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[Background] Patients with ulcerative colitis are reported to be at increased risk of colorectal cancer and are also at high risk of postoperative complications. However, the incidence of postoperative complications in these patients and how the type of surgery performed affects prognosis are not well understood. [Methods] Data collected by the Japanese Society for Cancer of the Colon and Rectum on ulcerative colitis patients with colorectal cancer between January 1983 and December 2020 were analyzed according to whether total colorectal resection was performed with ileoanal anastomosis (IAA), ileoanal canal anastomosis (IACA), or permanent stoma creation. The incidence of postoperative complications and the prognosis for each surgical technique were investigated. [Results] The incidence of overall complications was not significantly different among the IAA, IACA, and stoma groups (32.7%, 32.3%, and 37.7%, respectively; p = 0.510). The incidence of infectious complications was significantly higher in the stoma group (21.2%) than in the IAA (12.9%) and IACA (14.6%) groups (p = 0.048); however, the noninfectious complication rate was lower in the stoma group (13.7%) than in the IAA (21.1%) and IACA (16.2%) groups (p = 0.088). Five-year relapse-free survival was higher in patients without complications than in those with complications in the IACA group (92.8% vs. 75.2%; p = 0.041) and the stoma group (78.1% vs. 71.2%, p = 0.333) but not in the IAA group (90.3% vs. 90.0%, p = 0.888). [Conclusion] The risks of infectious and noninfectious complications differed according to the type of surgical technique used. Postoperative complications worsened prognosis.

Chromophobe renal cell carcinoma (chRCC) patients have good prognosis. Only 5%-10% patients die of metastatic disease after tumorectomy, but tumor progression cannot be predicted by histopathological parameters alone. chRCC are characterized by losses of many chromosomes, whereas gene mutations are rare. In this study, we aim at identifying genes indicating chRCC progression. A bioinformatic approach was used to correlate chromosomal loss and mRNA expression from 15287 genes from The Cancer Genome Atlas (TCGA) database. All genes in TCGA chromophobe renal cancer dataset (KICH) for which a significant correlation between chromosomal loss and mRNA expression was shown, were identified and their associations with outcome was assessed. Genome-wide DNA copy-number alterations were analyzed by Affymetrix OncoScan$^{®}$ CNV FFPE Microarrays in a second cohort of Swiss chRCC. In both cohorts, tumors with loss of chromosomes 2, 6, 10, 13, 17 and 21 had signs of tumor progression. There were 4654 genes located on these chromosomes, and 13 of these genes had reduced mRNA levels, which was associated with poor outcome in chRCC. Decreased CDKN1A expression at mRNA (p = 0.02) and protein levels (p = 0.02) were associated with short overall survival and were independent predictors of prognosis (p <0.01 and <0.05 respectively). CDKN1A expression status is a prognostic biomarker independent of tumor stage. CDKN1A immunohistochemistry may be used to identify chRCC patients at greater risk of disease progression.

Chromophobe renal cell carcinoma (chRCC) is a renal tumor subtype with a good prognosis, characterized by multiple chromosomal copy number variations (CNV). The World Health Organization (WHO) chRCC classification guidelines define a classic and an eosinophilic variant. Large cells with reticular cytoplasm and prominent cell membranes (pale cells) are characteristic for classic chRCC. Classic and eosinophilic variants were defined in 42 Swiss chRCCs, 119 Japanese chRCCs and in whole-slide digital images of 66 chRCCs from the Cancer Genome Atlas (TCGA) kidney chromophobe (KICH) dataset. 32 of 42 (76.2%) Swiss chRCCs, 90 of 119 (75.6%) Japanese chRCCs and 53 of 66 (80.3%) TCGA-KICH were classic chRCCs. There was no survival difference between eosinophilic and classic chRCC in all three cohorts. To identify a genotype/phenotype correlation, we performed a genome-wide CNV analysis using Affymetrix OncoScan$^{®}$ CNV Assay (Affymetrix/Thermo Fisher Scientific, Waltham, MA, USA) in 33 Swiss chRCCs. TCGA-KICH subtypes were compared with TCGA CNV data. In the combined Swiss and TCGA-KICH cohorts, losses of chromosome 1, 2, 6, 10, 13, and 17 were significantly more frequent in classic chRCC (p < 0.05, each), suggesting that classic chRCC are characterized by higher chromosomal instability. This molecular difference justifies the definition of two chRCC variants. Absence of pale cells could be used as main histological criterion to define the eosinophilic variant of chRCC.

Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS (CYCLOPS) genes have been recently identified as the most enriched class of copy-number associated gene dependencies in human cancer. These genes are cell essential and render tumor cells highly sensitive to the expression of the remaining copy. Chromophobe renal cell carcinoma (chRCC) is characterized by frequent chromosomal deletions, but the relevance of CYCLOPS genes in this tumor subtype is unclear. We found 39 (31%) of 124 recently published candidate CYCLOPS genes (B. Paolella et al., eLife 2017;6:e23268) located on 7 autosomes that are frequently lost in chRCC. GISTIC and RNA-seq data obtained from the TCGA-KICH database showed that 62% of these CYCLOPS genes had significantly lower expression levels in samples with deletion of the respective gene. As copy number (CN) loss of the CYCLOPS gene SF3B1 (Splicing factor 3B subunit 1) has been recently reported in 71% chRCC, we explored the relevance of SF3B1 CN alteration and SF3B1 expression in a set of chRCC and additional oncocytic renal neoplasms. The frequency of SF3B1 CN loss (65%) was similar to that obtained from the TCGA-KICH database and correlated significantly with both lower SF3B1 mRNA (P < .05) and protein expression (P < .001). Other tumor subtypes with oncocytic cytoplasm had normal SF3B1 CN and displayed strong SF3B1 protein expression. These results suggest that CN loss of CYCLOPS genes is a characteristic feature in chRCC. Since many CYCLOPS genes code for components of proteasomes and transcriptional regulation, their alteration could make chRCC vulnerable to targeted drugs.

Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The Grading of Recommendation Assessment, Development and Evaluation' method was used to determine the strength of recommendations and quality of evidence. The following 10 statements achieved consensus: Tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%). Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%). Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%). Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%). Tumor budding is counted on H&E (19/22, 86%). Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%). Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm 2) at the invasive front (22/22, 100%). A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%). Tumor budding and tumor grade are not the same (23/23, 100%). Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%). Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guid

"p53遺伝子変異は同蛋白過剰発現として免疫組織学的に同定することが可能とされているが, 免疫染色に用いられるモノクローナル抗体にはさまざまなものがあり, どのような染色態度を蛋白過剰発現とするかについても一定の基準はない. 本研究では免疫染色による蛋白過剰発現判定法の確立を目的として, 市販・汎用されている2種類(PAb1801, DO7)のモノクローナル抗体を用いて, それぞれの染色態度と遺伝子変異との相関を検討した. 外科切除ホルマリン固定大腸進行癌29病変, 内視鏡的に切除された大腸粘膜内腫瘍53病変を対象とし, 2種類の抗体を用いた免疫染色で同一領域の染色態度を判定した. 次に, 各領域からマイクロダイセクションによりDNAを抽出して, p53遺伝子のエクソン5-8をPCRで増幅し, シークエンス解析により遺伝子変異を検索した. 進行癌29病変から42領域, 粘膜内腫瘍53病変から237領域の合わせて279領域が検索対象として抽出された. 2種類の抗体間の免疫染色態度の対比では, DO7染色はPAb1801染色に比べ陽性細胞頻度がより高く, 染色強度がより強く表現される傾向があった. 蛋白過剰発現の判定は, 用いる抗体により異なる. PAb1801染色では, nested(陽性細胞が混在しない陽性細胞集簇巣が散在)とdiffuse(陰性細胞が混在することなく陽性細胞がびまん性に存在)が, DO7染色では, nestedとdiffuse/strong(染色強陽性)が, 他の染色態度に比べ有意に高い遺伝子変異率(71.1-93.8%)を示したことから, これらの染色態度を蛋白過剰発現とすることが妥当と考えられた. 蛋白過剰発現を示す領域の遺伝子変異はその大半(69.2-100%)が, アミノ酸置換を伴うmissense mutation(またはmissense mutationを伴う)であり, 変異型p53蛋白が免疫染色により同定されたものと考えられた. 他方, DO7染色ではdiffuse/weak(染色弱陽性)のものに遺伝子変異は認められず, 同染色態度を蛋白過剰発現としないよう注意が必要である. 一方, 免疫染色陰性領域でもPAb1801染色の50%, DO7染色の77.3%には遺伝子変異が認められ, それらの変異パターンはdeletion, insertion, nonsense mutation, splicing site mutationなど蛋白のtruncationをきたす変異であった. p53免疫染色陰性例にもp53蛋白不活化をきたす遺伝子変異が存在する可能性を考慮する必要がある. "

