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Follicular thyroid carcinoma (FTC) has different clinicopathological characteristics than papillary thyroid carcinoma. However, there are no independent systems to predict cancer-specific survival (CSS) in FTC. Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. Thus, it could be a potential prognostic marker. The aim of this study was to refine the CSS risk prediction using TERT promoter mutations in combination with the fourth edition of World Health Organization (WHO 2017) morphological classification. We investigated 77 FTC patients between August 1995 and November 2020. Cox regression was used to calculate hazard ratios to derive alternative groups. Disease-free survival (DFS) and CSS predictability were compared using Proportion of variation explained (PVE) and C-index. CSS was significantly different in encapsulated angioinvasive (EA)-FTC patients stratified by TERT promoter mutations [wild-type (WT-TERT) vs. mutant (M-TERT); P more...

Histologically poor differentiation is associated with lymph node metastasis. Thus, pathological evaluation of biopsy specimens is crucial when treating stomach cancers. Deep learning of WSIs is challenging because the images are enormous. Given the computing limitations, patch-level supervised learning methods have been proposed. However, valuable information is lost when dividing WSIs into smaller patches. Another drawback is the need for pixel-level annotation by a pathologist. It is acceptable to differentiate, i.e., grade, gastric cancer at the holistic tissue level (i.e., under low magnification). We developed a weakly supervised learning technique for tissue-level gastric adenocarcinoma histological differentiation (well-to-moderately or poorly differentiated) and applied global reasoning to tissue-level features. The tissue-level AUROCs of the histological differentiation classifiers were 0.953, 0.969, and 0.943, respectively when data from five hospitals were subjected to threefold cross-validation. Comparison of the Grad-CAM heatmaps of the trained classifier and the pathologists’ annotations confirmed that our weakly supervised model exhibited performed well. more...

Background Lymph node fine-needle aspiration (LN FNA) cytology indicates necrosis in various diseases. Dominant necrotic features make the diagnosis of underlying conditions very difficult. Methods We retrospectively reviewed 460 patients who underwent cervical LN aspiration cytology that revealed necrotic findings at Keimyung University Dongsan Hospital in Daegu, Korea, from 2003-2017. Each specimen was evaluated and analyzed in association with the clinical findings, biopsy findings, and/or other ancillary tests, including acid-fast bacilli staining and molecular testing for Mycobacterium tuberculosis. Results When necrotic features were noted upon cervical LN FNA cytology, the most common pathologic LN FNA category was necrosis alone (31.5%). The second most common category was granulomatous inflammation (31.3%), followed by Kikuchi disease (20.0%) and malignant neoplasm (8.7%). In cases where the cervical LN FNA revealed necrosis alone, the most common final diagnosis was tuberculosis. In young patients, Kikuchi disease should be considered as one cervical LN FNA category, while metastatic carcinoma should be suspected in older patients. Conclusions Even when necrosis alone is observed in LN FNA cytology, it is important to determine the cause through further evaluation. more...

Study Objective MONOFIX, a new absorbable barbed suture device, has a triangular stopper at the end to hold the suture to the tissue without hooking the looped end or knotting. The aim of this study was to compare the biomechanical strength and histologic features of MONOFIX with other barbed suture devices using a porcine model. Design Well-designed, controlled trial without randomization. Setting Animal laboratory in university hospital. Subjects Sixteen, 60-kg, mature female domestic pigs (skin closure group) and 5, 60-kg, mature female domestic pigs (fascial closure group). Interventions In the skin closure group, 3-0 MONOFIX versus 2 widely used 3-0 absorbable barbed sutures (3-0 V-Loc 180 or Stratafix). In the fascial closure group, 2-0 MONOFIX versus 1 widely used 2-0 absorbable barbed sutures (2-0 Stratafix). Measurements and Main Results In the skin closure group, the biomechanical wound strength of skin sutured with size 3-0 MONOFIX, V-Loc 180, or Stratafix was evaluated by postoperative day assessment (days 0, 3, 7, 14, and 28). In the fascial closure group, pigs underwent 2 paramedian incisions and were sutured with 2-0 MONOFIX or with 2-0 Stratafix to evaluate histologic reaction. At 6 weeks the tissues around the suture line were excised and microscopically evaluated. The biomechanical strength of the MONOFIX had similar tissue tensile strength compared with the control, regardless of postoperative day. In the fascial closure model, there was no significant difference in the average tissue reaction score between MONOFIX and Stratafix (1.2 ± .3 vs 1.3 ± .3, p = .478). Conclusion This study demonstrated that MONOFIX has equivalent tensile strength and histologic reaction when compared with commonly used barbed suture devices. Accordingly, this preclinical study suggests that the use of MONOFIX is a safe alternative to other barbed suture devices. more...

