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Intrahepatic cholangiocarcinoma (ICC) is highly invasive and carries high mortality due to limited therapeutic strategies. In other solid tumors, immune checkpoint inhibitors (ICIs) target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD1), and the PD1 ligand PD-L1 has revolutionized treatment and improved outcomes. However, the relationship and clinical significance of CTLA-4 and PD-L1 expression in ICC remains to be addressed. Deciphering CTLA-4 and PD-L1 interactions in ICC enable targeted therapy for this disease. In this study, immunohistochemistry (IHC) was used to detect and quantify CTLA-4, forkhead box protein P3 (FOXP3), and PD-L1 in samples from 290 patients with ICC. The prognostic capabilities of CTLA-4, FOXP3, and PD-L1 expression in ICC were investigated with the Kaplan–Meier method. Independent risk factors related to ICC survival and recurrence were assessed by the Cox proportional hazards models. Here, we identified that CTLA-4+ lymphocyte density was elevated in ICC tumors compared with peritumoral hepatic tissues (P + tumor-infiltrating lymphocytes (TILsCTLA-4 High) showed a reduced overall survival (OS) rate and increased cumulative recurrence rate compared with patients with TILsCTLA-4 Low (P P = .024, respectively). Similarly, patients with high FOXP3+ TILs (TILsFOXP3 High) had poorer prognoses than patients with low FOXP3+ TILs (P = .021, P = .034, respectively), and the density of CTLA-4+ TILs was positively correlated with FOXP3+ TILs (Pearson r = .31, P PD-L1 High) and/or TILsCTLA-4 High presented worse OS and a higher recurrence rate than patients with TILsCTLA-4 LowTumorPD-L1 Low. Moreover, multiple tumors, lymph node metastasis, and high TumorPD-L1/TILsCTLA-4 were independent risk factors of cumulative recurrence and OS for patients after ICC tumor resection. Furthermore, among ICC patients, those with hepatolithiasis had a higher expression of CTLA-4 and worse OS compared with patients with HBV infection or undefined risk factors (P = .018). In conclusion, CTLA-4 is increased in TILs in ICC and has an expression profile distinct from PD1/PD-L1. TumorPD-L1/TILsCTLA-4 is a predictive factor of OS and ICC recurrence, suggesting that combined therapy targeting PD1/PD-L1 and CTLA-4 may be useful in treating patients with ICC.

INTRODUCTION: Compared with endoscopic variceal ligation (EVL), cap-assisted endoscopic sclerotherapy (CAES) improves efficacy in the treatment of small esophageal varices (EVs) but has not been evaluated in the management of medium EVs. The aim of this study was to compare CAES with EVL in the long-term management of patients exhibiting cirrhosis with medium EVs and a history of esophageal variceal bleeding (EVB), with respect to variceal eradication and recurrence, adverse events, rebleeding, and survival. METHODS: Cirrhotic patients with medium EVs and a history of EVB were divided randomly into EVL and CAES groups. EVL or CAES was repeated each month until variceal eradication. Lauromacrogol was used as a sclerosant. Patients were followed up until 1 year after eradication. RESULTS: In total, 240 patients (age: 51.1 ± 10.0 years; men: 70.8%) were included and randomized to the EVL and CAES groups. The recurrence rate of EVs was much lower in the CAES group than in the EVL group (13.0% vs 30.7%, P = 0.001). The predictors for variceal recurrence were eradication by EVL (hazard ratio [HR]: 2.37, P = 0.04), achievement of complete eradication (HR: 0.27, P < 0.001), and nonselective β-blocker response (HR: 0.32, P = 0.003). There was no significant difference in the rates of eradication, rebleeding, requirement for alternative therapy, and mortality or the incidence of complications between groups. DISCUSSION: CAES reduces the recurrence rate of EVs with comparable safety to that of EVL in the long-term management of patients presenting cirrhosis with medium EVs and a history of EVB.

