Publications by authors named "Atsuko Kasajima"

59 Publications

Ac2-26-Nanoparticles Induce Resolution of Intestinal Inflammation and Anastomotic Healing via Inhibition of NF-κB Signaling in a Model of Perioperative Colitis.

Inflamm Bowel Dis 2021 Jan 29. Epub 2021 Jan 29.

Technical University of Munich, School of Medicine, Department of Surgery, Munich, Germany.

Background: Although in most patients with inflammatory bowel diseases, conservative therapy is successful, a significant proportion of patients still require surgery once in their lifetime. Development of a safe perioperative treatment to dampen colitis activity without disturbance of anastomotic healing is an urgent and unmet medical need. Annexin A1 (ANXA1) has been shown to be effective in reducing colitis activity. Herein, a nanoparticle-based perioperative treatment approach was used for analysis of the effects of ANXA1 on the resolution of inflammation after surgery for colitis.

Methods: Anxa1-knockout mice were used to delineate the effects of ANXA1 on anastomotic healing. A murine model of preoperative dextran sodium sulfate colitis was performed. Collagen-IV-targeted polymeric nanoparticles, loaded with the ANXA1 biomimetic peptide Ac2-26 (Ac2-26-NPs), were synthesized and administered perioperatively during colitis induction. The effects of the Ac2-26-NPs on postoperative recovery and anastomotic healing were evaluated using the disease activity index, histological healing scores, and weight monitoring. Ultimately, whole-genome RNA sequencing of the anastomotic tissue was performed to unravel underlying molecular mechanisms.

Results: Anxa1-knockout exacerbated the inflammatory response in the healing anastomosis. Treatment with Ac2-26-NPs improved preoperative colitis activity (P < 0.045), postoperative healing scores (P < 0.018), and weight recovery (P < 0.015). Whole-genome RNA sequencing revealed that the suppression of proinflammatory cytokine and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was associated with the treatment effects and a phenotypic switch toward anti-inflammatory M2 macrophages.

Conclusions: Proresolving therapy with Ac2-26-NPs promises to be a potent perioperative therapy because it improves colitis activity and even intestinal anastomotic healing by the suppression of proinflammatory signaling.
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http://dx.doi.org/10.1093/ibd/izab008DOI Listing
January 2021

Neuroendocrine neoplasms of lung, pancreas and gut: a morphology-based comparison.

Endocr Relat Cancer 2020 11;27(11):R417-R432

Department of Pathology, Technical University Munich, Munich, Germany.

The bronchopulmonary (BP) and gastroenteropancreatic (GEP) organ systems harbor the majority of the neuroendocrine neoplasms (NENs) of the body, comprising 20 and 70% of all NENs, respectively. Common to both NEN groups is a classification distinguishing between well- and poorly differentiated NENs associated with distinct genetic profiles. Differences between the two groups concern the reciprocal prevalence of well and poorly differentiated neoplasms, the application of a Ki67-based grading, the variety of histological patterns, the diversity of hormone expression and associated syndromes, the variable involvement in hereditary tumor syndromes, and the peculiarities of genetic changes. This review focuses on a detailed comparison of BP-NENs with GEP-NENs with the aim of highlighting and discussing the most obvious differences. Despite obvious differences, the principle therapeutical options are still the same for both NEN groups, but with further progress in genetics, more targeted therapy strategies can be expected in future.
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http://dx.doi.org/10.1530/ERC-20-0122DOI Listing
November 2020

Pancreatic neuroendocrine tumors with somatostatin expression and paraganglioma-like features.

Hum Pathol 2020 08 12;102:79-87. Epub 2020 Jul 12.

Department of Pathology, Technical University of Munich, 81675, Munich, Germany. Electronic address:

A small fraction of pancreatic neuroendocrine tumors (PanNETs) shows a solid, paraganglioma-like (PG-like) histology. We wanted to know whether these PanNETs have a special hormone expression and are related to paragangliomas (PGs)/pheochromocytomas (PCs). We screened a series of 48 surgically resected PanNETs for their histological growth patterns and their association with expression of islet hormones. The PanNETs were divided into PG-like and non-PG-like tumors and immunohistochemically monitored for the expression of islet hormones, cytokeratins, and S100. The results were correlated to histological pattern, lymph node status, and data in 28 PGs/PCs, including 2 PGs attached to the pancreas. All PanNETs, in contrast to PGs/PCs, were cytokeratin positive. A PG-like growth pattern was identified in 9 of 48 PanNETs and correlated with somatostatin expression. Only half of the non-PG-like PanNETs also contained somatostatin-positive cells. Eight of 28 PGs/PCs expressed somatostatin, mostly in individual cells. PG-like PanNETs and non-PG-like PanNETs infiltrated the adjacent pancreatic tissue, whereas 2 to the pancreas-associated PGs were well demarcated. Lymph node metastases were detected in 58%, 39%, 57%, and 53% of the somatostatin-producing, somatostatin-negative, PG-like, and non-PG-like PanNETs, respectively. PG-like PanNETs, in contrast to PG/PCs, are characterized by the expression of cytokeratin and somatostatin, the development of lymph node metastasis, and the infiltration into pancreatic parenchyma. Non-PG-like PanNETs may also express somatostatin and show lymph node metastases to the same extent. A literature review of cases reported as PG of the pancreas reveals that only a small fraction of these tumors probably represents true pancreatic PGs.
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http://dx.doi.org/10.1016/j.humpath.2020.07.004DOI Listing
August 2020

p16 in highly malignant esophageal carcinomas: the correlation with clinicopathological factors and human papillomavirus infection.

