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Background Periampullary cancers (PAC) including pancreatic, ampulla of Vater (AOV), and common bile duct (CBD) cancers are highly aggressive with a lack of useful prognostic markers beyond T stage. However, T staging can be biased due to the anatomic complexity of this region. Recently, several markers related to cancer stem cells and epithelial-mesenchymal transition (EMT) such as octamer transcription factor-4 (Oct4) and fibroblast growth factor receptor 1 (FGFR1) respectively, have been proposed as new promising markers in other solid cancers. The aim of this study was to assess the expression and prognostic significance of stem cell/EMT markers in PACs. Methods Formalin-fixed, paraffin-embedded tissues of surgically excised PACs from the laboratory archives from 1998 to 2014 were evaluated by immunohistochemical staining for stem cell/EMT markers using tissue microarray. The clinicopathologic parameters were documented and statistically analyzed with the immunohistochemical findings. Survival and recurrence data were collected and analyzed. Results A total of 126 PAC cases were evaluated. The average age was 63 years, with 76 male and 50 female patient samples. Age less than 74 years, AOV cancers, lower T & N stage, lower tumor size, no lymphatic, vascular, perineural invasion and histologic well differentiation, intestinal type, no fibrosis, severe inflammation were significantly associated with the better overall survival High expression levels of FGFR1 as well as CK20, CDX2, and VEGF were significantly related to better overall survival, while other stem cell markers were not related. Similar findings were observed for tumor recurrence using disease-free survival. Conclusions In addition to other clinicopathologic parameters, severe fibrosis was related to frequent tumor recurrence, and high FGFR1 expression was associated with better overall survival. Histologic changes such as extensive fibrosis need to be investigated further in relation to EMT of PACs.

Kikuchi-Fujimoto disease (KFD) is a rare benign lymphadenitis that mainly involves cervical lymph nodes of young Asian women with unknown etiology. Recently, we experienced a case of KFD found with Torque teno virus/Torque teno-like mini virus (TTV/TTMV) from a 26-year-old woman. TTV/TTMV is a genus of Circoviridae that causes necrotizing lymphadenitis in pigs, which shares the key histologic finding of KFD. The purpose of this study is to investigate the pathogenic role of TTV/TTMV in KFD by quantitative polymerase chain reaction (qPCR) analysis.We performed two-step qPCR specific to TTV/TTMV with formalin-fixed paraffin-embedded tissue of sequentially selected 100 KFD patients and 50 randomly selected, matched normal controls. Consequent direct sequencing was done for confirmation with PCR products.PCR amplification of TTV and TTMV was found in a significantly higher proportion in KFDs than normal controls (TTV, 85% vs. 18%, p0.000; TTMV, 91% vs. 24%, p0.000). After the sequencing, KFD samples showed more sequence matching than control samples for TTMV (94% vs. 30%, p0.000).This finding strongly suggests the possible implication of TTV/TTMV in the pathogenesis of KFD. Animal or in vivo experimental design should be followed in the future.Key Points• Kikuchi-Fujimoto disease (KFD) is rare and its etiology is still unclear.• Torque teno/Torque teno-like minivirus (TTV/TTMV) is a recently introduced virus in the Circoviridae family that causes necrotizing lymphadenitis in pigs, histologically similar to KFD.• We discovered the significantly increased TTV/TTMV viral loads in the KFD patients than normal controls, which implicates TTV/TTMV in the pathogenesis of KFD.

Objective Conventional smear (CS) using fine-needle aspiration cytology (FNAC) has been established as the test of choice for diagnosing thyroid lesions, despite low sample adequacy and inter-individual variations. Although a liquid-based preparation (LBP) technique has been recently applied to overcome these limitations, its clinical utility and its accuracy over CS are controversial. This study aimed to determine the true sensitivity and specificity of LBP in thyroid FNAC by meta-analysis. Design Systematic review with meta-analysis. Methods We searched major electronic databases (MEDLINE, EMBASE, Cochrane library, Google Scholar) with queries of ‘thyroid’, ‘LBP’ and ‘liquid-based cytology’. Original articles including cytohistologic correlation data comparing the accuracy of any LBP technique, such as ThinPrep, SurePath and Liqui-Prep, with CS were included for qualitative meta-analysis and preparation of synthesized reporter-operating curves (sROC). Results A total of 372 studies were screened and 51 original articles were eligible for full-text review; finally, 24 studies were chosen for the meta-analysis. Average sample inadequacy was significantly lower in two mainstream LBP methods (ThinPrep and SurePath) than CS. Specificity and sensitivity by sROC were similar or slightly superior for LBP vs CS. Various cytomorphologic changes by each method have been reported. Conclusions Although a learning curve is essential for adapting to the cytomorphologic features of the LBP technique, our results support the use of two mainstream LBPs alone in thyroid FNAC that LBP will increase the sample adequacy and reduce the workload with similar accuracy. More data and further evaluation are needed for the other LBP methods.

Background While fine-needle aspiration cytology (FNAC) using conventional smear has been widely accepted as the primary diagnostic tool for thyroid lesions, liquid-based preparations (LBPs) are increasingly replacing it. A new automated LBP method, EASYPREP® (EP), was recently introduced and has shown relevant diagnostic efficacy in gynecologic samples. We compared the diagnostic utility of EP and SurePath® (SP), a more widely established LBP method, in thyroid FNAC. Methods Under the ultrasonographic guidance, 253 thyroid FNAC samples were collected by sample-splitting manner. Three pathologists made cytologic diagnoses of EP and SP according to the Bethesda system independently and compared the cytomorphologic parameters. Cytohistologic correlation was performed in 30 resected cases. Results Fifteen (5.9%) and 21 (8.3%) samples were unsatisfactory in SP and EP, respectively, owing to the unequal sample-splitting. Cytologic diagnoses of SP and EP were consistent in 228 cases (90.1%), and inconsistent in remainder mostly owing to the unequal distribution of pathognomic cells. While cytomorphologic parameters were not significantly different between two methods, EP showed less three-dimensional configuration in benign lesions. Cytohistologic correlation showed no significant differences in sensitivity (100% vs. 95.5%) and specificity (100% vs. 100%) between SP and EP. Labor time for processing 48 cases was 42% shorter with EP than with SP (28 min vs. 48 min). Conclusions The diagnostic utility of EP in thyroid FNAC was comparable to that of SP. EP allowed better visibility owing to better fragmentation of follicular clusters. The automated system of EP has the advantages of a shorter labor time for batch processing. Diagn. Cytopathol. 2016. © 2016 Wiley Periodicals, Inc.

