Macrometastasis in Papillary Thyroid Cancer Patients is Associated with Higher Recurrence in Lateral Neck Nodes.

BACKGROUND: The use of routine central compartment neck dissection surgery for papillary thyroid carcinoma (PTC) is controversial. Although macroscopic central neck lymph node metastasis (CNLN) in PTC is a poor prognostic factor correlated with increased loco-regional recurrence, the significance of microscopic metastasis to the central lymph nodes is not established. Herein, we aimed to assess the influence of the size of CNLN on disease recurrence among PTC patients. METHODS: Data from 233 patients who underwent less than total thyroidectomy with CNLN dissection in 1989-1999 were retrospectively reviewed. The patients were assigned to three groups according to the central node metastasis: no metastasis (Group I), micrometastasis (<2 mm, Group II), and macrometastasis (≥2 mm, Group III). Clinicopathological features, recurrence rate, site of recurrence, and disease-free survival (DFS) were assessed. RESULTS: Of the 233 patients enrolled (mean follow-up period, 16.1 years), 134 (57.5%) had no central neck metastasis, 37 (15.9%) had micrometastasis, and 62 (26.6%) had macrometastasis. Demographics and tumour variables were similar among the three groups. Recurrence rates were 12.7, 16.2, and 43.5% in Groups I, II, and III, respectively (p < 0.001). Group III had a 3.2-fold increased relative risk of recurrence and a significantly decreased DFS compared to Group I. Group III showed significantly higher rates of lateral neck nodes metastasis than Groups I and II. CONCLUSIONS: In conclusion, macrometastasis significantly affects disease recurrence in PTC patients, whereas microscopic metastasis has only marginal effects. Macroscopic CNLN metastasis showed a significantly higher recurrence in the lateral neck node compared to micrometastasis.

Comparative analysis of the expression of E-cadherin, ß-catenin, and ß1 integrin in congenital and acquired cholesteatoma.

E-cadherin, ß-catenin, and ß1 integrin are important cell adhesion molecules to maintain epithelial structure and function. We investigated the expression of these cell adhesion molecules in cholesteatomas to understand the role of cell-cell and cell-extracellular matrix interaction in cholesteatomas. An immunohistochemical investigation was carried out on 35 cholesteatoma tissue samples (14 congenital, 21 acquired cholesteatomas) and 10 normal retroauricular skin (RAS) tissues which are obtained during middle ear surgery. The expression rate was measured to find out differences between retroauricular skin and cholesteatoma, as well as between congenital and acquired cholesteatoma. E-cadherin expression rate was significantly lower in the cholesteatoma (spinous layer 88.7 ± 17.9 %, granular layer 54.6 ± 22.6 %) than in the RAS (100 %, 74.4 ± 7.4 %) and in the acquired (83.3 ± 19.4 %, 48.1 ± 22.9 %) than in the congenital (96.7 ± 12.0 %, 64.4 ± 18.8 %). ß-catenin expression rate was significantly lower in the cholesteatoma (spinous layer 84.1 ± 17.2 %, granular layer 28.7 ± 30.8 %) than in the RAS (100 %, 75.9 ± 6.1 %) and in the acquired (78.1 ± 17.0 %, 17.1 ± 22.3 %) than in the congenital (93.2 ± 13.5 %, 46.1 ± 34.2 %). The expression pattern of ß-catenin is similar to that of E-cadherin. In ß1 integrin, there was no significant difference of the expression rate between RAS and cholesteatoma, as well as between congenital and acquired cholesteatoma. In conclusion, the expression of E-cadherin and ß-catenin is reduced in cholesteatoma, and the reduction is more pronounced in acquired cholesteatoma than in congenital cholesteatoma. Acquired cholesteatomas showed more aggressive characteristics than congenital cholesteatomas in terms of cell-cell adhesion.

Deep learning-based diagnosis of lung cancer using a nationwide respiratory cytology image set: improving accuracy and inter-observer variability.