MET amplification is a frequently observed genomic aberration in solid tumors. We conducted a phase I trial to evaluate dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) for the combination therapy. The following dose levels were tested in this single-arm phase I study: docetaxel as an intravenous infusion over 1 hour at 60 mg/m2 once every 3 weeks of a 21-day schedule plus savolitinib (level 1, 200 mg qd; level 2, 400 mg qd; level 3, 600 mg qd; level 4800 mg qd). In total, there were 17 patients enrolled on to this study [7 gastric cancer (GC) patients, 5 melanoma patients, 3 sarcoma patients, and 2 rectal cancer patients]. Most of the patients (14 of 17) were heavily pretreated (≥third line or greater lines of treatment). For the first 3 cohorts (200 mg savolitinib + docetaxel 60 mg/m2, 400 mg savolitinib + docetaxel 60 mg/m2, 600 mg savolitinib + docetaxel 60 mg/m2), there were no DLTs. In the fourth dose cohort (800 mg savolitinib + docetaxel 60 mg/m2), one DLT occurred with generalized edema grade 3 that required intensive management. One GC patient with both MET overexpression (3+) and MET amplification (MET/CEP7 ratio, 7.3) achieved a durable partial response for 297 days, and another MET-amplified GC patient (MET/CEP7 ratio, 7.6) achieved stable disease for 86 days. Due to the higher incidence of G4 neutropenia in cohort 4 (800 mg), we recommend savolitinib 600 mg qd in combination with docetaxel 60 mg/m2 as the RP2D for phase II trial. The combination therapy demonstrated a very promising antitumor activity with durable responses in MET amplified GC patients. more...

Left ventricular lipoma is a rare intracardiac tumour that is usually resected through sternotomy to effectively explore the left ventricular cavity. We introduce a simple technique to expose the left ventricular cavity and resect the intraventricular lipoma using a rolled up flexible ruler through right mini-thoracotomy. Imaging studies and gross and microscopic photography of intraventricular lipoma are presented in this report. more...

Purpose Tumor-associated macrophages (TAMs) are activated macrophages associated with tumor progression in various cancers. TAMs can polarize M1 or M2 type. M1 has a pro-inflammatory function and kills pathogens. Conversely, M2 shows immunosuppressive action and promotes tumor growth. There are various markers of TAMs. CD11c is considered as a specific marker of M1. CD163 is an optimal marker for M2. CD68 is known as a pan-macrophage marker. We evaluated the relationship between the clinicopathological parameters and immunohistochemical expressions of CD11c, CD163, and CD68 in invasive breast cancer (IBC), and the prognostic value of macrophage localization within the tumor stroma (TS) and tumor nest (TN). Methods Immunohistochemistry of CD68, CD11c, and CD163 was analyzed on tissue microarrays of 367 IBCs. The number of CD68+, CD11c+, or CD163+ macrophages in TN vs. TS was counted by 2 pathologists. The correlations between the degree of macrophage (CD68+, CD11c+, or CD163+) infiltration and the clinicopathological parameters were analyzed. We also assessed the impact of macrophages (CD68+, CD11c+, or CD163+) on disease free survival (DFS) and overall survival (OS). Results High numbers of macrophages (CD68+, CD11c+, or CD163+) were associated with higher histologic grade, higher Ki-67 proliferating index, estrogen receptor negativity, and progesterone receptor negativity. High numbers of macrophages (CD11c+ or CD163+) in TS were associated with a larger tumor size. Furthermore, CD163+ macrophages in TN were an independent prognostic marker of reduced OS and DFS. Conversely, CD11c+ macrophages in TS were an independent prognostic marker for higher OS and DFS. Conclusion TAMs, including M2 type, are associated with tumor progression in IBC. They can also act as a significant unfavorable or favorable prognostic factor. In addition to simply analyzing the degree of TAM infiltration, it is also important to analyze the location of TAMs. more...