Virchows Arch 2020 Jun 16. Epub 2020 Jun 16.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

p16 is generally considered to be a surrogate maker of human papillomavirus (HPV) infection and also a predictive marker of favorable clinical outcome of patients with squamous cell carcinoma of the oropharynx. p16 overexpression is also known to be induced by deregulation of RB1 in neuroendocrine carcinomas. In highly malignant esophageal neoplasms, however, the status of p16 has remained largely unknown. We immunolocalized p16 and Rb1 in 82 surgically resected esophageal high-grade squamous cell carcinomas (46 poorly differentiated and 36 basaloid squamous cell carcinomas) and 15 esophageal small-cell carcinomas in order to clarify the clinical and biological significance of p16. p16 immunoreactivity was detected in 7/82 (9%) high-grade squamous cell carcinomas and 15 (100%) small-cell carcinomas. p16 immunoreactivity was significantly associated with Rb1 protein loss in both groups (P < 0.001). HPV was detected in none of the p16-positive cases examined. Clinical outcome of the p16-positive high-grade squamous cell carcinomas was not different from that of the p16-negative counterparts (P = 0.687) but significantly better than those with the small-cell carcinomas (P = 0.023). p16 was therefore considered to be induced through an inactivation of the RB1 signaling pathway and not through HPV infection in highly malignant esophageal neoplasms. Nevertheless, patients' clinical outcome of these neoplasms significantly differs; therefore, small-cell carcinomas have to be carefully differentiated from other neoplasms. In addition, p16 overexpression is not predictive of favorable clinical outcome in high-grade squamous cell carcinomas of the esophagus.
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http://dx.doi.org/10.1007/s00428-020-02865-xDOI Listing
June 2020

Progesteron receptor expression in insulin producing cells of neuroendocrine neoplasms.

J Steroid Biochem Mol Biol 2020 07 11;201:105694. Epub 2020 May 11.

Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan.

Progesterone receptor (PgR) inhibits cell proliferation in pancreatic neuroendocrine neoplasms (PanNEN). In non-neoplastic pancreas, loss of PgR induces β-cell proliferation and insulin production. However, detailed association between PgR and insulin producing PanNENs is poorly understood. Insulin, proinsulin, and PgR were immunolocalized in 82 PanNENs (54 non-functioning PanNENs: NF-PanNENs and 28 insulinomas). The status of immunoreactivity was compared to the clinicopathological factors of the patients. Immunoreactivity was also confirmed by employing the double-immunohistochemistry. These results were also compared with those in non-neoplastic Langerhans islets. PgR immunoreactivity was significantly higher in insulinomas than that in NF-PanNENs (p < 0.001). Insulin and proinsulin immunoreactivity was also detected in 20 (37 %) of (single cell) insulin positive NFs (Ins-NF-PanNEN), in which PgR expression was higher than in insulin negative NF-PanNENs (Ins-NF-PanNEN, p = 0.03). The ratio of PgR-insulin double positive cells to overall insulin positive cells, as well as PgR-proinsulin double positive cells to proinsulin positive cells, was detected to the same degree in insulinoma (PgR-insulin 70 %, PgR-proinsulin 66 %), Ins-NF-PanNENs (PgR-insulin 65 %, PgR-proinsulin 68 %) and normal islet (PgR-insulin 80 %, PgR-proinsulin 72 %). PgR and insulin expressing cells colocalize in tumor cells of the PanNENs regardless of the hormone-related symptoms of the patients. Inhibitory effect of PgR on tumor cells might be associated with the favourable clinical outcome of insulinoma patients.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105694DOI Listing
July 2020

Annexin A1 Expression Capacity as a Determinant for Disease Severity in Crohn's Disease.

Dig Dis 2020 20;38(5):398-407. Epub 2020 Mar 20.

Department of Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany,

Introduction: Crohn's disease (CD) is characterized by relapsing intestinal inflammation. The anti-inflammatory protein annexin A1 (ANXA1) has been linked to inflammatory processes in the gut.

Objective: To examine ANXA1 expression patterns in the inflamed intestine of patients with CD and associate ANXA1 expression capacity with disease characteristics.

Methods: Surgical specimens of patients with CD operated between 2003 and 2015 were examined. Immunohistochemistry and immunofluorescence were performed to delineate ANXA1 expression. Those with pronounced ANXA1 expression were included in further analysis by qPCR. ANXA1 mRNA expression ratio of the inflamed to non-inflamed tissue was determined and defined as expression capacity of the tissue. Depending on their expression capacity, patients were divided into 2 groups (ANXA1-low vs. ANXA1-high), which were associated with clinical characteristics.

Results: Immunohistochemical ANXA1 expression was localized in inflamed regions of the intestine. In immunofluorescence, ANXA1 costained with myeloperoxidase as neutrophil marker, CD4 and CD8 as T cell marker but not CD20 as B cell marker or CD68 as macrophage marker. In qPCR, ANXA1 mRNA expression was upregulated by 20-fold in inflamed to noninflamed tissues. Patients with higher intrinsic ANXA1 expression capacity had significantly less severity of inflammation. Furthermore, the ANXA1-high group had significantly more locally restricted disease (p = 0.0070), more stricturating disease (p = 0.0037), and was less frequently treated by preoperative steroid therapy (p = 0.030).

Conclusions: ANXA1 expression was strongly associated with intestinal inflammation and expressed in T cells and neutrophils of the CD tissues. Patients with higher intrinsic ANXA1 expression capacity of the inflamed tissue presented milder inflammatory changes and indolent clinical course.
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http://dx.doi.org/10.1159/000505910DOI Listing
October 2020

Classification and Prognostic Stratification of Bronchopulmonary Neuroendocrine Neoplasms.

Neuroendocrinology 2020 19;110(5):393-403. Epub 2019 Aug 19.

Department of Pathology, Technical University Munich, Munich, Germany.