Deep learning (DL)-based image analysis has recently seen widespread application in digital pathology. Recent studies utilizing DL in cytopathology have shown promising results, however, the development of DL models for respiratory specimens is limited. In this study, we designed a DL model to improve lung cancer diagnosis accuracy using cytological images from the respiratory tract. This retrospective, multicenter study used digital cytology images of respiratory specimens from a quality-controlled national dataset collected from over 200 institutions. The image processing involves generating extended z-stack images to reduce the phase difference of cell clusters, color normalizing, and cropping image patches to 256 × 256 pixels. The accuracy of diagnosing lung cancer in humans from image patches before and after receiving AI assistance was compared. 30,590 image patches (1,273 whole slide images [WSIs]) were divided into 27,362 (1,146 WSIs) for training, 2,928 (126 WSIs) for validation, and 1,272 (1,272 WSIs) for testing. The Densenet121 model, which showed the best performance among six convolutional neural network models, was used for analysis. The results of sensitivity, specificity, and accuracy were 95.9%, 98.2%, and 96.9% respectively, outperforming the average of three experienced pathologists. The accuracy of pathologists after receiving AI assistance improved from 82.9% to 95.9%, and the inter-rater agreement of Fleiss' Kappa value was improved from 0.553 to 0.908. In conclusion, this study demonstrated that a DL model was effective in diagnosing lung cancer in respiratory cytology. By increasing diagnostic accuracy and reducing inter-observer variability, AI has the potential to enhance the diagnostic capabilities of pathologists.

Is use of PPIs related to increased intraepithelial lymphocytes in the colon?

BACKGROUND: The use of proton pump inhibitors (PPIs) is thought to increase the incidence of microscopic colitis (MC), although the exact mechanisms are not fully understood. Increased infiltration of intraepithelial lymphocytes (IELs) is a pathologic finding of MC (including collagenous or lymphocytic colitis). AIMS: We investigated whether PPI use is associated with increased IEL infiltration and inflammation in the lamina propria. METHODS: We retrospectively reviewed the medical records and histological reports of 78 patients receiving PPIs who had no symptoms of diarrhea, and their age- and gender- matched controls. The levels of IELs and inflammation in the lamina propria were assessed independently by two pathologists using H&E and immunohistochemical staining for CD3 and CD8. RESULTS: The IEL count was significantly higher in the PPI group than in controls (12.92 ± 6.27 vs. 8.10 ± 4.21 per 100 epithelial cells, p < 0.001), as was the extent of inflammation (1.74 ± 0.90 vs. 0.86 ± 0.78, p < 0.001). PPI use was associated with increased IEL infiltration in a multivariate analysis (OR, 3.232; 95 % CI, 1.631-6.404, p < 0.001). Within the PPI group, however, the IEL count was not significantly associated with gender, age, type of PPI, or duration of PPI use. CONCLUSIONS: The use of PPIs has a significant association with increased IEL infiltration for subjects without symptoms of diarrhea. This finding suggests that changes such histological alterations seen in the early phage seen in MC possibly represent the stage of the disease even before the onset of symptoms.

Gut Microbiome and Metabolome Profiles Associated with High-Fat Diet in Mice.

Obesity can be caused by microbes producing metabolites; it is thus important to determine the correlation between gut microbes and metabolites. This study aimed to identify gut microbiota-metabolomic signatures that change with a high-fat diet and understand the underlying mechanisms. To investigate the profiles of the gut microbiota and metabolites that changed after a 60% fat diet for 8 weeks, 16S rRNA gene amplicon sequencing and gas chromatography-mass spectrometry (GC-MS)-based metabolomic analyses were performed. Mice belonging to the HFD group showed a significant decrease in the relative abundance of Bacteroidetes but an increase in the relative abundance of Firmicutes compared to the control group. The relative abundance of Firmicutes, such as Lactococcus, Blautia, Lachnoclostridium, Oscillibacter, Ruminiclostridium, Harryflintia, Lactobacillus, Oscillospira, and Erysipelatoclostridium, was significantly higher in the HFD group than in the control group. The increased relative abundance of Firmicutes in the HFD group was positively correlated with fecal ribose, hypoxanthine, fructose, glycolic acid, ornithine, serum inositol, tyrosine, and glycine. Metabolic pathways affected by a high fat diet on serum were involved in aminoacyl-tRNA biosynthesis, glycine, serine and threonine metabolism, cysteine and methionine metabolism, glyoxylate and dicarboxylate metabolism, and phenylalanine, tyrosine, and trypto-phan biosynthesis. This study provides insight into the dysbiosis of gut microbiota and metabolites altered by HFD and may help to understand the mechanisms underlying obesity mediated by gut microbiota.

