大城 久

Bile duct cancer is known to contain numerous fibroblasts, and reported to recruit cancer- associated fibroblasts by secreting platelet-derived growth factor-D (PDGF-D) which needs serine proteases, such as matriptase, to behave as a ligand. However, their expression pattern, and prognostic value have not been clarified. In this study, we investigated the clinicopathological significance of PDGF-D and matriptase expression in patients with extrahepatic bile duct cancer. The samples were obtained from 256 patients who underwent the surgical resection between 1991 and 2015, and the expression levels of PDGF-D and matriptase were evaluated immunohistochemically. Staining intensities and distribution were scored, and finally classified into low and high expression groups in cancer cells and stroma respectively. High expression of matriptase in the cancer stroma was detected in 91 tumors (40%). The high stromal matriptase expression was significantly associated with shorter recurrence-free survival (RFS) and overall survival (OS) (P = 0.0027 and 0.0023, respectively). Multivariate analyses also demonstrated that the stromal matriptase expression level was an independent influential factor in RFS (P = 0.0050) and OS (P = 0.0093). Our findings suggest that the high stromal matriptase expression was strongly associated with tumor progression, recurrence and poor outcomes in patients with extrahepatic bile duct cancer.

RATIONALE: Liver heterotopia associated with congenital diaphragmatic hernia (CDH) is a rare condition; to the best of our knowledge, only 17 cases have been reported to date. The histogenesis and clinicopathological features are largely unknown. We herein report 2 cases of liver heterotopia associated with CDH along with 17 cases described in the literature to shed light on their clinicopathological characteristics. PATIENT CONCERNS: Case 1 was a vaginally delivered male newborn who presented with respiratory distress immediately after birth. Case 2 was a female fetus who was found to have left-sided CDH during gestation. DIAGNOSIS: In case 1, a chest X-ray revealed left-sided CDH. In case 2, magnetic resonance imaging performed at 33 weeks of gestation revealed left-sided CDH. INTERVENTIONS: Case 1 underwent diaphragmatic patch repair surgery 3 days after birth. Histopathological examination following surgery in case 1 revealed the presence of ectopic liver tissue in the hernia sac. Case 2 was delivered by Cesarean section, and diaphragmatic patch surgery was performed 3 days after birth. During surgery, an isolated nodule was identified on the peritoneal side of the border of the defective foramen of the diaphragm. Histopathological examination following surgery in case 2 confirmed the presence of an epidermal cyst in the hernia sac. In addition, the isolated nodule was histopathologically found to be ectopic liver tissue. OUTCOMES: In Case 1, CDH recurred at 6 months after surgery, and a second patch repair surgery was performed. The surgically removed hernia sac was found to contain microscopic ectopic liver tissue on histopathology. Case 1 recovered well after surgery, and there was no critical change during the 10-month postoperative period. Case 2 recovered well after surgery, and there was no critical change during the 20-month postoperative period. LESSONS: There were no secondary pathological conditions associated with the presence of ectopic liver in CDH, such as torsion, infarction, rupture, intra-abdominal bleeding, or tumorization. Our observations suggest that liver heterotopia is a rare but asymptomatic condition in patients with CDH.

Little is known concerning the prognostic significance of the degree of lymphatic vessel invasion in pancreatic head cancer. To address this gap in knowledge, we retrospectively examined 60 patients with locally advanced, surgically resectable pancreatic head cancer who underwent pancreaticoduodenectomy and lymph node (LN) dissection.All cases were histopathologically diagnosed as ductal adenocarcinoma, stage II (25 pT3N0 cases, 35 pT3N1 cases). The following variables were investigated: age; sex; neoadjuvant therapy; adjuvant therapy; tumor size; tumor grade; invasion into the serosa, retropancreatic tissue, duodenum, bile duct, portal venous system and perineural area; cut margins; LN metastasis; and the number of invaded lymphatic vessels (LVI-score).Univariate analysis demonstrated that LN metastasis and an LVI-score ≥5 were significantly associated with poor disease-free survival. Multivariate Cox regression analysis confirmed that LN metastasis and an LVI-score ≥7 were significantly associated with poor disease-free survival. Additionally, LVI-scores ≥9 and ≥10 were comparable to or surpassed the significance of LN metastasis based on the hazard ratio. Univariate analysis demonstrated that tumor size >30 mm, duodenal invasion, LN metastasis and an LVI-score ≥2 were significantly associated with poor overall survival. Multivariate Cox regression analysis confirmed that LN metastasis and LVI-scores ≥9 and ≥10 were significantly associated with poor overall survival, and an LVI-score ≥10 was comparable to or surpassed the significance of LN metastasis based on the hazard ratio.Our study strongly suggests that a high degree of lymphatic vessel invasion is associated with a poor prognosis in patients with locally advanced, surgically resectable pancreatic head cancer.