The purpose of this study was to evaluate the relationship between hypoxia-inducible factor-1α (HIF-1α) protein expression in hepatocellular carcinoma (HCC), and responses of abdominal metastatic lymph nodes (LNs) from HCC patients treated with external beam radiotherapy (EBRT). HIF-1α immunohistochemical staining was performed on tissue microarrays (TMAs) of primary HCC specimens from 69 HCC patients with abdominal LN metastases. All patients received abdominal metastatic LN EBRT at the Department of Radiation Oncology at Zhongshan Hospital. A receiver-operating characteristic (ROC)-based approach and logistical regression analysis were used to determine the predictive value of HIF-1α expression in primary tumors with HCC metastatic LN EBRT response. Kaplan-Meier curves and log-rank tests were used to analyze patient survival. Cox proportional hazards regression model was used to analyze independent prognostic factors. HIF-1α expression was correlated with blood hemoglobin (Hb: r = -0.280, P = 0.020), response of abdominal metastatic LNs to EBRT (r = 0.286, P = 0.017), locoregional recurrence (r = 0.278, P = 0.021), and cancer-specific deaths (r = 0.298, P = 0.013). HIF-1α expression was predictive of EBRT response of metastatic LNs [area under the curve (AUC): 0.646; 95% confidence interval (CI): 0.499-0.793; P = 0.047], locoregional recurrence (AUC: 0.657; 95% CI: 0.509-0.805; P = 0.049) and cancer-specific deaths (AUC: 0.671; 95% CI: 0.531-0.812; P = 0.035). Patients with tumors exhibiting high HIF-1α expression had significantly poorer overall survival (OS) than those with low tumor expression of HIF-1α (P = 0.016). Multivariate analysis showed that Hb (P = 0.035), vascular invasion (P = 0.026), Child-Pugh score (P < 0.001), intrahepatic tumor control (P < 0.001), and HIF-1α (P = 0.020) were independent prognosis factors for OS of HCC patients after receiving abdominal metastatic LN EBRT. HIF-1α expression in primary HCCs was associated with EBRT response of abdominal metastatic LNs and poor prognosis.

Gastrointestinal stromal tumors (GISTs) have a broad spectrum of biological behaviors ranging from benign, borderline and malignant. This study aimed to screen differentially expressed microRNAs (miRNAs) between malignant and borderline GISTs and to investigate the potential role of miRNAs in the malignant transformation of GISTs.Six GIST samples including borderline tumors (n = 3) and malignant tumors (n = 3) were collected based on the clinical and pathological characteristics. Total RNA was extracted, followed by miRNA microarray analysis to screen the differentially expressed miRNAs. The most significantly expressed 4 miRNAs were then chosen for further validation by real-time PCR in 22 additional GIST samples.Direct comparison of malignant group versus borderline group revealed 14 significantly and differentially expressed miRNAs (P0.05, with a fold change of0.5 or2). Five miRNAs were up-regulated and nine were down-regulated in the malignant group. Four miRNAs (miR-221, miR-135b, miR-675(*) and miR-218) were most significantly and differentially expressed between the two groups. The differential expression of 2 miRNAs (miR-221 and miR-675(*)) were subsequently confirmed with good concordance by real-time PCR.The differential miRNA expression profiles between two groups are revealed by miRNA microarray assay, and confirmed by real-time PCR. Among differentially expressed miRNAs, miR-221 and miR-675(*) might be related to the malignant transformation of GISTs, and have a potential value in predicting biological behavior of GISTs.

To study the clinicopathologic features, criteria for grading and prognostic factors of primary hepatic neuroendocrine neoplasms.Thirty-five cases of primary hepatic neuroendocrine neoplasm were retrieved from the archival files over a period of 11 years (with 32 cases having integrated data). According to the 2010 WHO classification of tumors of the digestive system, the cases were categorized into three groups: neuroendocrine tumor grade 1 (NET G1), neuroendocrine tumor grade 2 (NET G2) and neuroendocrine carcinoma (NEC). Statistical correlation between various histologic parameters and survival data was analyzed.Statistical analysis showed significant difference between NET [G1 (1 case)/G2 (14 cases)] and NEC (17 cases) groups in terms of tumor differentiation, necrosis, nuclear atypia, mitotic count and Ki-67 proliferative index (P0.05). There was no statistically significant difference in tumor size, growth pattern and presence of vascular tumor emboli (P0.05). The survival rate of patients correlated with tumor differentiation, growth pattern, necrosis, nuclear atypia, mitotic count and proliferative index (P0.05). There was no statistically significant difference between patient survival and tumor size or presence of vascular tumor emboli (P0.05).The subdivision of primary hepatic neuroendocrine neoplasm according to the 2010 WHO classification of tumors of the digestive system helps to evaluate the malignant potential and prognosis of the tumors. Prognostically useful histologic parameters include tumor differentiation, growth pattern, necrosis, nuclear atypia, mitotic count and proliferative index.

