담낭암의 조직 및 분자 병리학적 발병 기전

이경분 ( Kyoung-bun Lee ) 대한췌담도학회 2018 대한췌담도학회지 Vol.23 No.1

담낭암의 대표적인 조직형은 담낭 점막의 상피세포에서 기원하는 선암(adenocarcinoma)이며, 형태적 유사성에 따라 담도성(biliary), 장관성(intestinal), 위의 소와세포성(foveolar), 혹은 편평상피성(adenosquamous) 등으로 분류할 수 있다. 선암의 전암성 병변은 3가지가 있으며 1) 선종(adenoma), 2) 담도상피내종양(BilIN), 3) 담낭내 유두상 종양(intracystic papillary neoplasm)으로 구분할 수 있다. 이런 전암성 병변은 공통적으로 세포학적 이형성을 갖는 점막 상피 세포의 증식이라는 특징을 갖고 있으나, 종양 세포가 점막 아래 간질을 침습하지 않은 상태의 병변이다. 내강 내로 돌출된 폴립 모양의 병변이나 점막이 과립상으로 비후된 경우, 선종 혹은 담낭내유두상 종양의 경우가 많으며, 육안상 확인되지 않으나 현미경적으로 상피 세포의 이형성이 관찰될 경우 담도상피내종양에 해당한다. 이런 전암성 병변은 이형성의 정도에 따라 저등급(low), 중등급(moderate), 고등급 이형성(high grade dysplasia)의 3등급으로 평가하고 있으며, 고등급의 경우 상피내암(carcinoma in situ)과 동일한 병변으로 취급하고 있다. 선종과 담낭내 유두상 종양은 형태학적 특징이 중복되는 부분이 있어, 진단의 재현성을 높이기 위한 형태학적 기준 마련이 필요한 병변이다. 담낭 선암에서 보고된 가장 대표적인 분자유전학적 변이는 KRAS, TP53과 CDKN2A가 알려져 있고 ERBB2의 증폭도 알려져 있으나, 담도암에 특이적이면서 변이율이 높은 유전자는 많지 않다. 전암성 병변에서 선암으로 이어지는 암발생 과정에서 단계적으로 발견되는 분자유전적변이 또한 전암성 병변의 종류나 만성 담낭염, 췌담도 기형 등의 위험인자 유무에 따라 보고율이 서로 달라, 한 가지 기전으로 설명하기는 어렵다. 만성 담낭염을 선행인자로 갖는 경우 점막 상피의 증식 혹은 화생의 초기 단계에서 COX-2 과발현이나 TP53 변이, 마이토콘드리아 DNA 손상이 발생하고, 초기 이형성 단계에서 3p, 8p 염색체의 이형접합성 소실(loss of heterozygosity, LOH) 및 HER2 증폭이 보고되고 있고, 상피내종양에서는 9p, 18q, 22q, 17p 염색체의 LOH 및 CDK2A 변이가 관찰되는 것으로 알려져 있다. Adenocarcinoma is the major histology of gallbladder cancer. There are three subtypes of adenocarcinoma of the gallbladder: biliary, intestinal, and gastric foveolar subtypes. Also, there are three premalignant lesions of gallbladder adenocarcinoma: adenoma, biliary intraepithelial neoplasia (BilIN), and intracystic papillary neoplasm (ICPN). Premalignant lesion is hyperplasia of dysplastic epithelial cells with no evidence of stromal invasion. BilIN is invisible in gross inspection but can be microscopically identified around invasive tumor or chronic cholecystitis. ICPN is grossly identified as exophytic polypoid mass or diffuse friable thickening of mucosa and composed of mucinous epithelial cells with papillary and tubular arrangement. Dysplasia of BilIN and ICPN is classified by using a three-tiered system and high grade dysplasia is the same group with carcinoma in situ. Adenoma and ICPN have some ambiguities in definition and re-establishment of diagnostic criteria is needed for reproducibility of diagnosis. KRAS, TP53, and CDKN2A are the representative altered molecules in gallbladder cancer. Molecular alteration during dysplasia-carcinoma sequence is too heterogenous depending to the risk factors and type of premalignant lesion to explain the whole process by single process. Over-expression of COX2, mutation of TP53, impairment of mitochondrial DNA were reported in early hyperplastic or metaplastic epithelium. Loss of heterozygosity (LOH) of 3p, 8p chromosomes and amplification of HER2 were reported in low grade dysplasia and LOH of 9p, 18q, 22q, 17p chromosomes and mutation of CDK2A were reported in high grade dysplasia/ carcinoma in situ. Korean J Pancreas Biliary Tract 2018;23(1):1-6

