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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Breast plasmacytoma (BP) is an extremely rare extramedullary manifestation of multiple myeloma (MM). We report the imaging findings of an unusual case in which BP was the initial presentation of MM. A 53-year-old woman with no contributory medical history underwent chest computed tomography to evaluate intermittent nocturnal anterior chest pain, and bilateral multiple breast masses were found. Following an ultrasound-guided core needle biopsy, these lesions were confirmed to be BP.

Determining of HER-2/neu oncogene amplification has become clinically important for managing breast cancer. Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) are currently regarded as the standard methods. Chromogenic in situ hybridization (CISH) was investigated as a new modification with an accurate, sensitive technique. From 1998 to 2002, using CISH and IHC, the amplification and protein expression of the HER-2/neu oncogene were examined using paraffin sections in 130 breast carcinomas and to determine the prognostic role of HER-2/neu for outcome after a follow-up of 24- 64 months. Amplifications by CISH and overexpression by IHC were observed in 28 (22%) and 27 cases (20.8%), respectively. Of the 104 patients, 20 patients (19.2%) with amplification had a shorter disease-free interval (34.9 months vs. 38.0 months in controls) (p=0.372). 15 patients (14.4%) had a disease recurrence, but there is no significant difference between 3 patients amplifying the oncogene and 12 patients without oncogene (20.6 months vs. 19.6 months) (p=0.862). 6 patients (5.8%) of these died. CISH is a useful alternative, particularly for confirming the IHC results. There is no relationship between the early recurrence and the HER-2/neu positive group, but lymph node status was statistically significant.

Previous molecular genetic studies of laryngeal squamous cell carcinoma (SCC)have shown certain chromosomal regions with recurring alterations. But studies of sequential molecular alterations and genetic progression model of laryngeal SCC have not been clearly defined. To identify the chromosomal alterations associated with the carcinogenesis of laryngeal SCC, we analyzed genomic DNA from microdissected squamous metaplasia, squamous dysplasia, invasive SCC, and metastatic carcinoma samples from 22 laryngeal SCC patients for loss of heterozygosity (LOH) at microsatellite loci. Ten microsatellite markers on chromosome 3p, 8p, 9p, and 17p were used. LOH at 9p21 was observed in the all stages including squamous metaplasia, squamous dysplasia, invasive SCC and metastatic carcinoma. LOH at 17p13.1, 3p25 and 3p14.2 was observed from the squamous dysplasia, invasive SCC and metastatic carcinoma. LOH at 8p21.3-p22 was observed mainly from the invasive SCC and metastatic carcinoma. The results suggest that 9p21 in the early event, 17p13.1, 3p25 and 3p14.2 in the intermediate event and 8p21.3- p22 in the late event may be involved in the laryngeal carcinogenesis.

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 85–90% of all primary human cancers, implicating that the telomerase seems to be reactivated in tumors and that such activity may play a role in the tumorigenic process. The purpose of this study was to evaluate telomerase activity, human telomerase RNA (hTR), and telomerase reverse transcriptase (TERT) in stomach cancer and to determine their potential relationships to clinicopathologic parameters. 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. Tissue sections of all the samples were further investigated for hTR and TERT by in situ hybridization and a sensitive immunohistochemical technique, respectively. Telomerase activity was detected in 37 (73%) tumors. Telomerase positivity from methacarn-fixed paraffin blocks was found to be 35% of that from frozen tissues. hTR was overexpressed in 46 (90%) samples: 33/37 (89%) with and 13/14 (93%) without telomerase activation. Expression of TERT was demonstrated in 40 (78%) cases: 30/37 (81%) with and 10/14 (71%) without telomerase. Telomerase activity correlated well with depth of invasion (P = .037) and tumor differentiation (P = .022), whereas hTR significantly correlated with nodal metastasis (P = .047) and tumor size (P = .023). These data suggest that reactivated telomerase may play a significant role in the tumorigenesis of gastric cancer and may reflect, along with enhanced hTR, the malignant potential of the tumor. It is noteworthy that methacarn-fixed tissue cannot as yet substitute for the frozen section in the TRAP assay.