The accuracy and reproducibility of the World Health Organization (WHO) 2015 classification of bronchopulmonary neuroendocrine neoplasms (BP-NENs) is disputed. The aim of this study is to classify and grade BP-NENs using the WHO 2019 classification of digestive system NENs (DiS-NEN-WHO 2019), and to analyze its accuracy and prognostic impact. Two BP-NEN cohorts from Japan and Germany, 393 tumors (88% surgically resected), were reviewed and the clinicopathological data of the resected tumors (n = 301) correlated to patients' disease-free survival (DFS). The DiS-NEN-WHO 2019 stratified the 350 tumors into 91 (26%) neuroendocrine tumors (NET) G1, 52 (15%) NET G2, 15 (4%) NET G3, and 192 (55%) neuroendocrine carcinomas (NEC). NECs, but not NETs, were immunohistochemically characterized by abnormal p53 (100%) and retinoblastoma 1 (83%) expression. The Ki67 index, which was on average 4 times higher than mitotic count (p < 0.0001), was prognostically more accurate than the mitotic count. NET G3 patients had a worse outcome than NET G1 (p < 0.01) and NET G2 patients (p = 0.02), respectively. No prognostic difference was detected between NET G3 and NEC patients after 5 year DFS. It is concluded that stratifying BP-NEN patients according to the DiS-NEN-WHO 2019 classification results in 3 prognostically well-defined NET groups, if grading is solely based on Ki67 index. Mitotic count alone may underestimate malignant potential of NETs.
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http://dx.doi.org/10.1159/000502776DOI Listing
February 2021

A comparative analysis of clinicopathological factors between esophageal small cell and basaloid squamous cell carcinoma.

Medicine (Baltimore) 2019 Feb;98(8):e14363

Department of Gastroenterological Surgery.

Esophageal small cell carcinoma (E-SmCC) and basaloid squamous cell carcinomas (BSCCs) are both highly aggressive malignancies, but their detailed differences in clinical behaviors have remained virtually unknown. In addition, treatment strategies of the patients with E-SmCC have not been established. 29 cases of E-SmCC and 39 with BSCC were examined in this study to clarify the clinical features and outcome of the patients with E-SmCC and to compare the findings with those of BSCC. E-SmCCs presented a more advanced status than BSCC (TNM Stage: P = .002). Esophagectomy was performed in 15 small cell carcinoma patients and 14 were treated with non-surgical/systemic therapy. The clinical outcome of the small cell carcinoma cases was significantly worse than those with BSCC (P = .001), but results of a stage-stratified analysis revealed that the Stage I small cell carcinoma patients presented favorable prognosis (3-year survival rate 100%, n = 4). In contrast, among those with Stage II-IV, clinical outcome tended to be better in the systemic therapy group (3-year survival rate 49%, n = 13) than the surgically treated group (3-year survival rate 0%, n = 12). E-SmCC was a more aggressive neoplasm than BSCC. However, early detection could possibly improve the clinical outcome of patients with E-SmCC. Systemic therapy could also benefit the patients with advanced disease (Stage II-IV).
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http://dx.doi.org/10.1097/MD.0000000000014363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408094PMC
February 2019

Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index > 20.

Neuroendocrinology 2019 28;108(2):109-120. Epub 2018 Nov 28.

Department of Pathology, Technical University Munich, Munich, Germany.

The clinicopathological features of lung neuroendocrine neoplasms (NEN) with a high proliferative index at the border area between atypical carcinoid and neuroendocrine carcinoma have not been investigated so far. The aim of this study was, therefore, to search for lung NENs which are well differentiated but show Ki67 values that overlap with those of poorly differentiated (PD)-NENs. Resected lung NENs from 244 Japanese patients were reviewed, and Ki67 indices were assessed in all tumors. The data were then correlated to clinicopathological parameters and patient outcome. Among 59 (24%) well-differentiated (WD)-NENs and 185 (76%) lung PD-NENs, 7 were defined as WD-NENs with Ki67 indices > 20%. The Ki67 indices of these tumors (mean 29%, range 24-36) were significantly lower than those of PD-NENs (mean 74%, range 34-99). All WD-NENs with Ki67 > 20% lacked abnormal p53 and loss of retinoblastoma 1 (Rb1) expression. In contrast, many PD-NENs expressed p53 (48%) and showed loss of Rb1 (86%). The 2- and 5-year disease-free survival rates in WD-NEN patients with Ki67 > 20% were lower than those of WD-NEN patients with Ki67 ≤20% (p < 0.01 for disease-free and overall survival). No statistical differences were detected between outcome of WD-NEN patients with Ki67 > 20% and those of PD-NEN. It is concluded that WD-NEN patients with Ki67 > 20% share the morphological and immunohistochemical features of WD-NEN patients with Ki67 ≤20%, but they have a worse prognosis, suggesting that this tumor group requires particular attention in future classifications and probably new therapeutic regimes.
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http://dx.doi.org/10.1159/000495806DOI Listing
December 2019

Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3.

Hum Pathol 2018 07 26;77:70-79. Epub 2018 Mar 26.

Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address:

Pancreatic neuroendocrine carcinoma is a rare aggressive tumor commonly harboring TP53 and RB1 alterations and lacking neuroendocrine-related genetic changes such as mutations in MEN1 and ATRX/DAXX. Little is known about its genetic profile with regard to that of pancreatic ductal adenocarcinoma. We therefore conducted a detailed genetic study in 12 pancreatic neuroendocrine carcinomas of large cell (n = 9) and small cell type (n = 3) using massive parallel sequencing applying a 409-gene panel on an Ion Torrent system. The genetic data were compared with known data of pancreatic ductal adenocarcinoma and correlated with exocrine lineage marker expression. A similar analysis was performed in 11 pancreatic neuroendocrine tumors G3. Neuroendocrine carcinomas harbored 63 somatic mutations in 45 different genes, affecting most commonly TP53 (8/12 cases), KRAS (5/12 cases), and RB1 (loss of expression with or without deletion in 4/12 cases). Five carcinomas had both TP53 and KRAS mutations. Neuroendocrine tumors G3 only shared singular mutations in 5 different genes with neuroendocrine carcinomas, including TP53, CDKN2A, ARID1A, LRP1B, and APC, affecting 5 different cases. Most KRAS-positive neuroendocrine carcinomas also expressed MUC1 (4/5) and carcinoembryonic antigen (3/5) as markers of ductal differentiation. Our data indicate that almost half of the pancreatic neuroendocrine carcinomas are genetically and phenotypically related to pancreatic ductal adenocarcinoma, and might therefore respond to chemotherapies targeting the latter carcinomas.
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http://dx.doi.org/10.1016/j.humpath.2018.03.018DOI Listing
July 2018

Progesterone arrested cell cycle progression through progesterone receptor isoform A in pancreatic neuroendocrine neoplasm.