Context Mullerian-inhibiting substance/anti-Mullerian hormone (MIS/AMH) is produced in the ovarian granulosa cells, and it is believed to inhibit ovarian folliculogenesis and steroidogenesis in women of reproductive age. Objective To investigate the expression of MIS/AMH type II receptor (MISRII/AMHRII) that binds MIS/AMH in the ovaries of reproductive-age women; to identify the exact targets of MIS/AMH. Design Laboratory study using human ovarian tissue. Setting University hospital. Patients Tissue samples from 25 patients who had undergone ovarian surgery. Interventions The segregation of ovarian granulosa and theca cells by laser microdissection was followed by RT-PCR, analyzing MISRII/AMHRII mRNA expression. Afterward, in situ hybridization and immunohistochemistry were performed to determine the localization of MISRII/AMHRII mRNA and protein expression. Main outcome measures MISRII/AMHRII mRNA expression by RT-PCR, in situ hybridization, and immunohistochemistry. Results MISRII/AMHRII were expressed in granulosa and theca cells of preantral and antral follicles. The granulosa cells showed stronger MISRII/AMHRII expression than theca cells. MISRII/AMHRII mRNA staining of granulosa and theca cells in large antral follicles, early atretic follicles, and corpus luteum waned but were still detected weakly, showing higher expression in theca cells than in granulosa cells. However, MISRII/AMHRII protein in the granulosa layer of the atretic follicle and corpus luteum could not be assessed. Conclusions As MISRII/AMHRII is expressed in both granulosa and theca cells, this indicates that MIS/AMH, produced in the granulosa cells, is active in the theca cells as well. MIS/AMH is most likely actively involved not only in the autocrine and endocrine processes but also in the paracrine processes involving theca cells.

Necrotizing sarcoid granulomatosis (NSG) is a rare granulomatous disease that primarily affects the lung and presents as nodular masses of confluent sarcoid-like granulomas with extensive necrosis and vasculitis [1]. Proper diagnosis and treatment are challenging for clinicians, radiologists, and pathologists because of the rarity and diagnostic difficulty of this disease [2-4]. Since it was first described by Liebow [1], only 135 cases have been reported [2,4,5]. In addition to its rarity, the similarity of the clinical, radiological, and pathological features of NSG to other granulomatous diseases, such as granulomatous infection, nodular sarcoidosis, and Wegener’s granulomatosis (WG), is the largest obstacle in its proper diagnosis. The initial symptoms are non-specific or frequently do not present at all [2-4]. Radiologically, NSG can present as cavitary lesions, ill-defined pneumonic consolidations, or even as a solitary nodule or a mass [6,7]. Pathologically, NSG shares features of sarcoidosis and WG [1,4]. Thus, it is not surprising that NSG is often easily mistaken for granulomatous infections, such as tuberculosis, especially in endemic areas. Although the general level of hygiene in Korea has dramatically improved, the reported incidence of pulmonary tuberculosis remains the highest among the Organization for Economic Cooperation and Development member countries [8,9]. Identification of causal microorganisms is essential for proper treatment of tuberculosis; however, empirical treatment with anti-tuberculosis medication is often performed in endemic countries like Korea, in spite of tests failing to show any causative microorganisms [9]. Here, we report the first two cases of NSG in Korean patients, one of whom showed a dramatic response to immediate application of systemic corticosteroids, and the other of whom showed no response to empirical treatment with anti-tuberculosis medication.

Spindle cell ductal carcinoma in situ (DCIS) is a recently recognized subtype of DCIS, which is associated with a very rare and unique morphology. Although the histologic features have been relatively well described in a few reports, the cytologic features have not. Even though the distinction of this lesion from usual DCIS is not crucial clinically, it should be noted that this lesion might simulate the features of metaplastic carcinoma on fine needle aspiration cytology. Here, we report a case of spindle cell DCIS in a 45-year-old female, with the detailed cytologic features, both on conventional and liquid-based preparations, along with some useful immunohistochemical staining markers for the differential diagnosis.

A B S T R A C T Objective: Kikuchi–Fujimoto disease (KFD) is a self-limiting disorder characterized by histiocytic necrotizing lymphadenitis in the cervical lymph nodes of young women. Although an infectious etiology has been postulated, a definitive causative agent has not been identified. The few dozens of published studies are limited by small sample size and poorly structured study designs. The purpose of this study is to evaluate the association of each infectious agent to KFD that has been studied. Methods: We performed metaanalysis using major electronic database (MEDLINE (PubMed), Cochrane library, Embase, Web of Science, NML gateway, LILACS, and Google Scholar). Cross-sectional studies on the positivity of each agent in clinicopathologically diagnosed KFD and normal controls by polymerase chain reaction (PCR) or in situ hybridization (ISH) were carefully retrieved. The included infectious agents were herpes simplex virus (HSV) type 1, 2, varicella-zoster virus, cytomegalovirus, Epstein–Barr virus (EBV), human herpes virus (HHV) 6, 7, 8, parvovirus B19, human papilloma virus, hepatitis B virus, human T-lymphotropic virus 1, Brucella, and Bartonella henselae. Results: After an exclusion process of 2491 studies, five, two, four, two, two, and three studies on EBVPCR, EBV-ISH, HHV6-PCR, HHV8-PCR, parvovirus B19-PCR and HHV7-PCR, respectively, were suitable for quantitative meta-analysis. Conclusion: The most suspected pathogen, EBV was not associated to KFD than normal controls (odds ratio = 0.28, p = 0.005), while the HHV8 positivity was more likely to be associated (odds ratio = 8.24, p = 0.003) although it still needs further verification. None of other viruses was associated to KFD although the results are limited by small sample size. More studies with large sample size and strict sample selection criteria are necessary in future.