The incidence of posttransplantation lymphoproliferative disorders (PTLDs) has increased in recent years. Although rare, various types of T-cell lymphoma have been reported and their association with Epstein-Barr virus (EBV) has been compared with B-cell PTLDs. We report a case of splenic peripheral T-cell lymphoma occurring in a 47-yr-old male patient 7 yr after renal allograft transplantation. The spleen showed sinusoidal proliferation of focal CD30 positive, large, atypical lymphoid cells. Positivity for CD3 and cytolytic granule-associated proteins was also demonstrated in the tumor cells, while anaplastic large cell lymphoma kinase (ALK) and CD8 were not expressed. Strong nuclear signals for EBV mRNA were noted by EBER1 in situ hybridization. A molecular genetic study demonstrated a rearrangement of the gamma T-cell receptor gene. To our knowledge, this case is unique in terms of a posttransplant T-cell lymphoma that shows focal CD30, cytolytic granule-associated proteins, and EBV positivity.

Objective.—To investigate ras gene alteration in human gastric adenocarcinomas and its potential relationship to ras signal transduction mediators. Design.—Genomic DNA from 104 gastric tumors were analyzed by sequencing of polymerase chain reaction–amplified products for the presence of ras mutations. All the samples were further investigated with the use of immunohistochemical analysis for ERK1 and ERK2. Setting.—Tertiary care teaching hospital. Patients.—Seventy patients from a Korean population and 34 from a Midwestern US population composed of white Americans and African Americans. Results.—Fifteen tumors (14%) were positive for either H-ras or K-ras mutation: 9 (13%) of 70 Korean patients and 6 (18%) of 34 US patients. Seven (78%) of the 9 mutated tumors from Korean patients and all 6 (100%) from the US patients were intestinal-type lesions. Either ERK1 and/or ERK2 was overexpressed in 68 samples (65%). No association was established between ras mutations and overexpression of ERK1/2. However, the correlation between ERK1/2 and progression (early vs late) was statistically significant (P = .007). Conclusions.—These data suggest that ras mutations are uncommon in gastric adenocarcinomas and that differing racial and/or geographic mechanisms may not underlie ras gene alteration. Most ras mutations were, however, observed in the group of intestinal-type samples, supporting the different genetic mechanisms of carcinogenesis between the intestinal- and diffuse-type tumors. It is noteworthy that enhanced ERK1/2 activity could be one of the characteristics of tumor invasiveness in gastric cancers.

Breast carcinomas are an uncommon neoplastic condition in men, accounting for only 1% of all breast cancers, and less than 1% of all malignancies in men. A 70-year-old man who presented a right breast mass was found to have infiltrating ductal carcinoma. We herein report the case with a review of the literature.

Caspase 10 (Mch4/FLICE2) is a caspase homologous to caspase 8. A recent report described that inherited CASP10 gene mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome (ALPS). In this study, to explore the possibility that mutation of this gene might be involved in the development of non-Hodgkin lymphoma (NHL), we have analyzed the entire coding region and all splice sites of the CASP10gene for the detection of somatic mutations in 117 human NHLs. Overall, 17 NHLs (14.5%) were found to have CASP10mutations, which were identified in the coding regions of the prodomain (n = 3), the p17 large protease subunit (n = 11), and the p12 small protease subunit (n = 3). We expressed the tumor-derived caspase 10 mutants in 293 cells and found that apoptosis was suppressed. These data suggest that the inactivating mutations of theCASP10 gene might lead to the loss of its apoptotic function and contribute to the pathogenesis of some human NHLs.