Background. Hepatocellular carcinoma (HCC) most commonly develops in patients who have a viral infection, especially in the case of hepatitis B virus (HBV), and in patients with a chronic liver disease. HCC patients with bone metastasis (BM) suffer from pain and other symptoms that significantly reduce their quality of life. Identification of patients who are at high risk for BM after undergoing potentially curative treatment for HCC remains challenging. Here, we aimed to identify HCC BM-related genes and proteins to establish prediction biomarkers. Methods. RNA was extracted from 48 pairs of intratumoral and peritumoral formalin-fixed, paraffin-embedded tissue from HCC patients with and without BM. A cDNA-mediated annealing, selection, extension and ligation assay containing 502 cancer-related genes was used to identify novel BM-associated genes. An additional independent study with 350 HCC patients who had undergone hepatectomy was conducted to evaluate the expression of candidate genes at the protein level using immunohistochemistry on tissue microarrays (TMAs). Of the 350 patients, 273 (78.0%) were infected with HBV. Results. Seven intratumoral genes and 17 peritumoral genes were overexpressed in patients with BM, whereas 15 intratumoral genes and 28 peritumoral genes were underexpressed in patients with BM. We selected the following four genes for further analysis because they were differentially expressed in the cancer gene-specific microarray and were previously reported to be associated with BM: connective tissue growth factor (CTGF), matrix metalloproteinase-1 (MMP-1), transforming growth factor β1 (TGF-β1), and interleukin-11 (IL-11). We assessed the protein expression of these selected genes using immunohistochemistry on TMAs including 350 HCC patient specimens. We determined that expression of intratumoral CTGF, intratumoral IL-11, and peritumoral MMP-1 were independent prognostic factors for developing BM in HCC patients. Combining intratumoral CTGF and IL-11 expression was also an independent risk factor for BM development. Conclusions. Sixty-seven genes were differentially expressed in HCC patients with and without BM. High intratumoral CTGF, positive IL-11, and high peritumoral MMP-1 expression were associated with BM after hepatectomy. Intratumoral CTGF expression combined with IL-11 expression may serve as a useful predictive biomarker for HCC BM.

To study the clinicopathologic features of focal nodular hyperplasia (FNH) of liver.The clinical, radiologic, pathologic findings and follow-up data of 238 cases of FNH were retrospectively analyzed.The patients included 93 females and 145 males. The age of the patients ranged from 11 to 77 years (median = 39.1 years). Amongst the 233 patients who had clinical information available, 188 were asymptomatic, 216 had no history of hepatitis B and/or C infection and 232 had negative serum alpha-fetoprotein level. Amongst the 185 patients who had undergone radiologic examination, 123 (66.5%) were accurately diagnosed as such. Macroscopically, of the 284 lesions from 238 patients, the average diameter was 3.7 cm. Two hundred and fifteen cases (90.3%) were solitary, 172 cases were located in the right lobe and 115(40.5%) had central stellate fibrotic scars or lobulated cut surface. Histologically, 229 lesions belonged to classic type and 9 lesions were of non-classic type. The latter was further classified as the telangiectatic form (6 lesions) and the mixed hyperplastic and adenomatous form (3 lesions). There was no evidence of significant cytologic atypia. Follow-up data were available in 173 patients (72.7%). None of them died of the disease and 2 patients suffered from relapses after 2 and 4 years, respectively.FNH is a hyperplastic response of normal liver cells to local blood flow anomalies. It has no obvious sex predilection and more than 66% can be diagnosed accurately with radiologic examination. The lesions in the current study show no cytologic atypia.

To study the clinicopathologic features and metastasizing potential of solid pseudopapillary tumor of the pancreas (SPT).Forty-five cases of SPT were retrieved from the archival file and subdivided into metastasizing group (MG, n = 4), and non-metastasizing group (NMG, n = 41), according to the follow-up clinical information. The histological features were reviewed and immunohistochemical study for vimentin, alpha 1-antitrypsin, alpha 1-antichymotrypsin, CD10, neuron-specific enolase, progesterone receptor, chromogranin A, synaptophysin, AE1/AE3, beta-catenin, p53, cyclin D1, CD34 and Ki-67 was carried out. The results were correlated with follow-up data.There was no statistically significant difference between MG and NMG, in terms of age and gender of the patients, site, size and capsular status of the tumor. No single morphologic parameter could distinguish MG from NMG. In general, increased mitotic activity, tumor emboli in vessels and necrotic foci were more conspicuous in MG than in NMG. According to a morphologic scoring system, all cases of MG had score ≥ 5, in contrast to5 in 95.1% (39 cases) of NMG. Immunohistochemically, there was no statistically significant difference between MG and NMG for beta-catenin, p53, cyclin D1 and CD34 staining. Ki-67 positivity however was significantly higher in MG. Amongst the 37 cases with follow-up information available, the average duration of follow up was 37.4 months. Thirty-three patients were alive and disease-free.Four suffered from liver metastases; and none of them died of the tumor.Mitotic activity, presence of tumor emboli and necrotic foci represent as the useful parameters in predicting metastasizing potential of SPT, especially with application of morphologic scoring system. Immunostaining for Ki-67 can also serve as an additional prognostic indicator.