To investigate the usefulness of shear-wave speed and dispersion slope measurements obtained, using an ultrasound elastography system in rat livers with various degrees of necroinflammation and fibrosis. A total of 25 male Sprague Dawley rats were randomly divided into 5 groups of 5 rats each: G0 (control), G1 (CCl4 injected twice a week for 1 wk), G2 (CCl4 injected four times a wk for 1 wk), G3 (CCl4 injected twice a wk for 6 wk) and G4 (CCl4 injected twice a wk for 10 wk). The shear-wave speed (m/s) and the dispersion slope ([m/s]/kHz) were measured. Histologic features (inflammation, necrosis and fibrosis) were used as reference standards. In multivariable analysis with histologic features as independent variables, the fibrosis grade was significantly related to shear-wave speed (p < 0.05) and the necrosis grade was significantly related to dispersion slope (p < 0.05). Dispersion slope is more useful than shear-wave speed for predicting the degree of necroinflammation.

組織学的に診断した非アルコール性肝疾患(NAFLD)24症例を対象として、超音波エラストグラフィによる画像パラメータと肝生検による組織学的パラメータの相関性を評価した。その結果、粘弾性に関連するshear wave(SW)speedと粘性に関連するdispersion slope、脂肪化の程度を反映する減衰値とAlanine aminotransferase、SW speedと線維化の指標であるFIB4、dispersion slopeとFIB4との間にそれぞれ有意な相関関係を認めた。また、SW speedは線維化を反映し、dispersion slopeは小葉内炎症を反映しており、減衰値は組織学的肝脂肪化と関連する傾向を認めた。SW speedとdispersion slopeはNAFLDの病態評価において有用な指標と考えられた。

PURPOSE: Shear wave elastography (SWE) has been validated in chronic hepatitis C and B; however, limited data are available in non-alcoholic fatty liver disease (NAFLD). This study aimed to evaluate the accuracy of SWE and FIB4 index for the diagnosis of fibrosis in a cohort of consecutive patients with biopsy-proven NAFLD, and to evaluate the effects of other histologic parameters on SWE measurement. METHODS: Written informed consent was obtained from all patients, and this study was approved by our internal review board and ethics committee. Seventy-one patients with histologically proven NAFLD (mean age 50.8 years ± 15.7) were examined. All patients underwent SWE (Aixplorer™; SuperSonic Imagine) and FIB4 index (based on age, aspartate aminotransferase and alanine aminotransferase levels, and platelet counts) measurements. SWE measurements were compared with the histologic features based on the NAFLD activity score and FIB4 index. RESULTS: The area under the ROC curve for the diagnosis of hepatic fibrosis stage 3 or higher was 0.821 (optimal cut-off value 13.1 kPa, sensitivity 62.5%, specificity 57.4%) for SWE and 0.822 (optimal cut-off value 1.41, sensitivity 71.9%, specificity 53.9%) for FIB4 index. The median liver stiffness values measured using SWE showed a stepwise increase with increasing hepatic fibrosis stage (P < 0.001), inflammation score (P = 0.018), and ballooning score (P < 0.001), and showed a stepwise decrease with increasing hepatic steatosis stage (P = 0.046). CONCLUSIONS: SWE and FIB4 index are useful noninvasive tools for estimating the severity of fibrosis in NAFLD patients. However, the presence of severe steatosis may affect the liver stiffness measurement, resulting in underestimations of liver fibrosis.