PAX8 expression in anaplastic thyroid carcinoma is less than those reported in early studies: a multi-institutional study of 182 cases using the monoclonal antibody MRQ-50.

Anaplastic thyroid carcinoma (ATC) is an aggressive malignant tumor composed of undifferentiated thyroid follicular cells. Pathological diagnosis of ATC can be challenging as the tumor may show morphological overlap with other neoplasms with anaplastic morphology. Immunohistochemical demonstration of thyroid origin facilitates the diagnosis of ATC. Previous studies using the polyclonal anti-PAX8 antibody 10336-1-AP suggested that PAX8 was the most sensitive marker, expressed in up to 80% of ATC. According to a 2018 NordiQC report, the monoclonal anti-PAX8 antibody MRQ-50 has become the most commonly used anti-PAX8 antibody worldwide. However, validation of this antibody in ATC is lacking. In this study, we recruited 182 ATC cases from seven institutions. Pathology slides were subjected to histology review. PAX8 immunohistochemistry using the MRQ-50 antibody was performed in whole tissue slides (n = 147) or tissue microarray sections (n = 35). We found PAX8 expression in 54.4% of the cases, which was significantly lower than those reported in prior studies with the polyclonal antibody. PAX8 expression was positively correlated with the presence of an epithelial pattern (63.6% vs 37.5%, p = 0.0008) and a coexisting differentiated thyroid carcinoma component (71.6% vs 44.3%, p = 0.0004), but was not associated with age, gender, specimen type, or presence of giant cell and sarcomatoid patterns. In conclusion, we demonstrated PAX8 expression using the monoclonal antibody MRQ-50 in only half of the cases in a large ATC series. Pathologists should be aware that PAX8 expression in ATC is less than those reported in early studies to avoid misdiagnosis.

Varying appearances of cholangiocarcinoma: radiologic-pathologic correlation.

Intrahepatic cholangiocarcinoma is the second most common primary hepatic tumor. Various risk factors have been reported for intrahepatic cholangiocarcinoma, and the radiologic and pathologic findings of this disease entity may differ depending on the underlying risk factors. Intrahepatic cholangiocarcinoma can be classified into three types on the basis of gross morphologic features: mass-forming (the most common), periductal infiltrating, and intraductal growth. At computed tomography (CT), mass-forming intrahepatic cholangiocarcinoma usually appears as a homogeneous low-attenuation mass with irregular peripheral enhancement and can be accompanied by capsular retraction, satellite nodules, and peripheral intrahepatic duct dilatation. Periductal infiltrating cholangiocarcinoma is characterized by growth along the dilated or narrowed bile duct without mass formation. At CT and magnetic resonance imaging, diffuse periductal thickening and increased enhancement can be seen with a dilated or irregularly narrowed intrahepatic duct. Intraductal cholangiocarcinoma may manifest with various imaging patterns, including diffuse and marked ductectasia either with or without a grossly visible papillary mass, an intraductal polypoid mass within localized ductal dilatation, intraductal castlike lesions within a mildly dilated duct, and a focal stricture-like lesion with mild proximal ductal dilatation. Awareness of the underlying risk factors and morphologic characteristics of intrahepatic cholangiocarcinoma is important for accurate diagnosis and for differentiation from other hepatic tumorous and nontumorous lesions.

A Multi-institutional Study of Prevalence and Clinicopathologic Features of Non-invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP) in Korea.

BACKGROUND: In the present multi-institutional study, the prevalence and clinicopathologic characteristics of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were evaluated among Korean patients who underwent thyroidectomy for papillary thyroid carcinoma (PTC). METHODS: Data from 18,819 patients with PTC from eight university hospitals between January 2012 and February 2018 were retrospectively evaluated. Pathology reports of all PTCs and slides of potential NIFTP cases were reviewed. The strict criterion of no papillae was applied for the diagnosis of NIFTP. Due to assumptions regarding misclassification of NIFTP as non-PTC tumors, the lower boundary of NIFTP prevalence among PTCs was estimated. Mutational analysis for BRAF and three RAS isoforms was performed in 27 randomly selected NIFTP cases. RESULTS: The prevalence of NIFTP was 1.3% (238/18,819) of all PTCs when the same histologic criteria were applied for NIFTP regardless of the tumor size but decreased to 0.8% (152/18,819) when tumors ≥1 cm in size were included. The mean follow-up was 37.7 months and no patient with NIFTP had evidence of lymph node metastasis, distant metastasis, or disease recurrence during the follow-up period. A difference in prevalence of NIFTP before and after NIFTP introduction was not observed. BRAFV600E mutation was not found in NIFTP. The mutation rate for the three RAS genes was 55.6% (15/27). CONCLUSIONS: The low prevalence and indolent clinical outcome of NIFTP in Korea was confirmed using the largest number of cases to date. The introduction of NIFTP may have a small overall impact in Korean practice.