J Steroid Biochem Mol Biol 2018 04 11;178:243-253. Epub 2018 Jan 11.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

In pancreatic neuroendocrine neoplasms (Pan-NEN) progesterone signaling has been shown to have both inhibitory and stimulatory effects on cell proliferation. The ability of progesterone to inhibit tumor proliferation is of particular interest and is suggested to be mediated through the less abundantly expressed progesterone receptor (PR) isoform A (PRA). To date the mechanistic processes underlying this inhibition of proliferation remain unclear. To examine the mechanism of PRA actions, the human Pan-NEN cell line QGP-1, that endogenously expresses PR isoform B (PRB) without PRA, was transfected with PRA. PRA transfection suppressed the majority of cell cycle related genes increased by progesterone including cyclin A2 (CCNA2), cyclin B1 (CCNB1), cyclin-dependent kinase 1 (CDK1) and cyclin-dependent kinase 2 (CDK2). Importantly, following progesterone administration cell cycle distribution was shifted to S and G2/M phases in the naïve cell line but in PRA-transfected cells, this effect was suppressed. To see if these mechanistic insights were confirmed in patient samples PRA, PRB, CCNA2, CCNB, CDK1 and CDK2 immunoreactivities were assessed in Pan-NEN cases. Higher levels of cell cycle markers were associated with higher WHO grade tumors and correlations between the markers suggested formation of cyclin/CDK activated complexes in S and G2/M phases. PRA expression was associated with inverse correlation of all cell cycle markers. Collectively, these results indicate that progesterone signals through PRA negatively regulates cell cycle progression through suppressing S and G2/M phases and downregulation of cell cycle phases specific cyclins/CDKs.
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http://dx.doi.org/10.1016/j.jsbmb.2018.01.003DOI Listing
April 2018

Inflammation and PD-L1 expression in pulmonary neuroendocrine tumors.

Endocr Relat Cancer 2018 03 11;25(3):339-350. Epub 2018 Jan 11.

Department of PathologyTechnical University Munich, Munich, Germany.

In the light of novel cancer immune therapies, the status of antitumor inflammatory response and its regulation has gained much attention in patients with lung cancer. Ample datasets exist for non-small-cell lung cancer, but those for pulmonary neuroendocrine tumors are scarce and controversial. Here, tumor-associated inflammation, CD8+ cell infiltration and PD-L1 status were evaluated in a cohort of 57 resected carcinoids and 185 resected neuroendocrine carcinomas of the lung (58 large cell carcinomas and 127 small cell carcinomas). Data were correlated with clinicopathological factors and survival. Moderate or high tumor-associated inflammation was detected in 4 carcinoids (7%) and in 37 neuroendocrine carcinomas (20%). PD-L1 immunoreactivity was seen in immune cells of 73 (39%) neuroendocrine carcinomas, while tumor cells were labeled in 21 (11%) cases. Inflammatory cells and tumor cells in carcinoids lacked any PD-L1 expression. In neuroendocrine carcinomas, PD-L1 positivity in immune cells, but not in tumor cells, was associated with intratumoral CD8+ cell infiltration ( < 0.001), as well as with the severity of tumor-associated inflammation ( < 0.001). In neuroendocrine carcinomas, tumor-associated inflammation and PD-L1 positivity in immune cells correlated with prolonged survival and the latter factor was also an independent prognosticator ( < 0.01, hazard ratio 0.4 for overall survival,  < 0.001 hazard ratio 0.4 for disease-free survival). Taken together, in neuroendocrine tumors, antitumor inflammatory response and PD-L1 expression are largely restricted to neuroendocrine carcinomas, and in this tumor entity, PD-L1 expression in inflammatory cells is positively correlated to patient survival.
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http://dx.doi.org/10.1530/ERC-17-0427DOI Listing
March 2018

High interlaboratory and interobserver agreement of somatostatin receptor immunohistochemical determination and correlation with response to somatostatin analogs.

Hum Pathol 2018 02 24;72:144-152. Epub 2017 Nov 24.

Department of Oncology, University of Turin at San Luigi Hospital, Orbassano, 10043 Turin, Italy. Electronic address:

Monoclonal antibodies to somatostatin receptors 2A (SSTR2A, UMB-1) and 5 (SSTR5, UMB-4) were reported to be highly reliable for immunohistochemical detection of these receptors in neuroendocrine neoplasms. However, the standardization of either the immunohistochemical procedure and the methods of evaluation has yet to be established. Fifty-two tissues from 38 patients with neuroendocrine neoplasm were retrieved from 2 institutions in Italy and Japan. The tissues were immunostained using 3 staining methodologies: 1 automated and 2 manual protocols from the Italian and Japanese institutions. The slides were independently evaluated by 3 observers (2 experienced pathologists and 1 medical student) using 3 scoring systems (Volante-Score, HER2-Score, and H-Score). The scores obtained from the staining methods were highly correlated with each other (r>0.85, P<.0001). Especially, the Volante- and HER2-Scores were highly concordant (r≥0.95, P≤.0001). Very high interobserver agreement was obtained irrespective of the method used and the experience of the evaluator, with the best concordance obtained by experienced pathologists evaluating automated system-stained slides (SSTR2A, r>0.97; SSTR5, r>0.96). HER2- and H-Scores were reliable to represent the characteristics of the patients. SSTR2A expression evaluated by the HER2-Score was significantly associated with clinical efficacy to somatostatin analogs (P=.04). SSTRs determination is an easily standardizable tool in different laboratories and is highly reproducible irrespective of the method of evaluation used. Given the positive association with clinical efficacy to somatostatin analogs, as well as the simple and widespread use, HER2-Score can be proposed as a standard evaluation procedure of SSTR2A and SSTR5 expression in neuroendocrine neoplasms.
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http://dx.doi.org/10.1016/j.humpath.2017.11.008DOI Listing
February 2018

Pancreatic gangliocytic paraganglioma harboring lymph node metastasis: a case report and literature review.