四塩化炭素(CCL)投与にて急性肝障害モデルと肝繊維化モデルを作製し、各種病態における粘性と弾性との関係について考察した。5週齢の雄性SDラット25匹を用い、20匹にCCLを投与して急性肝障害モデルと肝繊維化モデルを作製し、残りの5匹は正常コントロール(G0)とした。CCL2回隔日投与群急性肝障害モデルG1群(n=5)、CCL4回連日投与急性肝障害モデルG2群(n=5)、CCL週2回6週間投与肝繊維化モデルG3群、CCL週2回10週間投与肝繊維化モデルG4群とした。実験の結果より、粘弾性に関連するSW伝搬速度と、粘性のみと関連するdispersion slopeとの間には弱い相関があるものの、dispersion slopeは弾性率とは独立した指標と捉えることができた。弾性は主に肝繊維化を反映し、粘性は主に肝臓の壊死・炎症を反映することが示唆された。粘性と関連する指標であるdispersion slopeは弾性率とは独立した指標であり、肝臓の病態を評価する上で有用であると考えられた。

<p>症例は39歳男性．37歳時に食道静脈瘤破裂で他院入院の際，両側肺門リンパ節腫脹および肺野粒状影を認め，リンパ節生検で非乾酪性肉芽腫を認めたため，肺サルコイドーシスの診断となった．食道静脈瘤のフォローアップと門脈圧亢進症の原因精査目的に当科紹介となった．腹腔鏡検査では肝表面は広範に凹凸不整で辺縁は鈍であった．また肝表面には粒状の白色結節が多数見られ，肝辺縁で一部癒合し斑状であった．同時に施行した肝生検では，非乾酪性肉芽腫を認め，肝表面の所見と合わせて，肝サルコイドーシスの診断に至った．肉芽腫は門脈域に認めており，門脈の壁外性圧迫や閉塞により門脈圧亢進症を来したと推定された．ステロイドによる加療を開始し，1年近く経過しているが，肝障害は軽度改善し，食道静脈瘤は増悪なく経過している．肝サルコイドーシスに門脈圧亢進症を合併することは稀であり，腹腔鏡検査にて合併症なく診断できたので報告する．</p>

Recent tissue microarray (TMA)-based studies have shown that cell proliferation- and apoptosis-related biomarkers are associated with clinical outcomes in patients with bladder urothelial carcinoma. However, little is known about the differences in these biomarker measurements between whole mount tissue preparations and TMAs. This study aimed to elucidate the discrepancy in the measurements of Ki-67 indices (KIs) and apoptosis indices (AIs) between whole mount tissue preparations and TMAs of bladder urothelial carcinoma samples.Whole mount tissue preparations for Ki-67 immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling were made from 30 patients who underwent transurethral resection of bladder urothelial carcinoma. Digital microscopy-assisted virtual TMAs, consisting of 3 small round areas (1 or 0.6 mm in diameter), were generated from the same whole mount tissue preparations. The measurement results in highly reactive areas of biomarkers were compared between the whole mount tissue preparation- and the TMA-based methods. Bland-Altman plot analysis, regression analysis, and Kendall τ were performed to investigate differences in the measurement results, systematic biases, and correlations between biomarkers.Although the Bland-Altman plot analysis demonstrated that almost all the plots were within the limits of agreement, fixed biases were detected in the 1- and 0.6-mm TMAs for the KI (0.181 and 0.222, respectively) and the AI (0.055 and 0.063, respectively). Proportional biases were also detected in the 1- and 0.6-mm TMAs for the AI (P < 0.001 and P < 0.001, respectively). Furthermore, positive correlations between KIs and AIs were observed in whole mount tissue preparations (r = 0.260, P = 0.044) and in the 1 mm TMAs (r = 0.375, P = 0.004); however, no such correlation was observed in the 0.6 mm TMAs.Our study suggests that the measurement results for certain biomarkers of bladder urothelial carcinoma obtained from TMA-based samples can be susceptible to systematic bias, and the lack of correlation between biomarkers cannot be avoided as it is in whole mount tissue preparations. Virtual TMAs can help identify systematic bias and establish a better sampling strategy prior to performing high-throughput TMAs for biomarker studies.