Laparoscopic enucleation of a nonfunctioning neuroendocrine tumor of the pancreas.

Laparoscopic approaches are increasingly used in pancreatic surgery. In the treatment of neuroendocrine tumors (NETs) of the pancreas, enucleation is one of the recommended surgery. Although many clinical experiences have reported the safety and efficacy of laparoscopic enucleation of functioning NETs, such as insulinomas, few reports have explored such treatment for non-functioning NETs. Here, we present a case of 70-year old female patient who underwent successful laparoscopic enucleation of a nonfunctioning NET located in the body of the pancreas.

The Usefulness of Immunocytochemistry of CD56 in Determining Malignancy from Indeterminate Thyroid Fine-Needle Aspiration Cytology.

BACKGROUND: Fine-needle aspiration cytology serves as a safe, economical tool in evaluating thyroid nodules. However, about 30% of the samples are categorized as indeterminate. Hence, many immunocytochemistry markers have been studied, but there has not been a single outstanding marker. We studied the efficacy of CD56 with human bone marrow endothelial cell marker-1 (HBME-1) in diagnosis in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) category III. METHODS: We reviewed ThinPrep liquid-based cytology (LBC) samples with Papanicolaou stain from July 1 to December 31, 2016 (2,195 cases) and selected TBSRTC category III cases (n = 363). Twenty-six cases were histologically confirmed as benign (six cases, 23%) or malignant (20 cases, 77%); we stained 26 LBC slides with HBME-1 and CD56 through the cell transfer method. For evaluation of reactivity of immunocytochemistry, we chose atypical follicular cell clusters. RESULTS: CD56 was not reactive in 18 of 20 cases (90%) of malignant nodules and showed cytoplasmic positivity in five of six cases (83%) of benign nodules. CD56 showed high sensitivity (90.0%) and relatively low specificity (83.3%) in detecting malignancy (p = .004). HBME-1 was reactive in 17 of 20 cases (85%) of malignant nodules and was not reactive in five of six cases (83%) of benign nodules. HBME-1 showed slightly lower sensitivity (85.0%) than CD56. The specificity in detecting malignancy by HBME-1 was similar to that of CD56 (83.3%, p = .008). CD56 and HBME-1 tests combined showed lower sensitivity (75.0% vs 90%) and higher specificity (93.8% vs 83.3%) in detecting malignancy compared to using CD56 alone. CONCLUSIONS: Using CD56 alone showed relatively low specificity despite high sensitivity for detecting malignancy. Combining CD56 with HBME-1 could increase the specificity. Thus, we suggest that CD56 could be a useful preoperative marker for differential diagnosis of TBSRTC category III samples.

Preoperative Cytologic Diagnosis of Warthin-like Variant of Papillary Thyroid Carcinoma.

BACKGROUND: Warthin-like variant of papillary thyroid carcinoma (WLV-PTC) is a relatively rare variant of papillary thyroid carcinoma with favorable prognosis. However, preoperative diagnosis using fine-needle aspiration (FNA) specimens is challenging especially with lymphocytic thyroiditis characterized by Hürthle cells and lymphocytic background. To determine a helpful cytological differential point, we compared WLV-PTC FNA findings with conventional papillary thyroid carcinoma with lymphocytic thyroiditis (PTC-LT) and conventional papillary thyroid carcinoma without lymphocytic thyroiditis (PTC) regarding infiltrating inflammatory cells and their distribution. Preoperative diagnosis or potential for WLV-PTC will be helpful for surgeons to decide the scope of operation. METHODS: Of the 8,179 patients treated for papillary thyroid carcinoma between January 2007 and December 2012, 16 patients (0.2%) were pathologically confirmed as WLV-PTC and four cases were available for cytologic review. For comparison, we randomly selected six PTC-LT cases and five PTC cases during the same period. The number of intratumoral and background lymphocytes, histiocytes, neutrophils, and the presence of giant cells were evaluated and compared using conventional smear and ThinPrep preparations. RESULTS: WLV-PTC showed extensive lymphocytic smear with incorporation of thyroid follicular tumor cell clusters and frequent histiocytes. WLV-PTC was associated with higher intratumoral and background lymphocytes and histiocytes compared with PTC-LT or PTC. The difference was more distinct in liquid-based cytology. CONCLUSIONS: The lymphocytic smear pattern and the number of inflammatory cells of WLV-PTC are different from those of PTC-LT or PTC and will be helpful for the differential diagnosis of WLV-PTC in preoperative FNA.