Diagn Pathol 2017 Aug 2;12(1):57. Epub 2017 Aug 2.

Department of Pathology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.

Background: Gangliocytic paraganglioma (GP) is a rare neuroendocrine neoplasm, which occurs mostly in the periampullary portion of the duodenum; the majority of the reported cases of duodenal GP has been of benign nature with a low incidence of regional lymph node metastasis. GP arising from the pancreas is extremely rare. To date, only three cases have been reported and its clinical characteristics are largely unknown.

Case Presentation: A nodule located in the pancreatic head was incidentally detected in an asymptomatic 68-year-old woman. Computed tomography revealed 18-, 8-, and 12-mm masses in the pancreatic head, the pancreatic tail, and the left adrenal gland, respectively. Subsequent genetic examination revealed an absence of mutations in the MEN1 and VHL genes. Macroscopically, the tumor located in the pancreatic head was 22 mm in size and displayed an ill-circumscribed margin along with yellowish-white color. Microscopically, it was composed of three cell components: epithelioid cells, ganglion-like cells, and spindle cells, which led to the diagnosis of GP. The tumor was accompanied by a peripancreatic lymph node metastasis. The tumor in the pancreatic tail was histologically classified as a neuroendocrine tumor (NET) G1 (grade 1, WHO 2010), whereas the tumor in the left adrenal gland was identified as an adrenocortical adenoma. The patient was disease-free at the 12-month follow-up examination.

Conclusions: Pancreatic GP is associated with a higher incidence of metastasis and larger tumor size than duodenal GPs, suggesting that the primary organ of GP is an important prognostic factor.
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http://dx.doi.org/10.1186/s13000-017-0648-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540335PMC
August 2017

The Risk Factors for Metastasis in Non-Ampullary Duodenal Neuroendocrine Tumors Measuring 20 mm or Less in Diameter.

Digestion 2017 18;95(3):201-209. Epub 2017 Mar 18.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background/aims: The treatment strategy for non-ampullary duodenal neuroendocrine tumors (NAD-NETs) ≤20 mm in diameter has not been established. In this study, we aimed to evaluate the detailed characteristics of NAD-NETs ≤20 mm in diameter to clarify the risk factors of subsequent metastasis.

Methods: The patients with NAD-NETs ≤20 mm in diameter who had been treated at 12 institutions between 1992 and 2013 were enrolled. Clinical records were retrieved, and histopathological findings of all cases were centrally reviewed by 2 pathologists.

Results: We studied 49 patients with a mean follow-up period of 66.5 months. Thirty-five patients were initially treated with endoscopic resection (ER), and 14 with surgery. A univariate analysis revealed the ORs and 95% CIs of the risk factors for metastasis were lymphovascular invasion (12.5 [2.01-77.9]), multiple tumors (9.75 [1.46-65.4]), a tumor size of 11-20 mm (6.67 [1.21-36.6]), and World Health Organization grade G2 (7.13 [1.16-43.9]). Five-year overall and disease-specific survival rates were 86.1 and 97.2%, respectively.

Conclusion: This is the first study to demonstrate the risk factors of metastasis in NAD-NETs ≤20 mm in diameter. These findings may be helpful for determining the appropriate therapeutic approach and the clinical strategy of treatment following ER.
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http://dx.doi.org/10.1159/000459619DOI Listing
February 2018

SOX2 and Rb1 in esophageal small-cell carcinoma: their possible involvement in pathogenesis.

Mod Pathol 2017 05 20;30(5):660-671. Epub 2017 Jan 20.

Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan.

Clinicopathological features and pathogenesis of esophageal small-cell carcinoma remain unclear. We hypothesized common cellular origin and pathogenesis in small-cell carcinoma of esophagus and lung associated with SOX2 overexpression and loss of Rb1. Expression of squamous-basal markers (CK5/6 and p40), glandular markers (CK18 and CEA), SOX2, and Rb1 were evaluated in 15 esophageal small-cell carcinomas, 46 poorly differentiated squamous cell carcinomas, and 88 small-cell lung carcinoma, as well as 16 embryonic esophagus. Esophageal small-cell carcinoma expressed higher levels of glandular markers and lower levels of squamous-basal markers than poorly differentiated squamous cell carcinoma. No significant differences were observed in immunohistochemistry profiles between small-cell carcinoma of the esophagus and the lung. SOX2 expression was high in esophageal small-cell carcinoma (70%±33% of nuclei), small-cell lung carcinoma (70%±26%), and the embryonic esophagus (75%±4%), and it was significantly lower in poorly differentiated squamous cell carcinoma (29%±28%). Rb1 expression was significantly lower in esophageal small-cell carcinoma (0.3%±1%), small-cell lung carcinoma (2%±6%), and the embryonic esophagus (7%±5%), and it was significantly higher in poorly differentiated squamous cell carcinoma (51%±24%). The immunohistochemistry profiles of small-cell carcinoma of the esophagus and the lung are highly similar. The loss of Rb1 function is a key contributor to the pathogenesis of both neoplasms. In addition, SOX2 overexpression observed in esophageal and lung small-cell carcinoma as well as in the embryonic esophagus indicated that esophageal small-cell carcinoma may arise from embryonic-like stem cells in the esophageal epithelium. The two distinct differentiation patterns (neuroendocrine and glandular) of esophageal small-cell carcinoma further support the fact that SOX2 has a pivotal role in the differentiation of pluripotent stem cells into esophageal small-cell carcinoma cells.
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http://dx.doi.org/10.1038/modpathol.2016.222DOI Listing
May 2017

Quantitative Analysis of Contrast-Enhanced Ultrasound Imaging in Invasive Breast Cancer: A Novel Technique to Obtain Histopathologic Information of Microvessel Density.

Ultrasound Med Biol 2017 03 29;43(3):607-614. Epub 2016 Dec 29.

Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, Sendai, Japan.