Introduction: The Hedgehog (Hh) signaling plays essential role in transcription regulation and embryonic development. In many cancers including lung cancer, it is related to carcinogenesis and poor prognosis. This signaling also mediates epithelial to mesenchymal transition (EMT) by paracrine mechanism in various diseases. We aim to study the interaction between Hedgehog and EMT pathway and its clinical implication in non-small cell lung cancer (NSCLC). Method: Total 271 cases of NSCLC who received surgical resection in Yeouido St. Mary’s Hospital between 1997 and 2011 were included. For immunohistochemical analysis of Hh and EMT related proteins, 4um sections were sliced from tissue microarray. Hh signaling proteins including Sonig hedgehog (Shh), Patched (Ptch), Smoothened (Smo), Glioma-associated oncogene (Gli-1) and Suppressor of fused (Sufu), and EMT associated molecules including E-cadherin and vimentin were analyzed. Staining intensity (IS) was estimated as follows 0 (no staining), +1 (weak), +2 (distinct), +3 (strong). Intensity score (IS) ≥1 was defined as positive. Medical record was retrospectively reviewed. The study was approved by the institutional review board the hospital. Result: The median age was 63 (18-84) years, and 65.3% were male. Squamous cell carcinoma was diagnosed in 113 (41.7%), adenocarcinoma in 153 (56.5%), and mixed type in 153 (56.5%). Stage 1 and 2 were 46.9% and 30.6%, respectively, and 8 cases had distant metastasis. The Hh proteins showed positive correlation each other. For EMT, the expressions of Hh protein was significantly correlated with tumoral and stromal positivity of vimentin, and inversely with positivity of E-cadherin (P = 0.002 and P = 0.028, respectively). The expression of Hh proteins were significantly associated with lymph node metastasis along with large tumor size (P = 0.021 and P = 0.035, respectively). In survival analysis, expressions of Shh and Gli1 were independent predictor of disease free survival and cancer-specific survival (P = 0.007 and P = 0.025, respectively). Conclusion: Expression of Hh protein is associated with epithelial-mesenchymal transition and associated with poor prognosis in NSCLC. Citation Format: Ho Jung An, Tae-Jung Kim, Young Jo Sa, Chang Suk Kang. The interaction between hedgehog and EMT pathway in non-small cell lung cancer and its prognostic implication [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 675. doi:10.1158/1538-7445.AM2017-675

Successful treatment with tandem consolidation using 90 yttrium-ibritumomab tiuxetan (Zevalin) and high-dose therapy with autologous PBSCT in a patient with relapsed mantle cell lymphoma presenting as multiple lymphomatous polyposis

Background: Clamydophila psittaci (C. psittaci) has been proposed as an etiologic factor for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in the ocular region. However, previous studies showed varied association rates ranging 0% to 87%, not constant even in the series of same geographical areas, which suggest that there could be some technical variance in detecting methods for C. psittaci. The authors validated five sets of primers for detecting C. psittaci DNA and investigated its association with ocular MALT lymphomagenesis. Material and Methods: Five sets of PCR primers including 4 previously reported and one newly designed were evaluated with positive control C. psittaci DNA (acquired from Korea Centers for Disease Control and Prevention). One hundred fifty cases of confirmed ocular MALT lymphomas were collected from pathology archives of our institutes from 2008 to 2014, and entered into this study. DNA was extracted from archival paraffin block sections with Qiagen DNA extraction kits. Quality of DNA was assessed with NanoDrop and beta-globin PCR. Standard PCR was performed together with negative (H2O and tonsil DNA) and positive control C. psittaci DNA. Results: In all five primer sets for C. psittaci DNA, each PCR product showed clear positive band and negative with appropriate positive and negative controls, respectively. All 150 ocular MALT lymphoma cases showed positive for Beta-globin DNA control, but negative for C. psittaci DNA in any of PCR product with five primer sets. Conclusion: These results suggest that possibility of the pathogenetic role of C. psittaci in ocular MALT lymphoma would have been overestimated so far, at least in Korean people. Disclosures No relevant conflicts of interest to declare.

Liver dysfunction is a common problem in BMT recipients and it is important to determine the etiology in order to institute appropriate therapy. The purpose of this study was to evaluate the possible causes of liver dysfunction during the first post-transplant year in BMT recipients and to identify a possible relationship between pre-existing liver dysfunction and viral hepatitis with prognosis after BMT. We reviewed liver status before and after BMT in 130 consecutive patients at the Catholic Hematopoietic Stem Cell Transplantation Center. Liver dysfunction during the first post-transplant year occurred in 85 out of 101 (84.2%) allogeneic BMT recipients and 13 out of 29 (44.8%) autologous BMT recipients. In allogeneic BMT, GVHD and drug hepatotoxicity were major causes. In autologous BMT, drug hepatotoxicity was the most common cause. Eighteen out of 130 patients (13.8%) had abnormal liver function tests before BMT. These patients did not have an increased risk of post-transplant liver dysfunction, GVHD, and death compared to patients who had normal liver function tests prior to BMT. Nine patients were hepatitis B antigen positive and three patients were anti-HCV positive prior to BMT. There was no significant increase in the incidence of post-transplant liver dysfunction, GVHD, and death in these patients. Bone Marrow Transplantation (2000) 26, 193–197.