The Intraoperative Immunohistochemical Staining of CD56 and CK19 Improves Surgical Decision for Thyroid Follicular Lesions.

BACKGROUND: When differential diagnosis is difficult in thyroid follicular lesions with overlapping histological features, the immunohistochemical staining can help confirm the diagnosis. We aimed to evaluate the effectiveness of rapid immunohistochemical stains of CD56 and cytokeratin 19 on frozen sections of thyroid follicular lesion and explore the possible gains and limitations of the practice. METHODS: Eighty-six nodules of 79 patients whose intraoperative frozen sections were selected as the control group, and 53 nodules of 48 patients whose intraoperative frozen sections were subject to rapid immunohistochemistry were selected as the study group. RESULTS: Five nodules (6%) in the control group were diagnosed as follicular neoplasm and six nodules (7%) were deferred. In the study group, six nodules (11%) were follicular neoplasm and none were deferred. Three nodules (4%) in the control group showed diagnostic discrepancy between the frozen and permanent diagnoses, but none in the study group. The average turnaround time for the frozen diagnosis of the control group was 24 minutes, whereas it was 54 minutes for the study group. CONCLUSIONS: Intraoperative rapid immunohistochemical stains significantly decreased the diagnostic discrepancy in this study. Considering the adverse effects of indefinite frozen diagnosis or discrepancy with permanent diagnoses, the intraoperative rapid immunohistochemical stain can help to accurately diagnose and hence provide guidance to surgical treatment.

Anaplastic Transformation of Papillary Thyroid Carcinoma Only Seen in Pleural Metastasis: A Case Report with Review of the Literature.

Anaplastic transformation of papillary thyroid carcinoma (PTC) at distant metastatic sites is extremely rare, and there have been fewer than 20 reported cases in the literature. A 61-year-old woman presented with 1-week history of dyspnea. Her past medical history was remarkable because, 19 years ago, she underwent nearly total thyroidectomy and radical neck dissection due to PTC. Computed tomography of the chest revealed a 1.7 cm nodule in the lung and diffuse pleural thickening. Gun biopsy of the lung nodule revealed metastatic PTC with typical histology. However, the pleural biopsy predominantly showed anaplastic pleomorphic and spindle sarcomatoid carcinoma with microscopic focus of PTC. Immunohistochemical results showed both anaplastic sarcomatoid and PTC components positive for TTF-1, galectin-3 and PAX-8, thus supporting anaplastic transformation of PTC at the metastatic site. Subsequently the patient received 1 cycle of cisplatin-based chemotherapy but died from the disease 4 months after diagnosis. Although it is rare, anaplastic transformation of PTC should be considered during differential diagnosis of patients who present with exclusive sarcomatoid morphology at metastatic sites and have a history of PTC. We report another case of anaplastic transformation of PTC, found at pleural metastasis, together with the immunohistochemical profile and a literature review.

Extremely Well-Differentiated Papillary Thyroid Carcinoma Resembling Adenomatous Hyperplasia Can Metastasize to the Skull: A Case Report.