We examined whether enhancement area ratios obtained by the new bubble detection method correlate with histologic microvessel density in invasive breast cancer. Forty consecutive patients with invasive breast cancer lesions underwent contrast-enhanced ultrasound. The ratio of enhanced area to manually segmented tumor area (enhancement area ratio) was obtained with the new method at peak and delayed phases (50-54, 55-59, 60-64 and 65-69 s). We also analyzed time-intensity curves to obtain peak intensity and area under curve. Enhancement area ratios in both peak and delayed phases (50-54, 55-59, 60-64 and 65-69 s) were significantly correlated with microvessel density (r = 0.57, 0.62, 0.68, 0.61 and 0.58; p = 0.0001, <0.0001, <.0001, <.0001 and 0.0001, respectively). In time-intensity curve analysis, peak intensity was significantly correlated (r = 0.43, p = 0.0073), whereas area under the curve was not (r = 0.29, p = 0.0769). Enhancement area ratios obtained by the new method were correlated with microvessel density in invasive breast cancer.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2016.11.009DOI Listing
March 2017

Advances in the diagnosis and treatment of pancreatic neuroendocrine neoplasms in Japan.

J Gastroenterol 2017 Jan 18;52(1):9-18. Epub 2016 Aug 18.

Neuroendocrine Tumor Center, Kansai Electric Power Hospital, Osaka, Japan.

Several new developments have occurred in the field of pancreatic neuroendocrine neoplasm (PNEN) recently in Japan. First, the utility of chromogranin A (CgA), useful for the diagnosis and monitoring of the treatment response of neuroendocrine neoplasm (NEN), has been demonstrated in Japan. For PNEN diagnosis and treatment, grading and correct histological diagnosis according to the WHO 2010 classification is important. Regarding the histological diagnosis, the advent of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has enabled correct pathological diagnosis and suitable treatment for the affected tissue. Furthermore, EUS-FNA has also facilitates the assessment of the presence or absence of gene mutations. In addition, patients who have a well-differentiated neuroendocrine tumor (NET) showing a Ki-67 index of higher than 20 % according to the WHO 2010 classification, have also been identified, and their responses to treatment were found to be different from those of patients with poorly differentiated neuroendocrine carcinoma (NEC). Therefore, the concept of NET G3 was proposed. Additionally, somatostatin receptor type 2 is expressed in several cases of NET, and somatostatin receptor scintigraphy (In-octreoscan) has also been approved in Japan. This advancement will undoubtedly contribute to the localization diagnosis, the identification of remote metastasis, and assessments of the treatment responses of PNEN. Finally, regarding the treatment strategy for PNEN, the management of liver metastasis is important. The advent of novel molecular-targeted agents has dramatically improved the prognosis of advanced PNEN. Multimodality therapy that accounts for the tumor stage, degree of tumor differentiation, tumor volume, and speed of tumor growth is required.
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http://dx.doi.org/10.1007/s00535-016-1250-9DOI Listing
January 2017

A case of pulmonary adenocarcinoma harboring osteoclast-like giant cells: Its evaluation by immunohistochemical and genetic analyses.

Pathol Int 2016 Apr 3;66(4):224-9. Epub 2016 Mar 3.

Department of Pathology, Tohoku University School of Medicine, Miyagi, Japan.

Tumors harboring osteoclast-like giant cells (OGCs) at extraosseous site are extremely rare. These rare tumors have been detected most frequently in the pancreas and few pulmonary tumors harboring OGCs have been previously reported. In addition, the genetic profiles of these tumors have remained virtually unknown. Therefore, we report a case of pulmonary adenocarcinoma harboring OGCs in which k-ras mutation and immunohistochemical study of proteins associated with OGCs were examined. The case was a 70-year-old man, who demonstrated a pulmonary mass associated with unusual radiological features. Histopathologically, three different cell types, mucinous adenocarcinoma cell, OGC and mononuclear cell were detected. OGCs were immunohistochemically negative for epithelial markers and positive for histiocytic markers but mononuclear cells were immunopositive for epithelial markers. In addition, both mononuclear and adenocarcinoma cells had the same k-ras mutation profiles and mononuclear cells were immunohistochemically positive for macrophage colony-stimulating factor (M-CSF), one of the factors associated with OGC differentiation. Therefore, mononuclear cells were considered to be derived from neoplastic epithelium and OGCs could represent non-neoplastic cells. In addition, M-CSF locally produced could promote the differentiation of OGCs.
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http://dx.doi.org/10.1111/pin.12395DOI Listing
April 2016

A Calcitonin Non-producing Neuroendocrine Tumor of the Thyroid Gland.

Endocr Pathol 2016 Dec;27(4):325-331

Department of Pathology, Tohoku University Hospital, Sendai, Japan.

Neuroendocrine tumors of the thyroid gland are generally considered to derive from parafollicular endocrine cells (C cells) and are generally referred to as medullary thyroid carcinomas (MTC). Calcitonin secretion is almost always detected in MTC and a prerequisite for both clinical and pathological diagnosis. Thyroid neuroendocrine tumors without any apparent calcitonin secretion reflect a diagnostic dilemma because non-calcitonin-producing MTCs have virtually not been characterized. Here, we report a case of primary thyroid neuroendocrine tumors lacking calcitonin secretion or expression. The tumor cells expressed cytokeratins, chromogranin A, and synaptophysin, all of which were consistent with epithelial and neuroendocrine differentiation. Thyroid transcription factor-1 paired box gene 8, and carcinoembryonic antigen were also immunohistochemically detected, consistent with its thyroid origin. However, the tumor was negative for calcitonin both by immunohistochemistry and in situ hybridization, hence, not meeting the definition of MTC. Despite the loss of calcitonin expression, immunoreactivity for the calcitonin-gene-related peptide was detected in the tumor. Somatic gene mutations of RET, H-RAS, K-RAS, or BRAF were not detected in this case. A limited number of calcitonin non-producing thyroid neuroendocrine tumors are available in the scientific literature available in English, and its etiology and clinical manifestations remain largely unknown. Our case, along with the rare, previously reported cases, suggests that calcitonin non-producing neuroendocrine tumors of the thyroid gland are most likely derived from C cells, but should be differentiated from ordinary MTCs.
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http://dx.doi.org/10.1007/s12022-016-9416-9DOI Listing
December 2016

Erratum to: Peritumoral apparent diffusion coefficients for prediction of lymphovascular invasion in clinically node-negative invasive breast cancer.