Objective We report a case of intramural florid cystic endosalpingiosis in the lower uterine segment of the uterus. Case report A 43-year-old female presented with vaginal bleeding. Abdominal computed tomography suggested a leiomyoma with cystic degeneration. A total hysterectomy revealed a 4.0 cm × 3.8 cm cystic mass in the lower uterine segment. The cystic space microscopically was lined with a single layer or stratified layer of ciliated columnar cells that resembled tubal epithelium without cytologic atypia. The glandular spaces were surrounded by normal myometrium with no evidence of periglandular endometrial stroma, which was consistent with the diagnosis of florid cystic endosalpingiosis. Conclusion Florid cystic endosalpingiosis involving the uterus is a rare and clinically unexpected finding; however, it should be considered in the differential diagnosis of a uterine mass.

Background: The objective of this study was to investigate the expression of human papilloma virus (HPV) L1 capsid protein in abnormal cervical cytology with HPV16 infection and analyze its association with cervical histopathology in Korean women. Material and Methods: We performed immunocytochemistry for HPV L1 in 475 abnormal cervical cytology samples from patients with HPV16 infections using the Cytoactiv® HPV L1 screening set. We investigated the expression of HPV L1 in cervical cytology samples and compared it with the results of histopathological examination of surgical specimens. Results: Of a total of 475 cases, 188 (39.6%) were immunocytochemically positive and 287 (60.4%) negative for HPV L1. The immunocytochemical expression rates of HPV L1 in atypical squamous cells of unknown significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and cancer were 21.8%, 59.7%, 19.1%, and 0.0%, respectively. LSIL exhibited the highest rate of HPV L1 positivity. Of a total of 475 cases, the multiple-type HPV infection rate, including HPV16, in HPV L1-negative cytology samples was 27.5%, which was significantly higher than that in HPV L1-positive cytology samples (p = 0.037). The absence of HPV L1 expression in ASCUS and LSIL was significantly associated with high-grade (≥cervical intraepithelial neoplasia [CIN] 2) than low-grade (≤CIN1) histopathology diagnoses (p < 0.05), but was not significantly different between HPV16 single and multiple-type HPV infections (p > 0.05). On the other hand, among 188 HPV L1-positive cases, 30.6% of multiple-type HPV infections showed high-grade histopathology diagnoses (≥CIN3), significantly higher than the percentage of HPV16 single infections (8.6%) (p = 0.0004) Conclusions: Our study demonstrates that the expression of HPV L1 is low in advanced dysplasia. Furthermore, the absence of HPV L1 in HPV16-positive low-grade cytology (i.e., ASCUS and LSIL) is strongly associated with high-grade histopathology diagnoses. The multiplicity of HPV infections may have an important role in high-grade histopathology diagnoses (≥CIN3) in HPV L1-positive cases.

The follicular variant of papillary thyroid carcinoma (FVPTC) presents distinct histologic subtypes and molecular genotyping. The preoperative diagnosis of FVPTC through fine-needle aspiration cytology (FNAC) is challenging.We reviewed 59 archival thyroid FNAC specimens of surgically confirmed FVPTC according to histologic subtype: encapsulated FVPTC (n = 30) and infiltrative FVPTC (n = 29). Galectin-3 immunostaining and molecular analyses for BRAF and three RAS genes (NRAS, HRAS, and KRAS) were performed.FNAC diagnoses of FVPTC included benign (5%), atypia of undetermined significance (19%), follicular neoplasm/suspicious for follicular neoplasm (14%), suspicious for PTC (29%), and PTC (34%). Galectin-3 immunostaining was positive in 50% of FNAC specimens. A BRAF mutation was found only in 14 (24%) tumors with the FNAC diagnosis of PTC or suspicious for PTC: 13 cases with the usual c.1799TA (p.V600E) mutation and 1 case with a 3 base-pair deletion (c.1799_1801delTGA), resulting in a deletion of lysine at codon 601 and a deletion c.1799_1801delTGA that results in a valine-to-glutamate substitution at codon 600 (p.V600_K601E) while preserving the reading frame. A BRAF K601E mutation was not found. RAS mutations were observed in 18 (33%) tumors (NRAS, 22%; HRAS, 6%; KRAS, 6%). Mutations of the three RAS genes were detected in codon 61 but not in codons 12 and 13. There was a decreasing trend of RAS mutation rates associated with an increasing risk of malignancy in the FNAC diagnostic categories. The triage efficacy of FNAC to make a recommendation for surgery was 73% for encapsulated tumors and 79% for infiltrative tumors. Addition of galectin-3 or the BRAF test to FNAC showed no significant improvement in the triage efficacy. However, RAS mutations significantly improved the triage efficacy of FNAC. There was no significant difference in the triage efficacy of FNAC, galectin-3 expression, and the prevalence of somatic mutations between encapsulated and infiltrative tumors.Thyroid FNAC has a low sensitivity for the detection of FVPTC regardless of histologic subtype. Encapsulated FVPTC and infiltrative FVPTC have similar molecular profiles and rates of galectin-3 expression. RAS mutational analysis is more useful than BRAF testing to improve the triage efficacy of FNAC for FVPTC.

Cancer stem cells are thought to be responsible for tumor recurrence and resistance in glioblastomas. An isocitrate dehydrogenase1 (IDH1) mutation, affecting codon132 of the isocitrate dehydrogenase1 gene, has prognostic significance in glioblastomas. We investigated whether stem cell marker expression [CD133, CD34, and vascular endothelial growth factor (VEGF)] and IDH1 mutation correlate with clinical factors and prognosis in glioblastoma. CD133, CD34, and VEGF expression was evaluated by immunohistochemistry in 67 cases of glioblastoma identified between 2005 and 2012. IDH1 mutation was assessed by immunohistochemistry, peptide-nucleic-acid mediated PCR clamping, and direct gene sequencing. Diffuse CD133 expression was detected in 12 (17.9 %) cases and was associated with poor overall survival (OS) (P = 0.010) and progression-free survival (P = 0.017). CD34 and VEGF expression were not associated with prognosis in these samples. IDH1 mutation was detected in ten (14.9 %) cases. Eight were clinically secondary tumors and two were primary tumors (P