【目的】血液透析患者数の増加に伴い, 腹部手術を要する血液透析患者が近年, 増加している. 本研究では, 慢性腎不全による血液透析患者の腹部手術症例の術後成績からその問題点を明らかにする. 【対象と方法】2011年1月から2012年12月までの2年間で当科で実施された手術1592例中, 腹部手術を実施された血液透析患者13例(0.8%)を対象とした. その内訳は, 待機手術6例(十二指腸乳頭部癌, 胃カルチノイド, 胆嚢癌, 横行結腸癌, 小腸潰瘍, 胆嚢ポリープ, 各々1例), 緊急手術7例(非閉塞性腸管虚血症2例, 穿孔性腹膜炎・腹腔内膿瘍, S状結腸憩室穿孔, 持続的腹膜透析カテーテル関連腹膜炎, 脳死膵腎同時移植, 出血性直腸ポリープ, 各々1例)であった. 待機手術症例と緊急手術症例との間で, 術後合併症, 術後在院死亡の発生率を比較した. 【結果】待機手術症例では2例(33%)に術後合併症(麻痺性イレウス, 胃内容排出遅延, 各々1例)を認めたが, いずれも軽症で比較的早期に退院が可能であった. 一方, 緊急手術症例では3例(43%)に術後合併症(敗血症性ショック, 敗血症性ショック+多臓器不全, 腹腔内膿瘍・出血+下大静脈血栓+髄膜炎, 各々1例)を認め, そのうち2例(緊急手術症例の29%)が在院死亡した. 待機手術症例と比較して緊急手術症例では, 術後合併症および在院死亡の発生率が高率であった. 【結論】日常の透析管理や周術期管理の進歩により, 血液透析患者の腹部待機手術は安全に施行されるようになったが, 腹部緊急手術の術後短期成績は未だ不良である. その原因として, 免疫力の低下, 易感染性といった特徴をもつ血液透析患者では病態が早期に重篤化しやすいことが示唆される. 血液透析患者の病態理解, 早期診断・治療が, 血液透析患者に対する腹部緊急手術の術後成績向上に必要と考えられる.

Yasushi Sano,1,2 Takahiro Fujii,3,4 Takahisa Matsuda,3 Yasushi Oda,5,6 Shin'ei Kudo,7 Masahiro Igarashi,8 Hiroyasu Iishi,9 Kazuhiro Kaneko,1,10 Kinichi Hotta,3,11,12 Nozomu Kobayashi,3,13 Yuichiro Yamaguchi,12 Kiyonori Kobayashi,8 Hideki Ishikawa,14 Yoshitaka Murakami,15 Tadakazu Shimoda,16 Takahiro Fujimori,17 Yoichi Ajioka,18 Hirokazu Taniguchi,16 Hiroaki Ikematsu,1,3 Kazuo Konishi,10 Yutaka Saito,3 Shigeaki Yoshida1,19 1Department of Gastroenterology, Endoscopy Division, National Cancer Center Hospital East, Kashiwa, 2Gastrointestinal Center and Institute of Minimally Invasive Endoscopic Care (iMEC), Sano Hospital, Kobe, 3Endoscopy Division, National Cancer Center Hospital, Tokyo, 4Takahiro Fujii Clinic, Tokyo, 5Hattori GI Endoscopy and Gastroenterology Clinic, Kumamoto, 6Oda GI Endoscopy and Gastroenterology Clinic, Kumamoto, 7Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, 8Department of Gastroenterology, Kitasato University East Hospital, Sagamihara, 9Department of Gastrointestinal Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 10Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, 11Department of Gastroenterology, Saku Central Hospital, Saku, 12Division of Endoscopy, Shizuoka Cancer Center, Mishima, 13Department of Diagnostic Imaging, Tochigi Cancer Center, Utsunomiya, 14Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 15Department of Medical Statistics, Shiga University of Medical Science, Otsu, 16Pathology and Clinical Laboratory Division, National Cancer Center Hospital, Tokyo, 17Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Mibu, 18Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 19Aomori Prefectural Hospital, Aomori, Japan Backgrou

【はじめに】直腸原発内分泌細胞腫瘍について種々の分類法が提案されている. 今回自験例で, 大腸癌取扱い規約による分類での具体的な悪性度の違いとその有用性について検討した. 【対象と方法】当科で経験した直腸内分泌細胞腫瘍60例を, カルチノイド腫瘍52例と内分泌細胞癌8例とに分け臨床病理学的検討を行った. 【結果】両群間で, 平均年齢, 腫瘍最大径, 5年生存率 (カルチノイド腫瘍 : 87.5%, 内分泌細胞癌 : 23.4%) に有意差を認めた. リンパ節郭清切除術が施行された22例で検討すると, カルチノイド腫瘍の1/14例 (7.7%) (深達度sm, 径8mm), 内分泌細胞癌の6/8例 (75%) にリンパ節転移を認めた. カルチノイド腫瘍死亡例は2例 (共に深達度sm, 径7mmと10mm) で, 共に初回発見時から肝転移を認め4年以上の経過で原病死していた. 【結論】大腸癌取扱い規約による直腸内分泌細胞腫瘍の分類は, それぞれの生物学的悪性度を反映し, 予後予測や治療選択の上で有用と考えられた.