We describe herein histologic, immunohistochemical, and molecular findings and clinical manifestations of a rare case of an extremely well differentiated papillary thyroid carcinoma (EWD-PTC). Similarly, it is also difficult to diagnose follicular variant papillary thyroid carcinoma (FVPTC), whose diagnosis is still met with controversy. A recently reported entity of well-differentiated tumor of uncertain malignant potential (WDT-UMP) is added to the diagnostic spectrum harboring EWD-PTC and FVPTC. We report this case, because EWD-PTC is different from FVPTC in its papillary architecture, and also from WDT-UMP in its recurrence and metastatic pattern. These morphologically deceptive entities harbored diagnostic difficulties in the past because the diagnosis depended solely on histology. However, they are now diagnosed with more certainty by virtue of immunohistochemical and molecular studies. We experienced a case of EWD-PTC, which had been diagnosed as adenomatous hyperplasia 20 years ago and manifested recurrence with lymph node (LN) metastasis 7 years later. After another 7 years of follow-up, a new thyroid lesion had developed, diagnosed as FVPTC, with LN metastasis of EWD-PTC. One year later, the patient developed metastatic FVPTC in the skull. Immunohistochemically, the EWD-PTC was focally positive for CK19, negative for galectin-3, and focally negative for CD56. Molecular studies revealed BRAF-positivity and K-RAS negativity. The FVPTC in the left thyroid showed both BRAF and K-RAS negativity. In conclusion, EWD-PTC and FVPTC share similar histologic features, but they are different tumors with different molecular biologic and clinical manifestations. A large cohort of EWD-PTC should be included in further study.

Thyroid Fine-Needle Aspiration Cytology Practice in Korea.

We reviewed the current status of thyroid fine-needle aspiration cytology (FNAC) in Korea. Thyroid aspiration biopsy was first introduced in Korea in 1977. Currently, radiologists aspirate the thyroid nodule under the guidance of ultrasonography, and cytologic interpretation is only legally approved when a cytopathologist makes the diagnosis. In 2008, eight thyroid-related societies came together to form the Korean Thyroid Association. The Korean Society for Cytopathology and the endocrine pathology study group of the Korean Society for Pathologists have been updating the cytologic diagnostic guidelines. The Bethesda System for Reporting Thyroid Cytopathology was first introduced in 2009, and has been used by up to 94% of institutions by 2016. The average diagnosis rates are as follows for each category: I (12.4%), II (57.9%), III (10.4%), IV (2.9%), V (3.7%), and VI (12.7%). The malignancy rates in surgical cases are as follows for each category: I (28.7%), II (27.8%), III (50.6%), IV (52.3%), V (90.7%), and VI (100.0%). Liquid-based cytology has been used since 2010, and it was utilized by 68% of institutions in 2016. The categorization of thyroid lesions into "atypia of undetermined significance" or "follicular lesion of undetermined significance" is necessary to draw consensus in our society. Immunocytochemistry for galectin-3 and BRAF is used. Additionally, a molecular test for BRAF in thyroid FNACs is actively used. Core biopsies were performed in only 44% of institutions. Even the institutions that perform core biopsies only perform them for less than 3% of all FNACs. However, only 5% of institutions performed core biopsies up to three times more than FNAC.

Clinicopathologic Characteristics and Mutational Status of Succinate Dehydrogenase Genes in Paraganglioma of the Urinary Bladder: A Multi-Institutional Korean Study.

CONTEXT: - Because of the limited number of available primary bladder paraganglioma (PBPG) cases, the rates of succinate dehydrogenase (SDH) mutations and the clinicopathologic characteristics of SDH-deficient tumors have not been fully studied. OBJECTIVE: - To define the clinicopathologic and molecular characteristics of PBPGs. DESIGN: - A total of 52 PBPGs were collected retrospectively. SDHA and SDHB immunohistochemical stains were performed. In cases of SDHB expression loss, mutation analyses of SDHB, SDHC, and SDHD were performed. RESULTS: - The clinicopathologic features were analyzed for 52 cases (M:F = 27:25), with a mean age of 56 years (range, 22-79 years). Tumor sizes were 0.5 to 8 cm (mean, 2.4 cm). Tumor necrosis was present in 5 of 52 cases (10%), involvement of muscularis propria in 41 (79%), and lymphovascular tumor invasion in 6 (12%). During a mean follow-up period of 41 months (range, 1-161 months), 3 of 52 patients (6%) developed metastases, but no one died from the disease. Immunohistochemistry for SDHA and SDHB showed that all cases were SDHA intact. Among them, 43 cases had intact SDHB, whereas 9 cases were SDHB deficient. Compared with the SDHB-intact cases, the SDHB-deficient cases were characterized by large tumor sizes (4.5 versus 1.9 cm; P < .001), a higher number of mitoses per 10 high-powered fields (2.6 versus 0.1; P = .002), and frequent lymphovascular tumor invasion (33% versus 7%; P = .02) and metastases (22% versus 2%; P = .02). Mutational analyses for SDHB, SDHC, and SDHD were performed in 9 SDHB-deficient cases. Among them, 6 cases were successfully sequenced and revealed SDHB mutations only. CONCLUSIONS: - Large tumor size, a higher number of mitoses, and the presence of lymphovascular tumor invasion and SDHB mutations suggest malignant paraganglioma.