Meningiomas are slow-growing neoplasms that recur locally. Their morphologic grading does not always correlate with patient outcome. We evaluated the status of several immunohistochemical markers with histopathologic parameters in various grades of meningioma.Eighty-eight meningioma specimens were examined immunohistochemically to determine the status of Ki-67, cyclin D1, epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and bcl-2. Several clinical and pathological parameters were investigated.Forty-nine Grade I, 33 Grade II, and 6 Grade III meningiomas were observed. VEGF and Ki-67 expression was correlated with higher tumor grade. The association between grade and other immunohistochemical markers expression was not significant. A correlation was observed between COX-2 expression and invasiveness to the brain or adjacent soft tissue. Tumor recurrence was correlated with brain or adjacent soft tissue invasion. We also observed a relationship between VEGF level and COX-2 expression, and they were both correlated with necrosis.Immunohistochemical evaluation of VEGF, COX-2, and Ki-67 expression can provide information regarding the behavior of meningiomas, particularly for cases in which histological grading is not straightforward.

The tall cell variant (TCV) of papillary thyroid carcinoma (PTC) is the most common among the aggressive variants of the disease. We aimed to investigate the clinicopathologic characteristics of TCV, and evaluate the diagnostic efficacy of liquid-based cytology (LBC) in TCV detection compared with conventional smear in thyroid fine needle aspiration (FNA). A total of 266 consecutive patients (220 women and 46 men) with PTC were enrolled. We analyzed tumor characteristics according to histologic growth patterns as classic, classic PTC with tall cell features, and TCV. The cytomorphologic features of these subtypes were investigated according to the preparation methods of conventional smear and LBC. TCV and classic PTC with tall cell features comprised 4.9% and 6.0% of all tumors, respectively, and were significantly associated with older age at presentation, larger tumor size, high frequency of extrathyroid extension, and BRAF mutation in comparison with classic PTC. However, there was no statistically significant difference in clinicopathologic features between TCV and classic PTC with tall cell features. Tall cells were more easily detected by LBC than by conventional smear. The percentage of tall cells identified using LBC was well correlated with three histologic subtypes. Our results demonstrate that TCV is more common than previously recognized in Korea and any PTC containing tall cells may have identical biological behavior regardless of the precise proportions of tall cells. It is possible to make a preoperative diagnosis of TCV using LBC.

Perivascular epithelioid cell tumor (PEComa) is a rare collection of tumors arising in a wide array of anatomic locations. It is characterized by the presence of a peculiar population of myomelanocytic marker-positive perivascular epithelioid cells, and is commonly detected in the uterus. The colorectal area is an uncommon site for primary PEComa. In this study, we describe a 17-year-old patient presenting with a rectal polyp. Histologically, the tumor consisted of sheets of round to polygonal epithelioid cells with clear and granular cytoplasm, and a prominent capillary network. Some of the tumor cells were positive for Fontana-Masson staining. Immunohistochemically, the tumor cells were positive for HMB-45, and were negative for cytokeratin, vimentin, S-100 protein, actin, desmin, EMA, CD34, and c-kit. After finding melanosomes or premelanosomes at the ultrastructural level, the diagnosis of PEComa was made. Although PEComa arising within the intestinal tract is unusual and clinically unexpected, PEComa should be considered in the differential diagnosis of rectal polypoid lesions.

Objectives: The trefoil factor family (TFF) is composed of three thermostable, and protease-resistant proteins, named TFF1, TFF2 and TFF3, and plays a role in gastrointestinal mucosal defence and repair. Recently, TFFs have been found to be related to the development of various types of cancer. This study assessed the relationship between the expression of TFF1 and TFF3 and the clinicopathological parameters in gastric carcinoma (GC). Materials and Methods: The expression of TFF1 and TFF3 was analyzed by immunohistochemistry in 292 GCs and 20 normal gastric tissues. Results: All normal gastric tissues expressed TFF1, but 53.8% of GCs showed reduced TFF1 expression. However, TFF3 was not detected in normal gastric tissues and 44.2% of GCs showed a high level of expression. Highly expressed TFF3 was significantly correlated with lymph node metastasis, lymphatic invasion, vein invasion, and advanced stage. The overall survival was shorter in patients with high expression of TFF3 than in those with low expression of TFF3 in 292 GCs and in 125 early GCs (EGCs). Moreover, in patients with EGCs, high expression of TFF3, associated with reduced expression of TFF1, was determined as an independent poor prognostic marker. Conclusions: Reduced expression of TFF1 and increased expression of TFF3 may play a role in the carcinogenesis of gastric cancer. Furthermore, high expression of TFF3 with reduced expression of TFF1 may be a marker of poor prognosis for patients with EGC.

Objectives: The trefoil factor family (TFF) is composed of three thermostable, and protease-resistant proteins, named TFF1, TFF2 and TFF3, and plays a role in gastrointestinal mucosal defence and repair. Recently, TFFs have been found to be related to the development of various types of cancer. This study assessed the relationship between the expression of TFF1 and TFF3 and the clinicopathological parameters in gastric carcinoma (GC). Materials and Methods: The expression of TFF1 and TFF3 was analyzed by immunohistochemistry in 292 GCs and 20 normal gastric tissues. Results: All normal gastric tissues expressed TFF1, but 53.8% of GCs showed reduced TFF1 expression. However, TFF3 was not detected in normal gastric tissues and 44.2% of GCs showed a high level of expression. Highly expressed TFF3 was significantly correlated with lymph node metastasis, lymphatic invasion, vein invasion, and advanced stage. The overall survival was shorter in patients with high expression of TFF3 than in those with low expression of TFF3 in 292 GCs and in 125 early GCs (EGCs). Moreover, in patients with EGCs, high expression of TFF3, associated with reduced expression of TFF1, was determined as an independent poor prognostic marker. Conclusions: Reduced expression of TFF1 and increased expression of TFF3 may play a role in the carcinogenesis of gastric cancer. Furthermore, high expression of TFF3 with reduced expression of TFF1 may be a marker of poor prognosis for patients with EGC.