Eur Radiol 2016 Feb;26(2):340-1

Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, Seiryo 1-1, Sendai, 980-8574, Japan.

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http://dx.doi.org/10.1007/s00330-015-3888-8DOI Listing
February 2016

Peritumoral apparent diffusion coefficients for prediction of lymphovascular invasion in clinically node-negative invasive breast cancer.

Eur Radiol 2016 Feb 30;26(2):331-9. Epub 2015 May 30.

Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, Seiryo 1-1, Sendai, 980-8574, Japan.

Objectives: To evaluate whether visual assessment of T2-weighted imaging (T2WI) or an apparent diffusion coefficient (ADC) could predict lymphovascular invasion (LVI) status in cases with clinically node-negative invasive breast cancer.

Materials And Methods: One hundred and thirty-six patients with 136 lesions underwent MRI. Visual assessment of T2WI, tumour-ADC, peritumoral maximum-ADC and the peritumour-tumour ADC ratio (the ratio between them) were compared with LVI status of surgical specimens.

Results: No significant relationship was found between LVI and T2WI. Tumour-ADC was significantly lower in the LVI-positive (n = 77, 896 ± 148 × 10(-6) mm(2)/s) than the LVI-negative group (n = 59, 1002 ± 163 × 10(-6) mm(2)/s; p < 0.0001). Peritumoral maximum-ADC was significantly higher in the LVI-positive (1805 ± 355 × 10(-6) mm(2)/s) than the LVI-negative group (1625 ± 346 × 10(-6) mm(2)/s; p = 0.0003). Peritumour-tumour ADC ratio was significantly higher in the LVI-positive (2.05 ± 0.46) than the LVI-negative group (1.65 ± 0.40; p < 0.0001). Receiver operating characteristic curve analysis revealed that the area under the curve (AUC) of the peritumour-tumour ADC ratio was the highest (0.81). The most effective threshold for the peritumour-tumour ADC ratio was 1.84, and the sensitivity, specificity, positive predictive value and negative predictive value were 77% (59/77), 76% (45/59), 81% (59/73) and 71% (45/63), respectively.

Conclusions: We suggest that the peritumour-tumour ADC ratio can assist in predicting LVI status on preoperative imaging.

Key Points: • Tumour ADC was significantly lower in LVI-positive than LVI-negative breast cancer. • Peritumoral maximum-ADC was significantly higher in LVI-positive than LVI-negative breast cancer. • Peritumour-tumour ADC ratio was significantly higher in LVI-positive breast cancer. • Diagnostic performance of the peritumour-tumour ADC ratio was highest for positive LVI. • Peritumour-tumour ADC ratio showed higher diagnostic ability in postmenopausal than premenopausal patients.
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http://dx.doi.org/10.1007/s00330-015-3847-4DOI Listing
February 2016

Review of renal cell carcinoma with rhabdoid features with focus on clinical and pathobiological aspects.

Pol J Pathol 2015 Mar;66(1):3-8

Naoto Kuroda MD, Department of Pathology, Kochi Red Cross Hospital, Shin-honmachi 2-13-51, Kochi City,, Kochi 780-8562, Japan, tel. +81-88-822-1201, fax +81-88-822-1056, e-mail:

Rhabdoid morphology in renal cell carcinoma (RCC) may, like sarcomatoid change, be perceived as a type of dedifferentiation, and is a poor prognostic factor. Histologically, rhabdoid neoplastic cells are round to polygonal cells with globular eosinophilic cytoplasmic inclusions and eccentric vesicular nuclei and enlarged nucleoli. All types of RCC, including clear cell, papillary, chromophobe, collecting duct carcinoma, renal medullary carcinoma, acquired cystic disease-associated RCC, ALK-positive renal cancer and unclassified RCC, may display a variably prominent rhabdoid phenotype. Immunohistochemically, the cytoplasm of rhabdoid cells shows positivity for vimentin and/or cytokeratin. Ultrastructurally, cytoplasmic whorls/aggregates of intermediate filaments correspond to light microscopically observed inclusions. Genetically, a previous report suggests that combined loss of BAP1 and PBRM1 may be associated with rhabdoid morphology. As with sarcomatoid change, pathologists should describe, estimate and state the proportion of tumor cells with a rhabdoid phenotype in the routine pathology report of RCC.
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http://dx.doi.org/10.5114/pjp.2015.51147DOI Listing
March 2015

Precise preoperative localization of prostate cancer employing 12-core needle biopsy with a tissue-marking method for effective surgical strategy.

Tohoku J Exp Med 2015 05;236(1):55-61

Department of Pathology, Tohoku University Hospital.

Prostate needle biopsy plays a pivotal role not only in the diagnosis but also the management of patients with prostate cancer. Prostate cancer is often multifocal and diagnosis of the lesion could therefore be difficult with diagnostic imaging only; thus, multiple core biopsies are taken from several different regions of the prostate. In current practice, 10- or 12-core needle biopsy is considered the clinical standard. Several techniques have been reported to improve the orientation of the specimens, but tissue marking, which could theoretically provide important information on the location of the lesion in the prostate, has been rarely reported. Therefore, in this study, we evaluated the clinical significance of systematic 12-core needle biopsy with tissue marking for preoperative prediction of lesion sites and clinicopathological features of patients. We evaluated 93 patients who underwent 12-core prostate biopsy and subsequent radical prostatectomy. We correlated the biopsy results to the prostate sites in which biopsies were performed and prognostic factors of the patients, especially the degree of extraprostatic extension (EPE) obtained in surgical specimens. Among 253 cancer foci detected in 93 prostatectomy specimens, 168 (66.4%) foci were detected by biopsy. All patients had proven cancer. EPE-positive cancers were associated with a larger number of positive cores, larger tumor length, and higher percentage of cancer tissue in the corresponding cores. Systematic 12-core prostate biopsy with tissue marking is useful for preoperative detection of cancer foci and provides valuable information that enables effective surgical strategies.
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http://dx.doi.org/10.1620/tjem.236.55DOI Listing
May 2015

[WHO classification of pancreatic neuroendocrine tumor: overview].