A 57-year-old female was diagnosed as having primary breast cancer (invasive carcinoma of no special type), which was immunohistochemically negative for oestrogen receptor, androgen receptor and human epidermal growth factor receptor Type 2. The main tumour was 54 × 35 mm in size and was located in the internal upper area of the left breast. The tumour had markedly invaded the skin and a daughter nodule was observed in the external upper area of the ipsilateral breast. An enlarged lymph node measuring 12mm in diameter was present in the axilla and an affected parasternal lymph node was also observed. A blood test showed no abnormalities and the patient was negative for tumour markers. We performed three sessions of transcatheter arterial chemoembolization with docetaxel-loaded HepaSphere™. The treatment procedure was successfully performed in all the three sessions. No adverse events higher than Grade 3 were observed. The sizes of the primary lesion and axillary lymph node decreased to 26 × 14 mm (37% reduction) and 10mm, respectively. The parasternal lymph node completely resolved. 2 months later, left total mastectomy and axillary lymph node dissection were performed. The histopathological post-therapy effect was considered to be a mild response (Grade 1a) in the breast lesion and a complete response (Grade 3) in the axillary lymph node. The mean±standard deviation of the minor axis of the vessels embolized with spherical particles was 183.0±96.5 μm. Our results indicate that transcatheter arterial chemoembolization used together with HepaSphere can be an alternative and effective therapy for locally advanced breast cancer.

Despite exhaustive efforts to detect early-stage ovarian cancers, greater than two-thirds of patients are diagnosed at an advanced stage. Although diaphragmatic metastasis is not rare in advanced ovarian cancer patients and often precludes optimal cytoreductive surgery, little is known about the mechanisms and predictive factors of metastasis to the diaphragm. Thus, as an initial step toward investigating such factors, the present study was conducted to characterize the pathological status of ovarian cancer patients who underwent debulking surgery in combination with diaphragmatic surgery. This is a retrospective and cross-sectional study of patients who underwent debulking surgery in combination with diaphragmatic surgery at our institution between January 2005 and July 2015. Clinicopathological data were reviewed by board-certified gynecologists, pathologists, and cytopathologists. The rates of various pathological findings were investigated and compared by Fisher exact test between 2 groups: 1 group that was pathologically positive for diaphragmatic metastasis (group A) and another group that was pathologically negative for diaphragmatic metastasis (group B). Forty-six patients were included: 41 patients pathologically positive and 5 pathologically negative for diaphragmatic metastasis. The rates of metastasis to the lymph node (95.8% vs 20%, P = 0.001) and metastasis to the peritoneum except for the diaphragm (97.6% vs 60.0%, P = 0.028) were significantly increased in group A compared with group B. However, no significant differences between the 2 groups were found for rates of histological subtypes (high-grade serous or non-high-grade serous), the presence of ascites, the presence of malignant ascites, exposure of cancer cells on the ovarian surface, blood vascular invasion in the primary lesion, and lymphovascular invasion in the primary lesion. Our study demonstrated that metastasis to the lymph node and nondiaphragmatic metastasis to the peritoneum are significantly associated with metastasis to the diaphragmatic peritoneum, indicating that these factors may be pathological predictors of diaphragmatic metastasis in patients with ovarian cancer. However, as the data available are not sufficient to demonstrate the predictive power of these factors, a further comprehensive, large-scale study should be performed.

BACKGROUND: Lymphatic stomata are small lymphatic openings in the serosal membrane that communicate with the serosal cavity. Although these stomata have primarily been studied in experimental mammals, little is known concerning the presence and properties of lymphatic stomata in the adult human pleura. Thus, adult human pleurae were examined for the presence or absence of lymphatic stomata. METHODS AND RESULTS: A total of 26 pulmonary ligaments (13 left and 13 right) were obtained from 15 adult human autopsy cases and examined using electron and light microscopy. The microscopic studies revealed the presence of apertures fringed with D2-40-positive, CD31-positive, and cytokeratin-negative endothelial cells directly communicating with submesothelial lymphatics in all of the pulmonary ligaments. The apertures' sizes and densities varied from case to case according to the serial tissue section. The medians of these aperture sizes ranged from 2.25 to 8.75 μm in the left pulmonary ligaments and from 2.50 to 12.50 μm in the right pulmonary ligaments. The densities of the apertures ranged from 2 to 9 per mm(2) in the left pulmonary ligaments and from 2 to 18 per mm(2) in the right pulmonary ligaments. However, no significant differences were found regarding the aperture size (p=0.359) and density (p=0.438) between the left and the right pulmonary ligaments. CONCLUSIONS: Our study revealed that apertures exhibit structural adequacy as lymphatic stomata on the surface of the pulmonary ligament, thereby providing evidence that lymphatic stomata are present in the adult human pleura.