We investigated the relationship between frequently deregulated microRNAs (miRNAs) and enodometrial pathology in an attempt to find the most dependable miRNA or combination of miRNAs to identify normal, hyperplastic and malignant endometrial tissues. We also investigated the association between those miRNAs and PTEN status. We measured the expression of six miRNAs (miR-21, 182, 183, 200a, 200c and 205) in 75 formalin-fixed, paraffin-embedded normal, hyperplastic, and malignant endometrial tissue blocks using Taqman-based real-time PCR assays. PTEN loss of expression was assessed in the same endometrial tissues by immunohistochemistry. Expression of five miRNAs (miR-182, 183, 200a, 200c and 205) was significantly higher in endometrial carcinoma (CA) when compared with complex atypical hyperplasia (CAH), simple hyperplasia (SH) and normal endometrial tissue (P

Background: Understanding the biologic behavior of a tumor is a prerequisite for tumor registration code assignment. The aim of this report was to propose appropriate behavior codes of the International Classification of Disease Oncology 3 (ICD-O3) to rare, yet pathologically interesting hematopoietic and soft tissue tumors. Methods: The Study Group for Hematopathology, the Bone and Soft Tissue Pathology Study Group, and the Cancer Registration Committee prepared the questionnaire containing provisional behavior codes of selected diseases. Results: In situ lesions of mantle cell and follicular lymphomas, dendritic cell tumors, and neoplasms with perivascular epithelioid cell differentiation (PEComa), not otherwise specified were classified as malig nant (-/3). The fibromatosis group, with the exception of lipofibromatosis, was proposed as be nign (-/0). Lipofibromatosis and several diseases that belong to the PEComa group were pro posed as uncertain malignant potential (-/1). For the hematologic and soft tissue tumors, 274 and 288 members of the Korean Society of Pathologists, respectively, provided opinions through questionnaire, and most responders showed agreement with the provisional behavior code proposed. Conclusions: The determination of behavior codes for the rare diseases described in this study, especially those of the PEComa group or malignant lymphoma, could be viewed as impractical and premature, but this study provides the basis for future research on this topic.

Development of an efficient cancer control program is essential, considering that the incidence of cancer is increasing in Korea. Cancer registration and cancer screening are important cancer control programs that are closely related to and influenced by each other. The hospital-based cancer registry started in 1980 with 47 training hospitals participating in the cancer control program in Korea. Currently, the registry includes 80-90% of cancer cases from more than 150 training hospitals. The details of the history, objectives, and activities of the Korea Central Cancer Registry (KCCR) have been documented in 2005 and 2011.1,2 Cancer cases are classified according to the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3)3 and then converted according to the International Classification of Diseases, 10th edition (ICD-10).4 As discussed in our first proposal,5 the roles of pathologists are important for improving the quality of cancer statistics since they provide a correct diagnosis and classification of the cancer which is essential for the application of the ICD-O code, in particular the behavior code. In collaboration with the National Cancer Center, the Korean Society of Pathologists (KSP) has participated in confirmation of diagnostic terms, standardization of diagnostic formats, clarification and assessment of multiple primaries, primary sites and the ICD-O code, and education of the pathologists. In addition, the KSP has also contributed to the education of cancer registrars because they play a key role in entering the data in the cancer registry. We have previously noticed the differences in the diagnostic terms between pathologists and the ICD-O code book. It is likely that these differences may originate from numerous coexisting classification systems, synonyms, new entities, newly recognized tumor behavior, and time interval between identification of an entity and its application to the code book. Of these, clarification of the behavior code is important for the registry, because behavior code 2 (carcinoma in situ) and 3 (invasive carcinoma and sarcoma) must be registered and used for both cancer statistics and insurance reimbursement. It is noteworthy, however, that some tumors including microinvasive tumors of the breast and ovary are not included in the ICD-O code book.3 The Gastrointestinal Pathology Study Group of the KSP therefore proposed behavior codes for several gastrointestinal tumors in 2008.5 Whether a microinvasive tumor (especially diagnosed as ductal carcinoma in situ with microinvasion [DCISM]) of the breast should be treated as carcinoma in situ or invasive carcinoma has been an important issue. The behavior of microinvasive tumors remains undetermined. Therefore, there is a controversy regarding this matter even among specialists.6-14 In addition, some clinicians and pathologists don't have exact concept about this matter. Furthermore, there is even a controversy regarding how to abbreviate microinvasive tumor into DCISM or microinvasive carcinoma (MIC) between the pathologists. This poses a problem to the registrars when they should enter the data in the cancer registry. An appropriate behavior code can be assigned only when they understand the meaning of different pathologic terminology. It would therefore be necessary not only to standardize the pathologic terminologies but also to have an identical understanding of the biologic behavior of the tumor, which is essential for the registration of tumors. In addition, borderline serous or mucinous tumors are issues that remain unresolved in association with diagnostic criteria, diagnostic terminology, behavior and treatment.15-21 We have therefore made an additional proposal of behavior codes for microinvasive tumors of the breast and ovary based on our previous proposal. In addition, we have also focused on the clinically meaningful behavior code rather than diagnostic criteria. Given the above background, we made our second proposal. But this is not conclusive but subject to alterations with the accumulation of more experience and knowledge. However, reconsideration and understanding of the biological behavior of microinvasive tumors of the breast and ovary and sharing a common concept will be helpful in statistics and in changing after amending the rule. Thus, we would like to report a current progress on our second proposal.

Purpose Non-small cell lung carcinoma (NSCLC) comprises 75-85% of all lung cancers, and approximately 25% of all NSCLC patients develop brain metastasis. There are no reliable markers for predicting in which patients this metastasis will occur. DCUN1D1, also known as squamous cell carcinoma-related oncogene, is associated with tumor progression and poor outcomes in NSCLC. The objective of this study was to investigate the role of DCUN1D1 expression in cases of brain metastasis due to NSCLC. Materials and methods Primary tumor samples from a total of 71 cases of NSCLC, either with (n=40) or without (n=31) brain metastasis, were evaluated for DCUN1D1 expression by immunohistochemistry analysis. Results DCUN1D1 expression was detected in 16 patients (23%) and tended to correlate with T classification (15% of T1-2 tumors vs. 30% of T3-4 tumors, p=0.083). DCUN1D1 expression was significantly associated with tumor stage. It was observed in none of the patients with stage I disease, 10% of those with stage II disease, and 29% with stage III disease (p=0.009). In addition, 14 of 16 DCUN1D1-positive patients resulted in brain metastasis (p=0.01). The odds ratio of brain metastasis for patients with DCUN1D1 expression was 3.112 (p=0.009). Conclusion DCUN1D1 expression may play a role in tumor progression and development of brain metastasis in patients with NSCLC. Evaluation of DCUN1D1 expression may provide assistance in identifying those patients who are at higher risk for brain metastasis.