症例は87歳, 女性. 4年ほど前より慢性関節リウマチに対し diclofenac sodium (Voltaren^<(R)>) 75mg/日, prednisolone 15mg/日を内服, 疼痛時は坐薬50mgを1日1回頓用し治療中であった. 下血を主訴に当院内科に入院した. 上部消化管内視鏡検査, 腹部CT検査では異常は認められなかった. 保存的治療で下血は軽快し, その後の検査を希望せず退院した. 退院後9日目より下血・腹部膨満感が出現し, その2日後に緊急入院となった. 腹部CT検査で著明な遊離ガス像を認めたため, 消化管穿孔による汎発性腹膜炎の診断で緊急手術を行った. 術中所見では多発性の結腸および直腸穿孔による汎発性腹膜炎であったが, 穿孔部周囲の虚血性変化は認められなかった. 穿孔部を含めた左半結腸・直腸切除術と人工肛門造設術を施行した. 切除標本では潰瘍は境界明瞭で, 縦走傾向のある地図状不整形であった. NSAIDs起因性腸炎, 潰瘍型の穿孔例と考えて矛盾しなかった. 病理学的検索では潰瘍周囲粘膜にアポトーシスを認めた. しかし同時にアミロイドーシス沈着とサイトメガロウイルス感染を合併しており, これらの因子の病態への関与も否定はできなかった. 術後は敗血症性ショック, DICから多臓器不全に至り術後5日目に永眠された. NSAIDs長期使用例では下部消化管障害を引き起こす可能性があることを念頭に置く必要がある.

症例は74歳, 男性. 肝内結石・総胆管結石症に併存した肝内胆管癌の診断で根治切除目的に当科紹介された. 肝障害度C (血清 T.bil 値 1.8mg/dl, 血清 Alb 値 2.4g/dl, ICG15分停滞率41%) であったが, 本例は結石に起因した胆汁うっ滞による肝障害であり肝硬変は伴っていないと判断し, 胆道再建を伴う拡大肝左葉切除術を施行した. 術後肝不全は認めず退院となった. 本邦では, 術前ICG15分停滞率を基準として肝切除術式を決定しており, 本例のICG15分停滞率からは核出術が適切な肝切除術式と判断されるが, 本例のように肝硬変非併存で胆汁うっ滞が原因の肝障害の場合には, 必ずしもICG負荷試験値が肝予備能を正確に反映しているとは限らないことが示唆される. 非肝硬変症例における肝切除術式選択の際には, 病態を考慮した上で不良なICG負荷試験値を解釈し肝切除術式を決定する必要がある.

症例は75歳, 男性. 上部胆管癌の疑いで当院紹介受診した. 高齢者であることを考慮して肝外胆管切除術を立案していたが, 直接胆道造影で左肝内胆管壁に 毛羽立ち状 の壁不整像を認め, 表層拡大進展の存在が疑われた. 経口胆道鏡検査を施行し, 左肝内胆管に発赤調で乳頭状ないしは微細顆粒状の粘膜を認め, 表層拡大進展の存在を確認できたため, 肝左葉切除術および肝外胆管切除術を施行し癌遺残のない切除が実施可能であった. 直接胆道造影で胆管壁に毛羽立ち状 あるいは 鋸歯状 の壁不整像を認めた場合には, 表層拡大進展の存在を疑う必要がある. 表層拡大進展の存在診断には経口胆道鏡検査は有用であり, 適切な術式を決定する上で考慮すべき術前検査法の1つである.

To establish a standardized immunohistochemical method for detecting isolated tumor cells (ITC) in lymph nodes of patients with colorectal cancer (CRC), we examined the detection rates of ITC using sections of various thicknesses and two different kinds of cytokeratin monoclonal antibodies, CAM5.2 and AE1/AE3. According to the sixth edition of the TNM classification, ITC was defined as a single tumor cell or small cell clusters not greater than 0.2 mm. From 29 patients with stage III colorectal cancer, 149 lymph nodes diagnosed as negative for cancer metastasis by routine hematoxylin and eosin (H&E) staining were randomly selected. Twelve serial sections were cut for each lymph node. Sections one to eight were cut at a 4 μm thickness, and sections nine to 12 were cut at a 10 μm thickness. Sections one and eight, two to six and nine to 11, and seven and 12, were stained with H&E, the CAM5.2 antibody, and the AE1/AE3 antibody, respectively. Comparisons of cumulative ITC positive rates in sections of varying total thicknesses stained with the CAM5.2 antibody revealed that no significant differences were found when the total thickness of the sections examined exceeded 8 μm. There was no significant difference in ITC positive rates between CAM5.2 and AE1/AE3 staining. Our data indicate that, when monoclonal antibodies CAM5.2 or AE1/AE3 are used, ITC can be optimally detected immunohistochemically in sections with a total thickness of more than 8 μm. This practical suitable procedure can be used for standardizing the detection method for ITC.