Nihon Rinsho 2015 Mar;73 Suppl 3:321-6

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March 2015

Progesterone Receptor Isoforms A and B in Pancreatic Neuroendocrine Tumor.

Neuroendocrinology 2015 16;101(4):309-20. Epub 2015 Mar 16.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: Pancreatic neuroendocrine tumors (PNETs) have been reported to express progesterone receptor (PR), and its expression has been demonstrated to be a favorable prognostic factor in these patients. We examined the status of the PR isoforms PRA and PRB in the human PNET cell line and their association with cell proliferation of the tumor cells, which is closely related to the clinical outcome of PNET patients.

Methods: Quantitative RT-PCR and cell proliferation assays were performed following treatment with progesterone and RU-486 as a PR antagonist in nontransfected and PRA-transfected cells of the NET cell line QGP-1, which expresses PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases, and the results were compared with clinicopathological parameters.

Results: CCND1, c-Fos and c-Jun mRNA levels were all significantly increased by treatment with progesterone in QGP-1 cells with PRB expression compared with PRA-transfected cells (p = 0.02, p = 0.007 and p = 0.001, respectively). The proliferative activity of QGP-1 cells with PRB expression was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher-grade PNETs (p = 0.04), whereas CCND1 was significantly elevated in higher-grade PNETs (p = 0.035).

Conclusion: The results of the present study demonstrate that PRA could play an inhibitory role in the cell proliferation of PNETs, possibly by inhibiting PRB-mediated signals in the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be a prognostic factor in PNETs.
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http://dx.doi.org/10.1159/000381455DOI Listing
April 2016

G-cell hyperplasia of the stomach induces ECL-cell proliferation in the pyloric glands in a paracrinal manner.

Pathol Int 2015 May 2;65(5):259-63. Epub 2015 Mar 2.

Department of Pathology, Tohoku University Hospital, Sendai, Japan.

An inhibitory mechanism toward gastrin hypersecretion is significantly different between G-cell hyperplasia and gastrinoma despite the common clinical manifestations; hypergastrinemia and its related persistent gastric ulcers. We recenlty studied the G-cell, d-cell and ECL-cell density in a case of G-cell hyperplasia. The 70-year-old patient has been treated for persistent gastric ulcers with a markedly increased plasma gastrin (5600 pg/mL). The stomach was surgically resected because of the obstruction associated with ulcer scars. The number of G-cells in the pyloric glands was quantified on the surgical specimens and G-cell hyperplasia was histolopathologically identified. Immunostainig of histidine decarboxylate revealed the presence of ECL-cell hyperplasia in the pyloric glands and its density was significantly and positively correlated with G-cell density. Somatostatin immunoreactive cells (D-cells) increased in their number in the oxyntic glands. These results all indicated that hypersecretion of gastrin in G-cell hyperplasia could induce ECL-cell proliferation in a paracrinal manner. In addition, relatively non-prominent endocrinological features in the G-cell hyperplasia compared to gastrinoma could be also related to the paracrinal somatostatin inhibitory effects upon ECL-cells in the pyloric glands.
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http://dx.doi.org/10.1111/pin.12276DOI Listing
May 2015

Pathology diagnosis of pancreatic neuroendocrine tumors.

J Hepatobiliary Pancreat Sci 2015 Aug 2;22(8):586-93. Epub 2015 Feb 2.

Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan.

Histopathology of pancreatic neuroendocrine tumors (PNETs) typically displays characteristic features. However, pathologists may encounter histological variants that may resemble other pancreatic tumors. Immunohistochemistry is a powerful tool in confirming neuroendocrine differentiation and differentiating PNETs with other pancreatic neoplasms. Histopathological features could be associated with inherited syndromes. Once the pathology diagnosis of neuroendocrine tumor was made, an accurate grading based on World Health Organization (WHO) classification is required. This review will focus on histology variants, immunohistochemistry and WHO classification of PNET.
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http://dx.doi.org/10.1002/jhbp.208DOI Listing
August 2015

Microvessel density in hepatocellular carcinoma: Prognostic significance and review of the previous published work.

Hepatol Res 2015 Dec 12;45(12):1185-94. Epub 2015 Feb 12.

Department of Pathology.

Aim: Assessment of the microvessel density (MVD) may yield important information leading to an effective antiangiogenic treatment for hepatocellular carcinoma (HCC).

Methods: The intratumoral MVD of 136 HCC patients was retrospectively evaluated using CD34. The correlation between the MVD and clinicopathological findings was assessed. In addition, the prognostic factors influencing the 2-year disease-free survival (DFS) and overall survival (OS) were analyzed.

Results: The MVD of each tumor size group (<2, 2-5 and >5 cm) was 196 ± 51, 181 ± 63 and 147 ± 69. The MVD of each histological grade (well-, moderately and poorly differentiated) was 200 ± 56, 184 ± 61 and 114 ± 55. The optimum cut-off values of the MVD for the 2-year DFS and OS were 118.3 and 112.7, respectively. For the 2-year DFS, high tumor marker levels (α-fetoprotein >100 ng/mL and protein induced by vitamin K absence/antagonist-II >100 mAU/mL), poorly differentiated hepatocellular carcinoma (HCC), a high Ki-67 index (>20%), a large tumor size (>5 cm), vascular invasion, high tumor-node-metastasis (TNM) stage (III/IV) and a low MVD were the significant unfavorable prognostic factors. For the OS, a high Ki-67 index, a large tumor size, vascular invasion, high TNM stage and a low MVD were the significant risk factors for death. By the multivariate analysis, a low MVD was identified as an independent predictor of the 2-year DFS as well as the OS.

Conclusion: A low MVD can be used to predict an unfavorable prognosis in HCC patients.
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http://dx.doi.org/10.1111/hepr.12487DOI Listing
December 2015