It remains unclear whether endoscopic submucosal dissection (ESD) can be indicated for differentiated-type-predominant early gastric cancer mixed with a minor undifferentiated component (EGC with histological heterogeneity (HH)). Here, we reviewed and compared clinicopathologic characteristics and long-term outcomes of ESD of 257 patients with EGC-HH and those of 2386 patients with pure differentiated-type EGC (PuD-EGC). After ESD, EGC-HH was managed in the same way as PuD-EGC. EGC-HHs were significantly associated with larger tumor size, more frequent submucosal invasion, and lymphovascular invasion compared to PuD-EGCs. Despite these aggressive features of EGC-HH, no local recurrence or gastric cancer-related death occurred during a median of 58 months of follow up after ESD for EGC-HH, if curative resection was achieved. After curative ESD for EGC-HH, six patients had metachronous recurrence (5.0%) and one patient underwent extragastric recurrence in a regional lymph node (0.8%). All these recurrence cases were curatively treated with ESD or gastrectomy. For patients with EGC-HH, five-year overall survival and recurrence-free survival rates after curative ESD were 97.0% and 94.8%, respectively, which were comparable to those of patients with PuD-EGC. In conclusion, ESD showed favorable long-term outcomes after curative resection and may be an acceptable treatment option for EGC-HH meeting curative endoscopic resection criteria. more...

Automatic quantification of biomarkers such as tumor‐infiltrating lymphocytes and PD‐L1 is one of the most studied topics in digital pathology image analysis (DIA). However, direct comparison between the DIA of a whole‐slide image (WSI) and that of regions of interest (ROIs) chosen by pathologists has not been performed. In this study, we aimed to compare the prognostic value of tumor microenvironment markers CD8 and PD‐L1, measured by DIA of WSIs and ROIs. We selected 153 primary gastric cancer tissues and stained them with CD8 and PD‐L1. All IHC slides were scanned at ×200 magnification and ratios of CD8 and PD‐L1 were measured in WSIs and ROIs from the invasive front, within the tumor, and the mucosa. Patients with high CD8 and PD‐L1 ratios showed more favorable outcomes compared to those with low ratios. Pathologist‐aided DIA predicted the survival of patients more accurately than WSI analysis (CD8, p = 0.025 versus p = 0.068; PD‐L1, p = 0.008 versus p = 0.2). Although a high density of CD8+ T cells at the invasive front correlated best with patient survival, CD8 ratio in the mucosa could also predict patient outcome. In conclusion, CD8 and PD‐L1 ratios measured by pathologist‐aided DIA predicted survival more accurately than WSI analyses and ROIs at the invasive front correlated best with patient outcome. more...

Hydroxyapatite (HA) does not fully degrade, which raises concerns about poor remodeling and incorporation into the bone after open-wedge high tibial osteotomy (HTO). The purpose of this study was to compare the results between gap filling with allogenous chip bone and HA chip after open-wedge HTO using propensity score matching and to analyze the radiological unabsorbed area of opening gaps histologically in HA using patients.The matched variables were age, body mass index, sex, correction angle, and smoking status. After matching, the allogenous group and HA group included 33 patients each with two years of follow-up. The range of motion (ROM), International Knee Documentation Committee (IKDC) subjective score, Knee Injury and Osteoarthritis Outcome Score (KOOS), mechanical axis (MA), tibial slope, osteoconductivity, and absorbability were evaluated and compared between both groups. Among the HA group, 20 patients underwent bone biopsy and histologically analyzed of the radiological unabsorbed area.The postoperative ROM, IKDC subjective score, and KOOS were similar in both groups. The osteoconductivities did not differ significantly. The absorbability in the HA group was significantly lower than allogenous group (59.6% vs. 22.6%, P .001). The histological sections of the radiological unabsorbed area showed mature lamelliform bone tissues were significantly greater than structurally degraded remnant HA (30.4% and 4.2%, P .001).The HA chips showed an inferior absorbability, however, a mature lamelliform bone was observed in significantly larger amounts than remnant HA in the radiological unabsorbed area. The allogenous bone chips and HA chips showed similar clinical and radiological results after open-wedge HTO. more...