症例は26歳の男性.8年(診断後4年)の全大腸炎型潰瘍性大腸炎罹患歴がある.近医でのフォローの大腸内視鏡検査でS状結腸に平坦隆起を認め,生検でGroup5と診断されたため,精査加療目的に当科に紹介となった.大腸内視鏡でS状結腸に散在する陥凹を伴う発赤調の低い隆起性病変を認めた.拡大観察でIII s-V_N pit patternを呈し,超音波内視鏡検査では粘膜下層主体で一部筋層浸潤を疑う癌と診断した.CT上転移は認めず,腫瘍マーカーも正常範囲内であった.D3リンパ節郭清を含む大腸全摘術,W型回腸嚢肛門吻合術,一時的回腸人工肛門造設術を施行した.切除標本上,下行結腸から肛門側に小結節の集籏部と粘膜脱落部が散在していたが,術前診断どおりS状結腸にcolitic cancerを認めた.病理組織検査では低分化腺癌成分を伴う中分化腺癌で,粘膜下層浸潤が主体であったが一部固有筋層に浸潤していた.他部位にdysplasiaの所見は認めなかった.

We studied the macroscopic features of differentiated-type gastric carcinomas to discern mucin phenotypes using 50 cases (54 lesions) of early gastric depressed type carcinomas, employing MUC5AC, MUC6, MUC2 and CD10 immunostains. We identified the G-phenotype (gastric phenotype) in 12 lesions, the gastrointestinal phenotype in 26 lesions, and the intestinal phenotype in 16 lesions. Carcinomas with the gastric phenotype revealed a significantly higher incidence of discolored surface (58.3%) than those with the intestinal phenotype (18.7%) (p<0.05). Carcinomas with the gastric phenotype also demonstrated a significantly higher incidence of non-wavy tumor margins (83.3%); those with the intestinal phenotype had only an 18.7% incidence of non-wavy tumor margins (p<0.01). No difference in the clarity of the marginal outline was found among the mucous phenotypes. The mucosal heights measured under a microscope revealed that the shallowest depressions among the nuclear-margin group were associated with gastric phenotype lesions., departmental bulletin paper

Mucin core protein expression in ulcerative colitis-associated colorectal carcinoma (UC-CRC) has not been investigated to date. We immunohistochemically examined expression of MUC2, MUC5AC, and MUC1 mucin core proteins in 8 UC-CRCs (4 mucinous carcinomas and 4 well and/or moderately differentiated adenocarcinomas) in order to characterize their mucin phenotypes. We then compared these with sporadic colorectal carcinomas (sporadic CRCs) (30 mucinous carcinomas and 60 well and/or moderately differentiated adenocarcinomas) in order to confirm whether any specific cellular lineage differentiation occurs in UC-associated carcinogenesis. MUC2, MUC5AC, MUC1 are normally synthesized in goblet cells of gastrointestinal tract, in gastric foveolar epithelium, and in columnar and goblet cells of the colorectum, respectively. UC-CRC exhibited extensive expression of MUC2 (50-100%), MUC5AC (50-75%), and MUC1 (75%), irrespective of histological type, and MUC2+/MUC5AC+/MUC1+ was the most common mucin phenotype (4/8). Six of 8 UC-CRCs had the MUC2+ phenotype, and co-expression of MUC5AC or MUC1 was demonstrated in 5 of these. These findings were similar to those of sporadic mucinous CRCs. The present results indicate that both UC-CRCs and sporadic mucinous CRCs are predominated by cancer cells of goblet cell lineage (MUC2+) with gastric differentiation (MUC5AC+), and up-regulation of gelforming mucin MUC2 and MUC5AC would account for the frequently observed mucinous histology. This suggests that UC-associated carcinogenesis may originate from MUC5AC+ gastric metaplasia and is similar to UACL (ulcer-associated cell lineage) generated in colorectal mucosa exhibiting long-term chronic inflammation., departmental bulletin paper

Objectives: The present study aimed to clarify the definitions and histogenesis of ovarian-type stroma (OTS) in mucinous cystic neoplasms (MCNs) of the pancreas. Methods: Expression and density of cells positive for estrogen receptor (ER) and progesterone receptor (PR) were immunohistochemically studied in 16 MCNs (6 adenomas, 10 carcinomas), 22 intraductal papillary mucinous neoplasms (IPMNs), 10 common-type invasive ductal carcinomas (IDCs) and 24 non-neoplastic pancreatic tissues. Results: OTS comprised densely packed spindleshaped cells with round or elongated nuclei. Stromal cells were diffusely positive for ER and PR in all 16 MCNs. OTS-like stromal cells in IPMNs and IDCs were negative or only sporadically positive for ER or PR in all cases. In non-neoplastic pancreatic tissue, ER- and PR-reactive stromal cells were scattered sporadically irrespective of site in the pancreas (head, body or tail) or sex. Conclusions: OTS is an absolute marker for diagnosis of pancreatic MCNs and should be confirmed as ER- and PR-reactive on immunostaining in addition to findings from sections stained using hematoxylin-eosin. ER- and PR-reactive stromal cells may become hypersensitive to female sex hormone stimulation and start to proliferate and form OTS in the pancreas., departmental bulletin paper