The Usefulness of $SurePath^{TM}$ Liquid-Based Smear in Sono-Guided Thyroid Fine Needle Aspiration; a Comparison of a Conventional Smear and $SurePath^{TM}$ Liquid-Based Cytology

김동훈,김민경,채승완,이경분,한은미,강성희,손진희,Kim, Dong-Hoon,Kim, Min-Kyung,Chae, Seoung-Wan,Lee, Kyoung-Bun,Han, Eun Mee,Kang, Sung-Hee,Sohn, Jin-Hee The Korean Society for Cytopathology 2007 대한세포병리학회지 Vol.18 No.2

Sono-guided fine needle aspiration (FNA) of the thyroid is widely used, but the aspirated samples are typically not well preserved and low cellularity makes diagnosis difficult in many cases. The object of the current study is to evaluate the adequacy and diagnostic accuracy of the use of $SurePath^{TM}$ liquid-based cytology (SP-LBC) in the sonoguided fine needle aspiration of the thyroid nodule and to compare its use with that of the use of a conventional smear (CS). A total of 172 sono-guided FNAs of thyroid nodules from April to June, 2006 were prepared by the use of the split method with either SP-LBC or CS; the samples were stained with the use of hematoxylin-eosin (H&E) and Papanicolaou (Pap) stains. A cyto-histological correlation was performed in 69 (30 SP and 39 CS) cases that had been histologically confirmed. The rate of producing unsatisfactory slides by the use of the SP-LBC method (9.3%) was less than that of the use of the CS method (20.9%). The diagnostic accuracy of the SP method (93.3%) was better than that of the CS method (85.3%). The sensitivity and specificity of the SP method (94.4% and 92.3%) was better than that of the CS method (83.3% and 70%), respectively (p < 0.05). The CS of sono-guided aspirated specimens had some unavoidable limitations related to inadequate sampling such as a bloody background, low cellularity and an indication that some clinicians smeared many useless slides (averaging four to ten slides), and that most slides showed only blood that included few follicular cells. The SP method resulted in more thinly smeared slides and showed cleaner background and greater cellularity than the use of the CS method. Each follicular cell shows superior nuclear detail, and more distinct cytoplasmic features than with the use of the CS method. SP-LBC appears to be an easy, highly accurate, and reliable cytological method for employ for a diagnostic approach of thyroid disease and thyroid nodules. The SP-LBC method is a suitable alternative to the CS method to overcome diagnostic difficulties.

증례 : 소화기 ; 소장출혈로 나타나 소장절제술로 완치된 장림프관확장증 1예

이재은 ( Jae Eun Lee ),박정호 ( Jung Ho Park ),박완 ( Wan Park ),서미혜 ( Mi Hye Seo ),최원석 ( Won Seok Choi ),송창석 ( Chang Suk Song ),이경분 ( Kyoung Bun Lee ) 대한내과학회 2011 대한내과학회지 Vol.80 No.2S