Background MET is a tyrosine kinase receptor for the hepatocyte growth factor, and its overexpression is a poor prognostic factor in gastric carcinomas. Programmed death-ligand 1 (PD-L1) is an important biomarker of immunotherapy and is frequently positive in microsatellite instability-high (MSI-H) gastric carcinomas. In lung cancers, MET activation up-regulates PD-L1 expression. In this study, we investigated expression of MET and PD-L1 in MSI-H gastric carcinoma and the effects on prognosis. Methods MET and PD-L1 (SP142) immunohistochemistry was performed in 73 gastric carcinomas with MSI-H. In cases with MET overexpression, we performed fluorescent in situ hybridization (FISH). PD-L1 expression was calculated from both tumor cells (2+ and 3+ in > 10% of tumor cells was defined as PD-L1TC+) and immune cells (positive in >5% immune cells was PD-L1IC+), and also used a combined positive score (CPS; number of PD-L1 staining cells relative to all viable tumor cells; > 1 was PD-L1+). Results In 73 MSI-H gastric carcinomas, MET overexpression was observed in 11 cases (15.1%). In all 11 cases with MET overexpression,MET amplification was not found. MET overexpression was not related to any of clinico-pathological variables and PD-L1 expression. However, the PD-L1 CPS tended to be higher in tumors that were MET positive. Although MET overexpression alone was not a prognostic indicator, combined MET overexpression/PD-L1 predictive models showed that patients with MET+/PD-L1+ showed the best prognosis for overall survival as compared to other groups. Conclusion MET overexpression was observed in 15% of MSI-H gastric carcinomas and was associated with high level expression of PD-L1. more...

With targeted therapies becoming the new standard of care in oncology, next generation sequencing (NGS) is emerging as a valuable method for analyzing the molecular underpinnings of individual tumors. Cyclin E1, encoded by CCNE1 causes activation of E2F mediated transcription and drives cells from G1 into S phase with cyclin-dependent kinase 2 (CDK2). CCNE1 amplification has been found in 11–12% of gastric cancers, but the clinical significance of this amplification remains controversial, and its association with liver metastasis has not been studied. This study included 226 patients diagnosed with advanced gastric adenocarcinoma. We performed multi-gene panel tests containing 143 genes using DNA and RNA obtained from primary (n = 197; 120 endoscopic biopsies and 77 resections) or metastatic cancer tissues (n = 29; 26 biopsies, 2 excisions, and 1 fin. needle aspiration). Among the 226 cases, 28 cases (12.4%) had CCNE1 amplification, almost half of which (n = 13, 46.4%) showed liver metastasis. In patients with CCNE1 amplification (n = 28), TP53 mutations (n = 23, 82.1%) and ERBB2 amplification (n = 8, 28.6%) were the most frequent concurrent genetic alterations. In contrast, 42 (21.2%) of 198 patients without CCNE1 amplification showed liver metastasis. CCNE1 amplification was significantly associated with liver metastasis (p = 0.004; odds ratio, 3.219). Our results show that CCNE1 amplification is significantly associated with liver metastasis in a TP53-mutated gastric cancer subtype. Given the frequent association of CCNE1 amplification with liver metastasis, close follow up for liver metastasis and further clinical trials targeting CDK2 inhibitors are warranted. more...