The immunohistochemical expression of p21^ and Ki-67 of serrated adenoma (SA) (n=19) of the colorectum was evaluated in order to elucidate its cell differentiation/maturation status and its relationship with cell proliferation. This was then compared with those of a hyperplastic polyp (HP) (n=18), traditional tubular adenoma (TA) (n=21), and normal colonic mucosa (n=11). Longitudinally sectioned hemicrypts were selected from each sample, and the percentage of the p21^ (+) portion and the proliferative zone (PZ) per entire hemicrypt length were determined. In SA, although the topographic regulation of cell differentiation/maturation and proliferation was maintained, the percentage of PZ (26.5±1.8%) decreased and that of the p21^ (+) portion (61.4±2.1%) increased compared with those of normal colonic mucosa (31.8±1.3% and 30.6±1.4%) (p<0.05, respectively), indicating that the cell kinetic balance of SA was inclined toward cell differentiation/maturation. A similar cell kinetic imbalance was seen in HP, whereas the cell kinetic balance was inclined toward cell proliferation in TA. These findings suggest that, unlike TA, SA is a disorder of cell differentiation/maturation rather than cell proliferation, and the elongation of the cell life span and the subsequent reduction of exfoliation, which are the known fundamental cell kinetics of HP, may contribute to its neoplastic growth., departmental bulletin paper

We report an interesting case with a primary ulcerating tumor of the ampulla of Vater associated with multiple primary pancreatic ductal microadenocarcinomas. All of these pancreatic microcarcinomas (number, 69; size, 0.04-1.25mm) were histologically proved to be primary and independent of each other, and were distributed throughout the head, body, and tail of the pancreas. They were all located in the small interlobular ducts and the ductules (including intercalated ducts and centroacinar cells). Sixty-three of 69 microcarcinomas were in-situ carcinomas, and the remaining 6 were microinvasive. All microcarcinomas were well-differentiated tubular adenocarcinomas with ordinary cell phenotypes, high-grade cytologic atypia, and adjacent only to normal ordinary pancreatic ductal cells, but not to mucous cell hyperplasia. Immunohistochemically, all of the microcarcinomas showed p53-protein overexpression (p53 positive index: 91.6 ± 8.10% in 12 tumors tested), high proliferative activity (Ki-67 positive index: 64.9 ± 13.3% in the same 12 tumors), and no Ki-ras mutation detected by nested PCR-RFLP in the 12 carcinomas. We concluded that pancreatic microcarcinoma in this case arose from ordinary pancreatic ductal cells of the small ducts and ductules by way of p53 alteration without Ki-ras mutation, and that histogenesis was different from that of the more common Ki-ras-mutated carcinoma arising from metaplastic mucous cells of mucous cell hyperplasia.

We report an interesting case with a primary ulcerating tumor of the ampulla of Vater associated with multiple primary pancreatic ductal microadenocarcinomas. All of these pancreatic microcarcinomas (number, 69; size, 0.04-1.25mm) were histologically proved to be primary and independent of each other, and were distributed throughout the head, body, and tail of the pancreas. They were all located in the small interlobular ducts and the ductules (including intercalated ducts and centroacinar cells). Sixty-three of 69 microcarcinomas were in-situ carcinomas, and the remaining 6 were microinvasive. All microcarcinomas were well-differentiated tubular adenocarcinomas with ordinary cell phenotypes, high-grade cytologic atypia, and adjacent only to normal ordinary pancreatic ductal cells, but not to mucous cell hyperplasia. Immunohistochemically, all of the microcarcinomas showed p53-protein overexpression (p53 positive index: 91.6 ± 8.10% in 12 tumors tested), high proliferative activity (Ki-67 positive index: 64.9 ± 13.3% in the same 12 tumors), and no Ki-ras mutation detected by nested PCR-RFLP in the 12 carcinomas. We concluded that pancreatic microcarcinoma in this case arose from ordinary pancreatic ductal cells of the small ducts and ductules by way of p53 alteration without Ki-ras mutation, and that histogenesis was different from that of the more common Ki-ras-mutated carcinoma arising from metaplastic mucous cells of mucous cell hyperplasia., departmental bulletin paper