A case of intestinal angiocentric T/NK-cell lymphoma in a 58-year-old man is reported. The patient presented initially with panperitonitis because of perforation of sigmoid colon diverticulum. He underwent segmentectomy of involved bowel. Histologically, the intestinal wall showed diffuse infiltration of medium or large size lymphoma cells with angiocentric growth and necrosis. The lymphoma cells were CD56+, CD45RO+, CD3+, CD4-, CD8-, CD20-, and CD30- in paraffin sections with germline configuration of TCR-gamma gene, consistent with T/NK-cell lymphoma. Further staging revealed splenomegaly. Intestinal angiocentric T/NK cell lymphoma represents a distinct etiology of diverticulum with perforation.

Background: Even modern automatic cell counters cannot count basophils precisely. Therefore, we need a rapid, accurate, precise, and easy method for counting basophils. Methods: Using flow cytometry, basophils (CD22+/CD19-) and B cells (CD22+/CD19+) were counted. Within a large lymphocyte light scatter gate, % basophils (G%baso) and % B cells (G%B) were determined from the total count. Another method of analysis was to make two regions (R1 for basophils and R2 for B cells) and to determine in those the % basophils (R1%baso) and % B cells (R2%B) without gating. The flow cytometric basophil counts of the blood of 21 normal controls and 43 chronic myelogenous leukemia (CML) patients were compared with manual basophil count (Ma%baso) and basophil count by Coulter electronic cell counter (Hialeah, FL) (Auto%baso). CD22+/CD19- cells were sorted by a FACSCalibur (Becton Dickinson, San Jose, CA). Results: The G%baso of all samples was 4.66 ± 5.35%, and R1%baso was 4.23 ± 4.88%, and they were well-correlated (r = 0.996, P < 0.001). The G%B of all samples was 1.55 ± 1.68%, and R2%B was 1.59 ± 1.67%, and they were also well-correlated (r = 0.993, P < 0.001). Their correlation was better in normal controls than in CML. G%baso was well-correlated to Ma%baso (r = 0.827) and Auto%baso (r = 0.806), and R1%baso was well-correlated to Ma%baso (r = 0.831) but showed poor correlation to Auto%baso (r = 0.734). Auto%baso revealed the poorest correlation to Ma%baso (r = 0.692). The sorted CD22+/CD19- cells were all basophils (99.48 ± 0.30%), and they revealed CD13, CD33, and dim CD45 expression, whereas CD3, CD14, CD16, and HLA-DR were not detected on them. Conclusions: We discovered a specific marker combination to identify basophils (CD22+/CD19-), and we suggest that flow cytometric analysis using these markers is an easy, reliable, and accurate method of basophil counting. Cytometry 37:178–183, 1999. © 1999 Wiley-Liss, Inc.

A case of therapy-related acute myeloid leukemia associated with inv(16), with subsequent development of t(9;22)

Objectives: Tumor hypoxia confers poor prognosis of a wide range of solid tumors due to increased malignancy, increased likelihood of metastasis and treatment resistance. The aim of this study was to assess the significance of the expression of HIF-1α and HIF-1α-inducible proteins in gastric cancer and their impact on prognosis. Materials and Methods: The expression of HIF-1α, GLUT-1, CA-9, and iNOS proteins was analyzed by immunohistochemistry in 193 gastric adenocarcinomas (GAs) and 20 normal gastric mucosa. Results: HIF-1α, GLUT-1, CA-9 and iNOS were expressed in 52.3%, 43.0%, 57.0%, and 43.0% of GAs, respectively, which are higher than the normal counterparts except for CA-9. HIF-1α expression was positively correlated with the expression of GLUT-1, CA-9 and iNOS. GLUT-1 expression was higher in the intestinal type (p = 0.012); however, iNOS expression was higher in the less-differentiated type and the diffuse type (p = 0.006, p = 0.032, respectively). The expression of HIF-1α and GLUT-1 was significantly correlated with lymph node metastasis (p = 0.009, p = 0.008, respectively), while the expression of GLUT-1 and iNOS was significantly correlated with the depth of invasion and advanced stage (p = 0.044, p = 0.004; p = 0.009, p = 0.008, respectively). Overall survival was shorter in patients with GLUT-1 expression than in those without GLUT-1 expression, which was statistically significant by univariate analysis (p = 0.042). On multivariate analysis, however, stage was determined as the only independent prognostic marker (p < 0.001). Conclusions: Our data suggest that overexpression of HIF-1α, GLUT-1, and iNOS may play an important role in gastric cancer progression. GLUT-1 is a potential candidate for predicting patient survival.