장림프관확장증은 장림프관의 확장과 파열로 인한 유미의 장내 유출을 특징으로 하는 드문 질환이다. 이것은 림프관의 선천적인 기형으로 인한 것일 수 있으며 이차적으로 선행하는 염증이나 종양에 의해 좌쇄골하 정맥의 압력이 증가하여 흉관으로 유입되는 림프액의 감소로 인할 수 있다. 장림프관확장증은 저단백혈증, 저알부민혈증, 부종, 복수, 흉수 등을 동반한 단백소실성 장질환의 형태로 나타날 수 있으나, 매우 드문 예에서 이러한 임상양상 없이 발생한 심각한 위장관 출혈을 보고하였다. 우리는 반복적인 혈변, 흑색변을 주소로 내원한 48세의 여자 환자를 이중 풍선 소장 내시경을 이용한 조직검사를 통해 장림프관확장증을 진단하고 공장 원위부부터 회장 원위부까지 관찰된 융기성 병변을 제거하여 수술적 치료로 완치한 예를 경험하였다. 결론적으로, 장림프관확장증은 본 예와 같이 증상 없는 만성 위장관 출혈로 나타날 수 있으며, 병변이 국소적일 경우 수술적 절제로 완치할 수 있다. Intestinal lymphangiectasia (IL) is a rare disorder, characterized by dilatation of intestinal lymphatics and leakage from ruptured lacteals to the intestinal lumen. Primary IL may be due to a congenital malformation of the lymphatic system, whereas secondary IL is caused by decreased lymph flow from thoracic ductsdue to elevated left subclavian vein pressure as a result of a preceding inflammatory or neoplastic disease. IL can present as protein-losing enteropathy with clinical manifestations of hypoproteinemia, hypoalbuminemia, edema, ascites, or pleural effusions. In very rare cases, it can present as severe intestinal bleeding. We experienced a 48-year-old woman presenting with recurring hematochezia and melena. She was diagnosed bydouble balloon enteroscopy, and surgical resection was needed to stop bleeding. In conclusion, IL can present clinically as painless chronic blood loss. If IL is locally distributed, surgical resection may be needed to control bleeding and to exclude other underlying causes in some patients. (Korean J Med 2011;80:S91-S95)

쥐의 파라쿼트 중독 모델에서 설포라판의 영향

장귀상 ( Gui Sang Jang ),이재혁 ( Jae Hyuk Lee ),김규석 ( Kyu Seok Kim ),조유환 ( You Hwan Jo ),이중의 ( Joong Eui Rhee ),이경분 ( Kyoung Bun Lee ),박찬종 ( Chan Jong Park ),강창우 ( Chang Woo Kang ),이수훈 ( Soo Hoon Lee ),김중희 대한외상학회 2013 大韓外傷學會誌 Vol.26 No.1

Purpose: Sulforaphane is a naturally-occurring isothiocyanate abundant in broccoli. It has been suggested as a promising antioxidant. In this study, the therapeutic effect of sulforaphane in paraquat intoxication was investigated. Methods: Paraquat was administered via the tail vein, after which sulforaphane or a vehicle (4% DMSO) was administered intraperitoneally 15 minutes after paraquat administration. Histological injury, lipid peroxidation, plasma cytokine (IL-6, IL-10), and nitric oxide were measured. In addition, the effect of sulforaphane on survival in paraquat-intoxication was observed. Results: Regarding histological injury, lipid peroxidation, and plasma cytokine and nitric-oxide response, sulforaphane administration showed no protective effects in paraquat-intoxicated rats. Rather, it increased mortality (log rank p=0.03) and caused lipid peroxidation, as well as plasma cytokine and nitric-oxide production, to be increased. Conclusion: Sulforaphane had no therapeutic effect on paraquat-intoxicated rats; rather, it increased mortality.