Mutation of the K-ras codon 12 was examined in 17 gallbladder carcinomas and 14 nonneoplastic gallbladder mucosa in patients with anomalous arrangement of the pancreaticobiliary duct (APBD), using nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. In addition, we investigated the relationship between the K-ras mutation and cellular proliferation using Ki-67 (MIB1) monoclonal antibody. Mutation of K-ras codon 12 was found in 7 of 17 (41.2%) gallbladder carcinomas but not in nonneoplastic gallbladder mucosa. There was neither a correlation between the presence of the K-ras mutation and the size or depth of invasion of the carcinoma, nor any statistically significant difference in cellular proliferation of the same grade of cytologic atypia between tumors with and without K-ras mutation (Ki-67 labeling index, high grade; 35.2 ±13.3% and 31.6±13.9%, low grade; 14.2±4.9% and 21.2± 12.8%, respectively). This indicates that mutation of K- ras codon 12 may be involved in the development of gallbladder carcinomas preferentially in patients with APBD, but not in the progression of the Ki-67 labeling index, tumor size, or tumor invasion.

Alterations in p53 were analyzed by immunochemistry in 131 lesions from 108 patients and by polymerase chain reaction single-strand conformation polymorphism(PCR-SSCP) in 69 tumors from 69 patients with esophageal squamous cell carcinomas, to elucidate the correlation between protein overexpression and mutation, and between p53 alteration and clinicopathological factors. The p53 gene-product was overexpressed in 83 (63%) of the 131, and mutations were detected in 24 (35%) of the 69 tumors examined. The mutations were predominantly located at exons 5 (58%) and 7 (27%), and detected in 13 (31%) of 42 overexpressing tumors, in none of 4 sporadic tumors and in 8 (40%) of 20 negative tumors. The p53 alteration did not correlate with the clinicopathological factors, including pTNM categories, stage, depth of invasion, and size of intramucosal carcinomas. These results indicate that p53 protein overexpression and gene mutation may occur during an early stage of esophageal carcinogenesis and have no impact on clinicopathological factors. The higher frequency of p53 overexpression compared to mutation suggests that p53 accumulation can occur by other mechanisms besides p53 mutation.

Alterations in p53 were analyzed by immunochemistry in 131 lesions from 108 patients and by polymerase chain reaction single-strand conformation polymorphism(PCR-SSCP) in 69 tumors from 69 patients with esophageal squamous cell carcinomas, to elucidate the correlation between protein overexpression and mutation, and between p53 alteration and clinicopathological factors. The p53 gene-product was overexpressed in 83 (63%) of the 131, and mutations were detected in 24 (35%) of the 69 tumors examined. The mutations were predominantly located at exons 5 (58%) and 7 (27%), and detected in 13 (31%) of 42 overexpressing tumors, in none of 4 sporadic tumors and in 8 (40%) of 20 negative tumors. The p53 alteration did not correlate with the clinicopathological factors, including pTNM categories, stage, depth of invasion, and size of intramucosal carcinomas. These results indicate that p53 protein overexpression and gene mutation may occur during an early stage of esophageal carcinogenesis and have no impact on clinicopathological factors. The higher frequency of p53 overexpression compared to mutation suggests that p53 accumulation can occur by other mechanisms besides p53 mutation., departmental bulletin paper

Mutation of the K-ras codon 12 was examined in 17 gallbladder carcinomas and 14 nonneoplastic gallbladder mucosa in patients with anomalous arrangement of the pancreaticobiliary duct (APBD), using nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. In addition, we investigated the relationship between the K-ras mutation and cellular proliferation using Ki-67 (MIB1) monoclonal antibody. Mutation of K-ras codon 12 was found in 7 of 17 (41.2%) gallbladder carcinomas but not in nonneoplastic gallbladder mucosa. There was neither a correlation between the presence of the K-ras mutation and the size or depth of invasion of the carcinoma, nor any statistically significant difference in cellular proliferation of the same grade of cytologic atypia between tumors with and without K-ras mutation (Ki-67 labeling index, high grade; 35.2 ±13.3% and 31.6±13.9%, low grade; 14.2±4.9% and 21.2± 12.8%, respectively). This indicates that mutation of K- ras codon 12 may be involved in the development of gallbladder carcinomas preferentially in patients with APBD, but not in the progression of the Ki-67 labeling index, tumor size, or tumor invasion., departmental bulletin paper

8624 tubular adenomas from 9 patients with familial adenomatosis coli were investigated to elucidate the mode of their macroscopic development. Our data indicate that most tubular adenomas remain smaller than 5 mm, suggesting that those larger than 5 mm detected clinically may already have deviated from the expected natural history of benign adenomas. Their initial macroscopic configuration appears to be the flat or sessile type, and they seem to change their macroscopic configurations to subpedunculated as they attain a size between 5 and 7 mm. Adenomas larger than 8 mm appear to take a pedunculated shape. This mode of macroscopic development may be affected by the location of adenomas, and tends to occur in adenomas of a smaller size in the rectum, sigmoid and ascending colon than in the rest of the organ.