The emergence of the targeted therapies for non-small cell lung carcinoma (NSCLC) has generated a need for accurate histologic subtyping of NSCLC. In this study, we assessed the utility of immunohistochemical markers that could be helpful in distinction between adenocarcinoma (ADC) and squamous cell carcinoma (SCC). We performed a battery of immunohistochemistry using tissue microarray for napsin-A, Thyroid transcription factor 1 (TTF-1), p63, cytokeratin (CK) 5/6, thrombomodulin (CD141), Epithelial-related antigen (MOC-31), carcinoembryonic antigen (CEA), Cyclooxygenase 2 (COX-2), high-molecular-weight CK (HMWCK), p27kip1 (p27), and Rb protein in 129 resected primary NSCLC with 81 ADCs and 48 SCCs and 10 metastatic ADC to the lung (primary in colon, 7 cases; stomach, 2 cases; vagina, 1 case). Cases of ADC and SCC were morphologically unequivocal and solid tumors with no definite squamous or glandular differentiation were excluded for this analysis. Napsin-A and TTF-1 were positive in 81% and 70% of ADC and in 0% and 2% of SCC, respectively, whereas P63 and CK5/6 were positive in 91% and 90% of SCC and in 9% and 4% of ADC, respectively (P < .001). CD141 stained significantly higher in SCC over ADC (positive in 2% of ADC and 46% of SCC. MOC-31, CEA, COX-2, HMWCK, p27, and Rb appeared to be not useful markers in distinction between ADC and SCC because of their low specificity. None of metastatic ADC to the lung showed positive for napsin-A and TTF-1. It was evident that combination of napsin-A, TTF-1, CK5/6, and p63 was the best immunohistochemical panel in differentiating ADC from SCC of the lung in this study. CD141 appeared to be a potential new marker for SCC with high specificity. Cyclooxygenase 2, MOC-31, CEA, HMWCK, p27, and Rb showed less specificity for differentiation ADC from SCC. more...

Epithelioid trophoblastic tumor is an unusual type of trophoblastic tumor. Here we report on the clinicopathologic and immunohistochemical features of three cases of epithelioid trophoblastic tumor. All three patients were of reproductive age and presented with vaginal bleeding and mild elevation of human chorionic gonadotropin (hCG). All patients underwent a hysterectomy. The tumors consisted of epithelioid intermediate trophoblastic cells that were mononucleated and eosinophilic, or showed clear cytoplasm on microscopic examination. One case presented with a focal choriocarcinoma component. Immunohistochemically, the tumors displayed diffuse positivity for cytokeratin 18, E-cadherin, epidermal growth factor receptor, and p53 and focal positivity for p63 and hCG. However, expression of α-inhibin and placental alkaline phosphatase was almost negative. Tests for human placental lactogen and epithelial membrane antigen were also negative in all cases. more...

Plexiform angiomyxoid myofibroblastic tumor (PAMT) is a recently described mesenchymal tumor of the stomach. We report the first case of PAMT in Korea. A 52-yr-old man underwent esophagogastroduodenoscopy due to dyspepsia for 2 yr. There was a submucosal mass with small mucosal ulceration in the gastric antrum. The tumor measured 3.5 × 2.3 cm in size and showed multinodular plexiform growth pattern of bland-looking spindle cells separated by an abundant myxoid or fibromyxoid matrix rich in small thin-walled blood vessels. The tumor cells were negative for CD117 (c-KIT), CD34 and S-100 protein, but diffusely positive for smooth muscle actin consistent with predominant myofibroblastic differentiation. The patient is doing well without recurrence or metastasis for 5 months after surgery. Although there have been limited follow-up data, PAMT is regarded as a benign gastric neoplasm with histological and immunohistochemical characteristics distinguished from gastrointestinal stromal tumor and other mesenchymal tumors of the stomach. more...

Recently we experienced three cases of human epidermal growth factor receptor 2 (HER2)-amplified invasive breast carcinomas associated with co-amplification or gain of chromosome 17 centromere (CEP17) in silver-enhanced in situ hybridization (SISH) analysis. These cases revealed 2+ or 3+ staining for HER2 immunohistochemistry and > 6 HER2 copies per cell on SISH analyses. However, the calculated HER2/CEP17 ratios were low ( 6 per cell vs HER2/CEP17 ratio> 2.2). We recommend reporting raw SISH or fluorescence in situ hybridization data, including number of cells counted, average numbers of HER2 and CEP17 signals, and the calculated HER2/CEP17 ratio to prevent underreporting of HER2 amplification. more...

Ovarian large cell neuroendocrine carcinoma is a rare tumor that is usually associated with surface epithelial tumors. Mucinous tumors are most common surface epithelial component identified in reported cases. Ovarian mucinous tumor associated with large cell neuroendocrine carci noma is almost always an intestinal type. However, large cell neuroendocrine carcinoma associated with pure mucinous borderline tumor of endocervical-like type has not been described previously. The present case report describes a large cell neuroendocrine carcinoma associated with endocervical-like mucinous borderline tumor of the ovary in a 35-year-old woman. The tumor was confirmed by histopathology and immunohistochemistry. A review of the pertinent literature is in cluded. more...