Glioblastoma is the most frequent and malignant brain tumor with most patients dying within 1 year after diagnosis. O6-Methylguanine DNA methyltransferase (MGMT) is implicated as a major predictive factor for treatment response to alkylating agents including temozolomide (TMZ). In general, epigenetic silencing of the MGMT gene by promoter methylation is associated with loss of MGMT protein expression. We investigated the correlation between MGMT protein expression and MGMT methylation status and the prognostic relevance of TP53 and Ki-67 in a series of glioblastomas. A total of twenty-eight patients between 2008 and 2011 were included in this study. Nineteen patients (68%) showed nuclear TP53 immunopositivity, and mean Ki-67 index was 27%. Immunohistochemistry for MGMT protein revealed high expression (>30% positive cells) in 11 tumors, and low expression (≤30% positive cells) in 17 tumors. There was a good correlation between immunoreactivity for MGMT protein, Ki-67 index and tumor extent. MGMT promoter methylation as well as MGMT protein expression was completely uncorrelated to survival prediction; neither TP53 nor Ki-67 were correlated to survival. Our study confirms the role of the Ki-67 index and the extent of tumor as two important factors associated with prognosis of glioblastoma. In contrast, MGMT protein expression as well as the MGMT promoter methylation status does not provide prognostically relevant information.

Background and Objectives The calcium-binding protein S100A4 promotes tumor progression and metastasis. We investigated the expression of S100A4 in colorectal cancer and its clinicopathologic significance in colorectal cancer. Methods A total of 526 colorectal cancer patients were examined for S100A4 protein by immunohistochemistry using tissue microarrays. S100A4 mRNA was subsequently investigated by in situ hybridization. Results S100A4 protein was expressed in various cell types including tumor cells, but S100A4 mRNA was only expressed in tumor cells. Cytoplasmic expression of S100A4 protein was seen in 127 (24.1%) of 526 tumors and significantly correlated with older age, depth of invasion, lymph node metastasis, and worse overall survival. Nuclear expression of S100A4 protein was observed in 136 (25.9%) tumors and significantly related to the depth of invasion, perineural invasion, and worse overall survival. However, there was no correlation between S100A4 mRNA expression and clinicopathological parameters. Upon multivariate analysis nuclear expression of S100A4 protein was found to be an independent prognostic factor of poor survival. Conclusions Expression of S100A4 protein in colorectal cancers may indicate tumor progression and lymph node metastasis and can be useful for prediction of overall survival of patients with colorectal cancers. J. Surg. Oncol. 2012; 105:119–124. © 2011 Wiley Periodicals, Inc.

Background The expression of Hedgehog (Hh) signaling pathway in prostate cancer is well-known but its clinicopathologic role has not been elucidated well. Methods Prostatectomy cases of prostate cancer (n = 155) were prepared and assessed by clinicopathologic parameters including new 2010 anatomic stage/prognostic groups (ASPG) of prostate cancer. The expression of five Hh signaling proteins including Sonic hedgehog (Shh), Patched, Smoothened, and GLIoma-associated oncogene, in addition with Suppressor of fused (Su(fu)) were analyzed immunohistochemically. Real-time polymerase chain reaction was performed to assess the mRNA expression status. Results The expression of each Hh signaling protein was significantly correlated with poor prognostic parameters such as larger tumor size, high pretreatment prostate-specific antigen (PSA), high Gleason score, perineural invasion and new ASPG. Among Hh signaling proteins, Sonic hedgehog and Smoothened expressions tend to have a significantly higher risk of PSA recurrence (P

Acinic cell carcinoma (ACC) of the breast is extremely rare and is characterized by widespread acinar cell-like differentiation. We report of a 39-year-old woman presented with a palpable breast mass with significant morphological, immunohistochemical and ultrastructural findings. Histologically, ACC showed a diffuse glandular infiltrative pattern, with small acinar or glandular structures mixed with solid nests. Neoplastic cells were monotonous proliferation of cells with a granular or clear cytoplasm, resembling acinar cells of the salivary glands or Paneth cells. Both glandular and solid tumor cell populations were strongly positive for lysozyme and α-1-antitrypsin.

The American Joint Committee on Cancer has proposed the tumor, node, metastasis (TNM) staging system to overcome the limitations of the Ann Arbor staging system for ocular adnexal lymphoma. We performed this study to evaluate the feasibility of the TNM staging system for ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (OAML). The data form 66 total eyes from 54 patients with biopsy-confirmed OAML according to World Health Organization classification were retrospectively analyzed. Using the TNM staging system, we reclassified all patients into two categories: (1) T1N0M0 stage group (n = 26), for patients with lymphoma involving only the conjunctiva; and (2) above T1N0M0 or bT1N0M0 stage group (n = 28), for patients with lymphoma extending to the orbit, eyelid, or adjacent structures, and/or bilateral OAML. After a 24-month median follow-up period for all patients, the T1N0M0 group revealed higher progression-free survival (PFS) than the above T1N0M0 or the bT1N0M0 group (P = 0.041). In a separate analysis of only 50 patients categorized as Ann Arbor stage IE, the T1N0M0 group demonstrated higher PFS (100%) than the above T1N0M0 or the bT1N0M0 group (84.7%; P = 0.067). Our data show that the poor prognostic group classified as Ann Arbor stage IE can be further distinguished by using the TNM staging system. Thus, further studies to develop treatment strategies for reducing relapse after treatment for OAML should use the TNM staging system.