PDGF-BB를 처리한 hTERT 간성상세포주의 유전자 발현 양상과 Wnt 신호 활성 양상 분석

신혜원 ( Hye Won Shin ),박수영 ( Soo Young Park ),이경분 ( Kyoung Bun Lee ),신은 ( Eun Shin ),남석우 ( Suk Woo Nam ),이정용 ( Jung Young Lee ),장자준 ( Ja June Jang ) 대한간학회 2009 Clinical and Molecular Hepatology(대한간학회지) Vol.15 No.4

목적: 간 성상세포의 증식은 간 섬유화 과정에서 중요한 역할을 한다. Platelet-derived growth factor (PDGF)는 매우 강력한 간성상세포 증식 촉진 물질이다. 사람의 간성상세포의 활성에 관여하는 유전자 발현 양상과 Wnt신호 활성화 과정을 이해하기 위하여 PDGF-BB로 증식이 유도된 인체간성상세포에서 올리고뉴클레오티드 마이크로어레이를 이용한 유전자 분석을 시행하였다. 대상과 방법: 본 연구에서는 Telomerase 역전사 효소가 첨가된 불사멸화된 사람의 간성상세포주 (hTERT HSC)가 사용되었다. PDGF-BB의 세포증식 촉진 효과는 WST-1 실험을 통해 확인하였다. PDGF-BB를 처리한 hTERT HSC의 전체적인 유전자 발현 정도를 보기 위해 1만 9천개의 사람 유전자가 포함된 칩을 사용하여 올리고뉴클레오티드 마이크로어레이를 수행하였다. 마이크로어레이 데이터는 실시간의 정량적 중합효소연쇄반응으로 검증하였다. Wnt 신호 활성화는 웨스턴블롯으로 확인하였다. 결과: PDGF-BB는 hTERT HSC의 증식을 강력하게 유도하였다. 마이크로어레이 데이터에서 PDGF-BB를 처리한 hTERT HSC의 경우 243개 유전자의 발현이 증가하였고 265개 유전자의 발현이 감소하였다. 무보정의 수직적인 군 분류 결과 PDGF-BB 처리군과 대조군은 유의하게 분리되었다. 마이크로어레이 데이터에서 대조군 대비 차이가 가장 큰 유전자들 중 glypican3(GPC3), BH3 interacting domain death agonist(BID) mRNA 실시간 PCR에서의 발현 양상은 마이크로어레이 데이터와 통계적으로 상응하였다. Wnt 신호 전달계 중 frizzled10 (FZD10), calcium/calmodulin-dependent protein kinase II alpha (CAMK2A)는 시간의 경과에 따라 증가하였고 FZD10 단백질 발현 증가는 웨스턴블롯에서도 확인되었다. 결론: PDGF-BB로 활성화된 인체 간성상세포의 전반적인 유전자 발현 및 Wnt 신호 전달계의 활성 양상은 간성상세포 활성 조절 유전자들을 찾는데 기여할 것으로 기대된다. 이런 결과들은 활성화된 간성상세포에 의한 초기 간섬유화의 기전을 이해하는 데에 중요한 단서를 제공해 줄 것이다. Background/Aims: This study aimed to better understand gene expression profiles of human hepatic stellate cell (HSC) activation and the relationship with the Wnt signaling pathway. Methods: The global transcript levels in platelet derived growth factor-BB (PDGF-BB)-stimulated hTERT HSCs were analyzed using oligonucleotide microarrays. Oligonucleotide microarrays with 19K human oligo chips were performed to obtain gene expression profiles associated with proliferation in human hTERT HSCs. The microarray data was verified by real time quantitative PCR and expression of the components of Wnt signaling was analyzed by Western blot. Results: Microarray data showed 243 up-regulated and 265 down-regulated genes in PDGF-BB-treated HSCs. The changes in expression of glypican3 and BH3 interacting domain death agonist (BID) mRNA in real time quantitative PCR, especially among the highly up- or down-regulated genes, were statistically consistent with the microarray data. The Wnt signaling pathway components, frizzled10 (FZD10) and calcium/calmodulin- dependent protein kinase II alpha (CAMK2A), showed increased expression in the short time course microarray and the up-regulation of FZD10 also occurred at the protein level. Our data showed various gene expression profiles during activation of human HSC. Conclusions: The up-regulated expression of FZD10 and CAMK2A suggests that the Wnt/Ca2+ signaling pathway is active in hTERT HSCs and may participate in HSC activation and proliferation. (Korean J Hepatol 2009;15:486-495)