OBJECTIVES: Shear wave elastography is a novel noninvasive method for assessing liver fibrosis by measuring liver stiffness. This study was conducted to evaluate how pathologic changes could have an impact on measured elasticity values in both resected hepatocellular carcinomas and adjacent liver tissue. METHODS: Intraoperative shear wave elastography was performed in 7 patients who underwent liver resection at our institution; 7 hepatocellular carcinomas and adjacent liver tissue were subjected to elastographic measurements. A total of 48 circular regions of interest (ROIs; 3-8 mm in diameter) were located in the hepatocellular carcinomas (n = 37) and adjacent liver tissue (n = 11), and mean stiffness values were obtained from each ROI. All of the histologic images corresponding to the 48 ROIs after surgery were transformed into digital microscopic images by a scanning system, and histologic parameters, such as the proportions of nuclear areas, fatty areas, fibrous areas, and vessel areas, were quantitatively assessed. Relationships between the mean stiffness and the histologic parameters were investigated by the mixed effects model. RESULTS: By univariate analysis, the proportions of collagen fiber areas (P = .039), fibrous areas (P = .045), hepatocellular nuclear areas (P = .045), and nuclear areas other than hepatocellular and lymphoplasmacytic areas (P = .039) showed statistically positive associations with mean stiffness values. Multivariate analysis indicated that the proportion of collagen fiber areas was the strongest pathologic determinant of mean stiffness (P = .008), with hepatocellular nuclear areas also having a significant effect (P = .010). CONCLUSIONS: Fibrosis predictably affects elastographic estimation, but hepatocellular density (ie, hepatocellular nuclear areas) also alters elastographic assessment.

症例は41歳の女性，検診で右乳房腫瘤を指摘され当院を受診した．29歳と36歳時に右乳房E領域の乳腺多形腺腫に対して，他院で腫瘍摘出術を施行されている．身体所見では，右乳房EAB領域に境界不明瞭な2.3cmの腫瘤を触知し，針生検では，乳腺多形腺腫の再発が疑われた．病理学的に明らかな悪性所見は認めなかったため，整容性を考慮して乳頭温存乳房部分切除術を施行した．術後2年，明らかな局所再発は認めていない．多形腺腫は唾液腺に多く認める良性腫瘍であるが，乳腺原発の報告は少ない．不十分な切除に起因する局所再発や悪性転化が報告されているため，術前に乳腺多形腺腫と診断された場合は，十分な切除断端距離を確保し，腫瘍被膜を損傷しないように切除する必要がある．

45歳男。約3年前から右側頭部皮膚に腫瘤が出現し徐々に増大したため受診となった。腫瘤は直径約2.5cm大の桑実状で表面にびらんを来たしており、PET-CTで結節は不規則な集積を示しているが骨の破壊は認めない所見で、腫瘤から1.5〜2.0cm離して全摘術を施行した。腫瘤は皮膚全層におよび不規則隆起性で充実性であり、表皮は反応性に増殖して淡明な腫瘍細胞に移行している所見で、免疫組織化学的には腫瘍細胞はサイトケラチン7や34βE12で陽性で、P53は約80%以上の腫瘍細胞の核で過剰発現しているのを認める所見でありclear cell hidradenomaと診断した。術後7ヵ月で再発や転移はない。

44歳，男性。平成19年1月より誘因なく頭頂部に腫瘤が出現。同時期に右頸部にも腫瘤を自覚。近医でMRI施行し右耳下腺腫瘍を指摘され当科紹介受診。初診時，頭頂部にドーム状隆起した2.2×1.7 cmの暗紅色腫瘤と右耳下腺に直径1.5 cm大の硬結を認めた。頭部皮膚腫瘤に対して皮膚生検術を施行し，血管肉腫と診断。右耳下腺腫瘍に関し耳鼻科へ併診したが経過観察となった。皮膚悪性腫瘍摘出術，全層植皮術を施行。病理組織学的所見で切除断端陽性であり，放射線治療を追加。右耳下腺腫瘍も針生検術で血管肉腫の転移と診断，放射線を追加照射した。術後2ヵ月で多発肺転移が出現し，術後3ヵ月で肺胞出血による呼吸不全にて永眠される。家族歴で両親に血族婚あり，長兄が30歳で白血病にて他界。既往に両眼の白内障あり。また外見上は鳥様顔貌を認め，頭髪や眉毛に白髪あり。血液検査でヒアルロン酸が高値であり，Werner症候群と診断。