In this paper, we demonstrated the machining process of a novel Light Emitting Diodes (LED) beam shaping lens, called TIR Fresnel lens, for GaN-based blue Chip Scale Packaged (CSP) LEDs. Upon achieving a precise alignment of the tool and identifying the best manufacturing condition, we have successfully fabricated a prototype of this lens on poly methyl methacrylate (PMMA) plate. The form error of the central aspheric lens was less than 1 μm deviation, and surface quality of the Fresnel facets were sufficient for Total Internal refraction without any burr or adhesion of the machined chip. Fabricated TIR Fresnel lens reduced the viewing angle of the testing CSP LED from 140° to 17.4° in FWHM. The proposed lens produced extreme compactness as well as high collimation efficiency, thereby applicable to an ultra-thin optical system.

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare malignancy derived from antigen-presenting cells, with 55 cases reported thus far. A standard treatment modality is still being debated. This report describes a 56-year-old female who presented with right tonsillar enlargement and right submandibular swelling for 6 months. Treatment with empiric antibiotics did not result in improvement of her symptoms. Fine needle aspiration of the tonsil revealed no malignant cells. Tonsillectomy was eventually performed due to persistent symptoms. Based on microscopic findings, immunohistochemical stains, and review of the literature, the present case was finally diagnosed as IDCS of the tonsil with cervical lymph node involvement. The patient received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy, and a clinically complete response was achieved followed by adjuvant radiation.

The usefulness of fresh-frozen, optimal cutting temperature (OCT) compound-embedded (FFOE) bone marrow (BM) aspirates was evaluated as a reliable resource for morphological, immunohistochemical and molecular examinations. One hundred BM aspirates were collected in polypropylene tubes and immediately frozen for 2 h in a deep freezer. Frozen BM was transferred to a cryomold filled with OCT compound and the prepared samples were stored in a deep freezer. Histological examination and immunohistochemical staining, polymerase chain reaction (PCR), sequencing and reverse transcription (RT)-PCR were performed to evaluate the quality of the FFOE BM sections in 10% of randomly selected samples. FFOE BM sections revealed better morphologies than paraffin-embedded clot sections in haematoxylin and eosin staining because mature erythrocytes were removed during the staining process in frozen BM sections. Immunohistochemical staining for CD34 revealed excellent staining quality and oil red O staining showed that fat vacuoles in cells were well preserved. The quality of genomic DNA in FFOE BM sections was suitable for obtaining about 2000 bp PCR product for the human leucocyte antigen-A locus followed by direct sequencing of the sample, and the quality of total RNA was suitable for detection of BCR-ABL fusion transcript. FFOE BM aspirates are a reliable resource for various laboratory tests of diagnostic and research arenas.

Background and aims: Notch signaling pathways are well known for their major role in stem cell differentiation. However, varied results have been reported in relation to their oncogenic role, depending on tumor type. We studied the expression of Notch receptors and other cell cycle proteins in human non-small cell lung carcinomas (NSCLC) and analyzed their relationship to tumor progression. Methods: We examined the tissue microarrays of 158 cases of NSCLC for Notch1 and 3, and cell cycle regulatory proteins p53, p16INK4a, pRb and CDK2 by immunohistochemistry. Results: Notch1 and 3 receptors were noted in 81.6% and 79.7% of cases, respectively. Notch1 expression was negatively correlated with lymph node metastasis (P = 0.043) and Notch3 was negatively correlated with more advanced pathologic T stage (P = 0.024). However, expressions of Notch receptors didn't show any significant prognostic value for NSCLC. Of the cell cycle proteins, CDK2 and pRb were negatively correlated with Notch1 (P = 0.013) and Notch3 (P = 0.018). Conclusions: Notch receptors play an inhibitory role in metastasis to lymph node and in the activity of cell cycle proteins, which may lead to suppression of NSCLC.

Purpose: Telomerase is an RNA-dependent DNA polymerase that synthesizes TTAGGG telomeric DNA onto chromosome ends to compensate for sequence loss during DNA replication. It has been detected in 8590% of all primary human cancers, implicating that its apparent reactivation in tumors may play a role in the tumorigenic process. The purpose of this study was to evaluate telomerase activity in stomach cancer, and to determine whether methacarn-fixed paraffin-embedded tissues can replace frozen tissue sections for the telomerase (TRAP) assay. Materials and Methods: Frozen and corresponding methacarn- fixed paraffin-embedded tissue samples were obtained from 51 patients with gastric adenocarcinoma and analyzed for telomerase activity by using a TRAPeze ELISA kit. Results: Telomerase activity was detected in 37 (73%) frozen samples, and in 13 (25%) methacarn-fixed paraffin blocks. Telomerase activity was well correlated with depth of invasion (p=.037) and tumor differentiation (p=.022). Conclusion: These data suggest that reactivated telomerase may play a significant role in the tumorigenesis of gastric cancer and may reflect the malignant potential of the tumor. It is noteworthy that methacarn- fixed tissue cannot as yet substitute for the frozen tissue in the TRAP assay.

While fine-needle aspiration cytology (FNAC) using conventional smear has been widely accepted as the primary diagnostic tool for thyroid lesions, liquid-based preparations (LBPs) are increasingly replacing it. A new automated LBP method, EASYPREP(®) (EP), was recently introduced and has shown relevant diagnostic efficacy in gynecologic samples. We compared the diagnostic utility of EP and SurePath(®) (SP), a more widely established LBP method, in thyroid FNAC.Under the ultrasonographic guidance, 253 thyroid FNAC samples were collected by sample-splitting manner. Three pathologists made cytologic diagnoses of EP and SP according to the Bethesda system independently and compared the cytomorphologic parameters. Cytohistologic correlation was performed in 30 resected cases.Fifteen (5.9%) and 21 (8.3%) samples were unsatisfactory in SP and EP, respectively, owing to the unequal sample-splitting. Cytologic diagnoses of SP and EP were consistent in 228 cases (90.1%), and inconsistent in remainder mostly owing to the unequal distribution of pathognomic cells. While cytomorphologic parameters were not significantly different between two methods, EP showed less three-dimensional configuration in benign lesions. Cytohistologic correlation showed no significant differences in sensitivity (100% vs. 95.5%) and specificity (100% vs. 100%) between SP and EP. Labor time for processing 48 cases was 42% shorter with EP than with SP (28 min vs. 48 min).The diagnostic utility of EP in thyroid FNAC was comparable to that of SP. EP allowed better visibility owing to better fragmentation of follicular clusters. The automated system of EP has the advantages of a shorter labor time for batch processing. Diagn. Cytopathol. 2016;44:283-290. © 2016 Wiley Periodicals, Inc.