총담관에 발생한 원발성 점액표피양암종

송병준 ( Byeong Jun Song ),권정희 ( Jung Hee Kwon ),김진주 ( Jin Joo Kim ),이정원 ( Jung Won Lee ),민선영 ( Sun Young Min ),이경분 ( Kyoung Bun Lee ),장진영 ( Jin Young Jang ),류지곤 ( Ji Kon Ryu ) 대한소화기학회 2011 대한소화기학회지 Vol.57 No.5

Mucoepidermoid carcinoma of the bile duct is an extremely rare tumor. Seventeen cases originating from intrahepatic bile duct and 2 cases from common hepatic duct have been reported in the English literature. Mucoepidermoid carcinoma arising from the common bile duct has not been previously reported. A 68 year-old man was admitted due to obstructive jaundice. Computed tomography showed a malignant tumor of the common bile duct located in the intrapancreatic segment. Filling defects of the distal common bile duct was seen on endoscopic retrograde cholangiogram. Under the impression of bile duct cancer, pylorus-preserving pancreatoduodenectomy was performed. Histologic diagnosis of the resected specimen was mucoepidermoid carcinoma of the common bile duct. After surgery, the patient received concurrent chemoradiotherapy, and planned to receive additional chemotherapy. We herein report on a first case of primary mucoepidermoid carcinoma of the common bile duct, and review the literature. (Korean J Gastroenterol 2011;57:319-322)

췌장의 비기능성 내분비 종양의 임상병리학적 특성 및 예후인자

박수민(Soo Min Park),장진영(Jin-Young Jang),강미주(Mee Joo Kang),윤유석(Yoo-Seok Yoon),한호성(Ho-Seong Han),조재영(Jai Young Cho),이승은(Seung Eun Lee),이경분(Kyoung Bun Lee),한인웅(In Woong Han),김선회(Sun-Whe Kim) 한국간담췌외과학회 2011 한국간담췌외과학회지 Vol.15 No.1

Purpose: Nonfunctioning endocrine tumors of the pancreas have no specific symptoms. Therefore, diagnosis is usually delayed and the malignancy rate at the time of diagnosis is reported to be higher than 50%. However, it is difficult to discriminate malignant from benign nonfunctioning endocrine tumors preoperatively. The purpose of this study was to investigate clinical characteristics of nonfunctioning endocrine tumors of the pancreas, including predictive factors of malignancy and prognostic factors affecting long-term survival. Methods: Between 1992 and 2010, clinicopathological data of 53 patients with nonfunctioning endocrine tumors proven by surgical pathology were reviewed retrospectively. Results: Of the 53 patients, mean age was 54 years-old and the male to female ratio was 1 : 1.2 Median follow up was 32.1 months. At the time of diagnosis, liver metastasis was detected in 4 patients. Curative resection was achieved in 49 patients, and 17% of them had recurrence, which was most common in liver. The overall 5-year survival rate was 85.1%. Both the WHO classification (p<0.001) and AJCC staging (p<0.001) correlated well with long-term survival. Univariate analysis revealed preoperative body weight loss (p<0.001), weak enhancement at the early arterial phase (p=0.043), lymph node metastasis (p<0.001), liver metastasis (p=0.001), perineural invasion (p=0.001), or lymphovascular invasion (p=0.010) as prognostic factors. Conclusion: Nonfunctioning endocrine tumor of the pancreas has favorable survival outcomes. Lymph node metastasis (p<0.001), liver metastasis (p=0.001), perineural invasion (p=0.001), and lymphovascular invasion (p=0.010) are poor prognostic factors.