Recently, as the use of ultrasonographic examination has increased, the possibility of incidental findings of thyroid nodules has also increased. In Korea, the prevalence of thyroid nodules detected by an ultrasonogram is approximately 19-67%.1,2 The fine needle aspiration cytology (FNAC) of the thyroid gland is an important and definitive method for the diagnosis of thyroid nodules.3,4 Follicular neoplasm (FN) and Hurthle cell neoplasm (HCN) are relatively rare diseases and their cytologic diagnosis is difficult when compared with papillary carcinoma (PC) which shows a cytologic accuracy of more than 90%. In addition, cytologic differentiation between benign and malignant tumors is not possible in FN and HCN cases. When the histologic correlation is made, the diagnostic accuracy and predictive malignancy rate of FN and HCN are much lower compared with PC. According to the guidelines for the treatment of thyroid nodules provided by the Korean Thyroid Association, surgery is recommended for patients when FN or HCN is diagnosed by FNAC because the possibility of malignancy in this case is not known until the histologic diagnosis is made from the lobectomy or total thyroidectomy specimen.1,3 In contrast, guidelines for the treatment of PCs are relatively well established according to the categories of cytologic diagnosis. FN and HCN are still rare FNAC findings. Follicular carcinoma (FC) comprises approximately 5% of thyroid cancers,5 and because the number of FN cases is limited and FC cannot be distinguished from benign follicular adenoma (FA) on the basis of cytologic findings, describing FN cytologically in an ambiguous manner may be inevitable. Therefore, more cytologic information regarding FN and HCN are required not only for the cytologic diagnosis but also for the development of appropriate treatment guidelines. In this study we evaluated the FNAC accuracy in FN cases based on the histologic diagnosis and investigated the cytologic findings to increase the probability of a correct cytologic FN diagnosis.

This study aimed to analyze expression of Mullerian inhibiting substance type II receptor (MISRII) protein and mRNA in cervical neoplasia, to demonstrate the growth inhibition of cervical cancer cells by administration of highly purified recombinant human Mullerian inhibiting substance (MIS) and, furthermore, to evaluate the clinical significance of MIS as a biological modifier for MIS receptor expressing tumors. Reverse transcriptase polymerase chain reaction (RT-PCR) was used for MISRII mRNA expression, and in situ hybridization and immunohistochemistry were used to observe expression, location of MISRII mRNA and protein, respectively. To demonstrate the effect of MIS on the viability of cervical cancer cells, methyl thiazole tetrazolium (MTT) assay was performed. Flow cytometry was used to evaluate the cell cycle distribution after exposure to MIS in cervical cancer cells, and the annexin-V-FITC staining method was performed to demonstrate apoptosis by MIS in cervical cancer cells. Expression of MISRII protein and mRNA were observed in all normal cervical and cervical carcinoma tissues. There was no significant difference in expression of MISRII protein and MISRII mRNA between normal cervical and cervical carcinoma tissues. MTT assay showed negative correlation between MIS exposure time and the viability of cervical cells (P=0.008). The changes in cell cycle distribution after MIS exposure suggest that MIS plays an important role in inducing cellular apoptosis by causing arrest at the G1 phase and increasing cells at sub-G0G1 phase. Annexin-V-FITC staining methods showed that cellular apoptosis was, respectively, 10.44 and 12.89% after 24 and 48 h of MIS exposure in cervical carcinoma cells. There was a negative correlation between cellular survival and MIS exposure time. This study demonstrates that MISRII is present on normal cervical and cervical carcinoma tissues, and MIS shows receptor-mediated antiproliferative effect on cervical cells in vitro. These data suggest that MIS may be used as a biological modifier or therapeutic modulator on MISRII-expressing tumors in the future.