Several reports attest to the absence of p53 immunoreactive cells within non-neoplastic colorectal mucosa, including histologically normal mucosa and inflamed mucosa from subjects with active ulcerative colitis (UC). Failure to detect p53 in these circumstances has been attributed to the short half-life of wild-type p53. Following our previous demonstration of p53 expression in non-neoplastic mucosa, we have studied specimens from ten subjects with ulcerative colitis with the aim of quantifying and correlating this aim with disease activity. The frequency of p53-positive tubules was 19.0% (245/1292) in active UC, 3.1% (46/1487) in resolving and 0.5% (4/863) in UC in remission and 0.3 % (59/17982) in controls. The number of p53-positive cells per tubule with p53-positive cells was 5.4±4.1 in active, 2.4±3.6 in resolving, and 1.3±0.5 in UC in remission and 1.1 ±0.3 in controls. Positive cells occurred singly and were limited to the proliferative zone of tubules in UC and controls. p53 labeling index (LI) in the proliferative zone was 9.0±7.7% in active, 1.5±1.4% in resolving, 1.1±0.5% in UC in remission and 1.2±0.3% in controls. Ki-67 LI in corresponding areas was 68.0± 16.4% in active, 63.1±10.2% in resolving, 48.5±14.4% in UC in remission and 60.9± 10.9% in controls. p53 LI/ Ki-67 LI percentage which is 100% or more in carcinomas with p53 protein overexpression was 14.3± 13.6% (max 52%) in active, 2.24±1.89% in resolving, 2.14±0.73% in UC in remission and 2.03±0.51% in controls. We conclude that p53 immunoreactive cells occur in non-neoplastic conditions and contain wild-type protein. Scattered expression of p53 is not a marker of neoplasia. If p53 immunostaining is to provide a useful diagnostic tool, then the limits of normal and abnormal expression need to be carefully defined.

Several reports attest to the absence of p53 immunoreactive cells within non-neoplastic colorectal mucosa, including histologically normal mucosa and inflamed mucosa from subjects with active ulcerative colitis (UC). Failure to detect p53 in these circumstances has been attributed to the short half-life of wild-type p53. Following our previous demonstration of p53 expression in non-neoplastic mucosa, we have studied specimens from ten subjects with ulcerative colitis with the aim of quantifying and correlating this aim with disease activity. The frequency of p53-positive tubules was 19.0% (245/1292) in active UC, 3.1% (46/1487) in resolving and 0.5% (4/863) in UC in remission and 0.3 % (59/17982) in controls. The number of p53-positive cells per tubule with p53-positive cells was 5.4±4.1 in active, 2.4±3.6 in resolving, and 1.3±0.5 in UC in remission and 1.1 ±0.3 in controls. Positive cells occurred singly and were limited to the proliferative zone of tubules in UC and controls. p53 labeling index (LI) in the proliferative zone was 9.0±7.7% in active, 1.5±1.4% in resolving, 1.1±0.5% in UC in remission and 1.2±0.3% in controls. Ki-67 LI in corresponding areas was 68.0± 16.4% in active, 63.1±10.2% in resolving, 48.5±14.4% in UC in remission and 60.9± 10.9% in controls. p53 LI/ Ki-67 LI percentage which is 100% or more in carcinomas with p53 protein overexpression was 14.3± 13.6% (max 52%) in active, 2.24±1.89% in resolving, 2.14±0.73% in UC in remission and 2.03±0.51% in controls. We conclude that p53 immunoreactive cells occur in non-neoplastic conditions and contain wild-type protein. Scattered expression of p53 is not a marker of neoplasia. If p53 immunostaining is to provide a useful diagnostic tool, then the limits of normal and abnormal expression need to be carefully defined., departmental bulletin paper

8624 tubular adenomas from 9 patients with familial adenomatosis coli were investigated to elucidate the mode of their macroscopic development. Our data indicate that most tubular adenomas remain smaller than 5 mm, suggesting that those larger than 5 mm detected clinically may already have deviated from the expected natural history of benign adenomas. Their initial macroscopic configuration appears to be the flat or sessile type, and they seem to change their macroscopic configurations to subpedunculated as they attain a size between 5 and 7 mm. Adenomas larger than 8 mm appear to take a pedunculated shape. This mode of macroscopic development may be affected by the location of adenomas, and tends to occur in adenomas of a smaller size in the rectum, sigmoid and ascending colon than in the rest of the organ., departmental bulletin paper