.252 in PTC without HT group (t-test p-value = 0.001). In microarray data analysis, 12 of 32 ROS-related genes showed the same differential expression pattern with statistical significance. In gene ontology analysis, up-regulated ROS-related genes were related with ROS metabolism and apoptosis. Immune function-related and carcinogenesis-related gene sets were enriched only in HT group in Gene Set Enrichment Analysis. Our results suggested that ROS levels may be increased in PTC with HT. Increased levels of ROS may contribute to PTC development in patients with HT.

Arytenoid cartilage chondroma.

Arytenoid chondroma is an extremely rare benign cartilaginous tumor. We report a case of a patient with arytenoid chondroma initially mimicking laryngopharyngeal reflux. Clinicians should consider the possibility of the arytenoid chondroma in the differential diagnosis of patients with vocal cord palsy, or arytenoid swelling caused by laryngopharyngeal reflux.

Epstein-Barr virus-positive nodal T/NK-cell lymphoma: an analysis of 15 cases with distinct clinicopathological features.

Nodal peripheral T-cell lymphoma, not otherwise specified, is a heterogeneous entity with variable biologic behavior. We analyze the clinicopathological features of 15 patients with Epstein-Barr virus-positive (EBV+) nodal T/NK-cell lymphoma, including 9 males and 6 females, with a median age of 64 years. All patients presented with multiple lymphadenopathy with common B symptoms (80%, 12/15) at an advanced Ann Arbor stage (III, IV) (87%, 13/15). The International Prognostic Index was high or high/intermediate in 87% (13/15) of patients, and the prognostic index for peripheral T-cell lymphoma was group 3 or 4 in 73% (11/15). Spleen and liver involvement was observed in 73% (11/15) and 60% (9/15) of patients, respectively. In contrast, extranodal involvement was infrequent, with no more than 1 site in 71% (10/15) of patients. Moreover, none had nasal lesions, and only 1 had mucocutaneous involvement. The cell lineage of EBV+ tumor cells was determined to be T cell in all except 1 patient, who was NK-cell lineage. Cytotoxic molecules were expressed in all cases, and 64% (9/14) of patients expressed the αßT-cell receptor. Moreover, most patients (67%, 10/15) showed CD8 positivity, with 2 of them being CD4CD8 double positive; the others were CD4 positive (n = 2) or CD4CD8 double negative (n = 3). The clinical course was very aggressive, with a median survival time of 3.5 months, and 10 patients died within 6 months of diagnosis. Taken together, our data demonstrate that EBV+ nodal T/NK-cell lymphoma is a distinct clinicopathological entity characterized by cytotoxic molecule expression, a frequent CD8-positive αßT-cell lineage, and a very aggressive clinical behavior.

VE1 immunohistochemical detection of the BRAF V600E mutation in thyroid carcinoma: a review of its usefulness and limitations.

The BRAF V600E mutation is a valuable prognostic factor in thyroid carcinoma despite lingering debate. Successful immunohistochemical (IHC) detection of the BRAF V600E mutation using a VE1 antibody was introduced recently. The objective of this study was to verify the usefulness of IHC detection of the BRAF V600E mutation in thyroid carcinoma using the VE1 antibody. IHC detection of BRAF V600E was performed on various thyroid carcinoma subtypes. IHC results were compared with those obtained from real-time polymerase chain reaction (PCR) detection. Discordant cases were re-examined using a direct sequencing method following nested PCR amplification. The BRAF V600E mutation was detected in 68 % (71/104) of papillary carcinoma cases and 78 % (7/9) of anaplastic carcinoma cases. The mutation was not detected in patients with follicular carcinoma (0/18) or in medullary carcinoma (0/21). The overall sensitivity and specificity of IHC using the VE1 antibody were 100 and 94 %, respectively, suggesting that molecular-based results were indeterminable in four VE1-positive cases. IHC using the VE1 antibody is a highly sensitive and specific method for BRAF V600E mutation detection and may represent a future replacement for DNA-based molecular tests.