Clinicopathologic Correlations of E-cadherin and Prrx-1 Expression Loss in Hepatocellular Carcinoma.

BACKGROUND: Developing predictive markers for hepatocellular carcinoma (HCC) is important, because many patients experience recurrence and metastasis. Epithelial to mesenchymal transition (EMT) is a developmental process that plays an important role during embryogenesis and also during cancer metastasis. Paired-related homeobox protein 1 (Prrx-1) is an EMT inducer that has recently been introduced, and its prognostic significance in HCC is largely unknown. METHODS: Tissue microarray was constructed using surgically resected primary HCCs from 244 cases. Immunohistochemical staining of E-cadherin and Prrx-1 was performed. The correlation between E-cadherin loss and Prrx-1 expression, as well as other clinicopathologic factors, was evaluated. RESULTS: E-cadherin expression was decreased in 96 cases (39.4%). Loss of E-cadherin correlated with a higher recurrence rate (p < .001) but was not correlated with patient's survival. Thirty-two cases (13.3%) showed at least focal nuclear Prrx-1 immunoreactivity while all non-neoplastic livers (n = 22) were negative. Prrx-1 expression was not associated with E-cadherin loss, survival or recurrence rates, pathologic factors, or the Ki-67 labeling index. Twenty tumors that were positive for E-cadherin and Prrx-1 had significantly higher nuclear grades than the rest of the cohort (p = .037). In Cox proportional hazard models, E-cadherin loss and large vessel invasion were independent prognostic factors for shorter disease-free survival. Cirrhosis and high Ki-67 index (> 40%) were independent prognostic factors for shorter overall survival. CONCLUSIONS: Prrx-1 was expressed in small portions of HCCs but not in normal livers. Additional studies with a large number of Prrx-1-positive cases are required to confirm the results of this study.

Repeated Panniculitis Induced by Pegylated Interferon Alpha 2a in a Patient with Chronic Hepatitis C.

Pegylated interferon alpha (PEG-IFN-α) is widely used to treat chronic hepatitis C in combination with ribavirin. Many adverse effects of PEG-IFN-α, such as hematologic, psychologic, dermatologic, immunologic, and other abnormalities, have been reported, and some serious adverse events lead to PEG-IFN-α treatment discontinuation. For very rare adverse events such as panniculitis, there are no established guidelines on whether to continue PEG-IFN-α treatment. Published reports on panniculitis induced by PEG-IFN-α 2a are sparse. Herein we report a case of repeated occurrences of panniculitis in a patient with chronic hepatitis C, leading to treatment cessation.

Significance of the Extracapsular Spread of Metastatic Lymph Nodes in Papillary Thyroid Carcinoma.

OBJECTIVES: The extracapsular spread (ECS) of metastatic lymph nodes is associated with aggressive tumor behavior, and is regarded as a major risk factor for local recurrence in patients with head and neck squamous cell carcinoma. However, the significance of ECS of metastatic lymph nodes has not been well established in well-differentiated thyroid carcinoma. The purpose of this study was to examine this question. METHODS: A retrospective review was performed of 335 patients with papillary thyroid carcinoma who underwent total thyroidectomy with lymph node dissection from April 2001 to December 2009. We analyzed various clinical characteristics, pathologic factors, and the size, number, and ECS of foci in metastatic lymph nodes. RESULTS: On pathologic review, 201 of the patients (56.6%) had lymph node metastasis. This was significantly related to age and tumor size. ECS was noted in 64 of these 201 patients (31.8%), and was significantly related to male gender, tumor size, presence of extrathyroidal extension, metastatic lymph node size, and focus size. Recurrence occurred in 13 patients (3.9%), and the presence of ECS was significantly related to recurrence. CONCLUSION: ECS of metastatic lymph nodes is an important prognostic factor for loco-regional recurrence in papillary thyroid carcinoma.