Transforming acidic coiled-coil containing protein 3 (TACC3) is known to be involved in the control of normal cell growth and differentiation and in mechanisms of unregulated growth leading to tumorigenesis. The aim of the present paper was to determine the rate of TACC3 expression in a non-small cell lung cancer (NSCLC) collection and to clarify its correlation with clinicopathological parameters. A total of 163 NSCLC were analyzed immunohistochemically using a polyclonal TACC3 antibody and monoclonal p53 and Ki-67 antibodies on NSCLC tissue microarrays. A high level of TACC3 expression was observed in 14.8% of cases, preferentially squamous cell carcinomas. Patients whose tumors had a high TACC3 expression had a significantly shorter median survival time. In the Cox regression-based multivariate analysis, TACC3 expression proved to be an independent prognostic parameter (P = 0.031). TACC3 expression was correlated with p53 expression, and patient whose tumors highly expressed TACC3 and p53 had a significantly poorer prognosis than patients whose tumors had low-level expression for both immunostainings (P = 0.006). It is suggested that increase in TACC3 may impart a proliferative advantage to NSCLC and contribute to tumor progression, and that TACC3 expression is a strong prognostic indicator of clinical outcome in NSCLC.

Benign tumorous condition can be encountered at very unusual location in oral cavity and pharyngeal region, which leads diagnostic difficulty. Here we describe a very unusual presentation of polypoid hamartoma on the root of the tongue. A 59-year-old woman presented with a polypoid tumor mass on the dorsal root of the tongue. Microscopically, it was hamartoma showing normal salivary glands of mucinous and serous types, lymphoid hyperplasia, and skeletal muscle bundles. Major differential diagnoses include accessory tongue, adenomatoid hyperplasia, and idiopathic hyperplasia of sublingual glands. To our knowledge, this is the first report of hamartoma arising in the root of the tongue presenting as polypoid mass. Correct diagnosis based on pathologic examination is essential for proper treatment.

Chronic tubulointerstitial injury (CTI), commonly a sequel to chronic glomerulonephritis (CGN), is associated with the proliferation of new blood vessels. Angiogenesis is an essential process in chronic inflammation, and is controlled by a number of angiogenic factors including thymidine phosphorylase (TP). Knowledge of TP in renal disease is still rudimentary, and its role in CGN has not been explored. We analyzed the expression of TP by RTPCR, immunohistology and in situ hybridization in 20 human kidneys with CGN. To evaluate the degree of angiogenesis, we counted the microvessel density (MVD). MVD was significantly higher in all categories of CGN, between 19.7 ± 7.7 and 58.9 ± 7.5, compared to control value, 12.7 ± 5.0 (p< 0.05). MVD was increased in areas of abundant mononuclear cell infiltration with minimal interstitial fibrosis, and decreased or absent in areas of marked fibrosis. There was a significant correlation between MVD and interstitial fibrosis (p < 0.0001). TP mRNA was upregulated for all categories of CGN. TP was strongly expressed by mononuclear inflammatory cells and in most atrophic tubules. Each MVD and interstitial volume was significantly correlated with both the number of TP+ mononuclear cells and TP+ tubular cells, respectively (p < 0.0001). We have demonstrated an upregulation of TP and increase in MVD in areas of CTI in a variety of CGN. The up-regulation of TP may contribute to angiogenesis, which may play a critical role in the progression of interstitial fibrosis in CGN.

Between March and July 2002, total of 612 clinical isolates of Serratia marcescens , Enterobacter cloacae , and Citrobacter freundii (201 S. marcescens , 228 E. cloacae , and 183 C. freundii ) were collected from 13 clinical laboratories in a nationwide distribution. Imipenem and meropenem minimum inhibitory concentrations (MICs) were determined using the agar dilution method according to the National Committee for Clinical Laboratory Standards guidelines. For the isolates with a decreased susceptibility to carbapenems (MICs of ≥2 μg/mL), isoelectric focusing, polymerase chain reaction (PCR) amplification of the carbapenemase genes ( bla IMP-1 , bla VIM-2 , bla SME-1 , bla OXA-23 , bla OXA-25 , bla KPC-1 ), and sequencing were performed. The prevalence of S. marcescens , E. cloacae , and C. freundii with a decreased susceptibility to imipenem was 17.9% (36/201), 0.4% (1/228), and 0.5% (1/183), respectively, and to meropenem, it was 11.4% (23/201), 0% (0/228), and 0.5% (1/183), respectively. The bla VIM-2 was the only carbapenemase detected, and was found in 0.5% (1/201) of S. marcescens and 0.5% (1/183) of C. freundii isolate.

The initial aim of this study was to examine the expression profiles of P53 and its upstream genes, downstream genes, and cell cycle regulators to determine whether these markers are useful for making a differential diagnosis among the benign, borderline, and malignant ovarian epithelial tumors. Between borderline and malignant tumors, the increased expression levels of P53, Bax, Cyclin E, and cyclin-dependent kinase-2 as well as the decreased expression levels of growth arrest and DNA damage (GADD45) and murine double minute-2 (MDM2) were significantly associated with malignancy (P0.01, each). Using the receiver operating curve (ROC), the most reliable cutoff value of the added-up staining scores of those markers was 4.5 with 79% sensitivity and 89% specificity for malignancy. Between benign and borderline tumors, the P21 and Bax expression levels were significantly higher in borderline tumors, whereas the Bcl-2 expression level was much higher in benign tumors (P0.01, each). Using the ROC, the cutoff value of the added-up staining scores used to discriminate between the two groups was 2.5 with 70% sensitivity and 74% specificity for borderline tumors. Thus, for the differential diagnosis between borderline and malignant tumors, the cutoff value 4.5 of the cumulative staining scores can be used. However, the cutoff value 2.5 for discrimination between benign and borderline tumors may not be useful because of its relatively low sensitivity and specificity. In addition, the P53, GADD45, Cyclin E, and MDM2 expression levels in malignant ovarian tumors might be useful for determining the histologic grade and type.