To study the clinicopathologic features, differential diagnosis and pathogenesis of sclerosing angiomatoid nodular transformation of spleen.Ten cases of sclerosing angiomatoid nodular transformation of spleen were retrieved from the archival file. Histochemical and immunohistochemical (EnVision method) studies were performed. Ultrastructural findings were also available in one of them.Sclerosing angiomatoid nodular transformation was characterized by micronodular appearance of vascular spaces lined by plump endothelial cells with interspersed ovoid spindle cells. Immunohistochemical study showed that the endothelial cells of vessels in the angiomatoid nodules had various expressions of immunologic phenotypes and could be mainly classified into 3 types: CD34(+)/CD31(+)/CD8⁻ endothelial cells of the capillaries, CD8(+)/CD31(+)/CD34⁻ lining cells of the sinusoids and CD31(+)/CD8⁻/CD34⁻ endothelial cells of the small veins. Collagen network and dilated lymphatic sinuses were evident under transmission electron microscope.Sclerosing angiomatoid nodular transformation of spleen is a rare benign entity. It may represent a reactive condition and bears some relationship with splenic angioma. It needs to be distinguished from borderline or malignant vascular tumors of spleen.

Lymphangioleiomyomatosis (LAM) is a rare disease that predominantly affects young females. It is considered as an "orphan" life-threatening disease of unknown etiology, with uncertain clinical prognosis, and no effective treatment. LAM can arise sporadically or in association with tuberous sclerosis complex (TSC), an autosomal inherited syndrome characterized by hamartoma-like tumor growth and pathologic features that are distinct from manifestations of pulmonary LAM. The clinical course of LAM is characterized by progressive dyspnea on exertion, recurrent pneumothorax, and chylous fluid collections.Fourteen cases of LAM from Zhongshan Hospital, Fudan University are reviewed, twelve were confirmed by lung biopsy, one by retroperitoneal lymphangioleiomyoma resection, and one by autopsy.All 14 patients were women, aged 18 to 69 years (mean 43.3 years, median 46.5 years). Haemoptysis (57.1%) and chylothorax (35.7%) were more frequent than those described in previous case series. Extrapulmonary findings such as renal angiomyolipoma (AML), enlarged abdominal lymph nodes, liver AML and retroperitoneal lymphangioleiomyoma were seen in 21.4%, 14.3%, 7.14% and 7.14% in 14 cases respectively, which is remarkably lower than in the previously reported. Abnormal smooth muscle cells (LAM cells) were found to line the airways, bronchioles, lymphatics and blood vessels leading to airflow obstruction and replacement of the lung parenchyma by cysts. There were some surprises in the autopsy case as several LAM cell emboli were found in the veins of mediastinum lymph nodes; LAM cells were found to be disseminated in soft tissues adjacent to the ilium.Women with unexplained recurrent pneumothorax, tuberous sclerosis, or a diagnosis of primary spontaneous pneumothorax or emphysema in the setting of limited or absent tobacco use should undergo high-resolution computed tomography (HRCT) scan screening for LAM. Routine abdominal and pelvic imaging examinations should be performed to detect extrapulmonary involvement. The autopsy studies histologically suggested that LAM could be a multisystemic disease and LAM cells might possess metastatic potential.

To study the clinicopathologic and immunohistochemical features of cystic neoplasms of the pancreas.Ninety-two cases of cystic neoplasm of pancreas were retrieved from the Department archival file during the period from 1999 to 2005. Histologic features were studied and the tumors were typed according to WHO classification. Immunohistochemistry was also carried out using paraffin-embedded tissues.The age of patients ranged from 16 to 80 years. The patients included 33 males and 59 females. The tumors varied from 2 cm to 21 cm in diameter. They consisted of intraductal papillary mucinous neoplasm (36/92), serous cystic neoplasm (18/92), solid pseudopapillary tumor (18/92), mucinous cystic neoplasm (14/92), cystic pancreatic ductal adenocarcinoma (4/92) and cystic pancreatic endocrine neoplasm (2/92). Immunohistochemical study revealed variable staining patterns, with frequent overlaps between different tumor types. In general, serous cystic neoplasm expressed MUC1, while mucinous cystic neoplasm was positive for MUC-5AC, intraductal papillary mucinous neoplasm for MUC-2 and cystic pancreatic ductal adenocarcinoma for MUC-1. On the other hand, solid pseudopapillary tumor expressed alpha-antitrypsin, alpha-antichymotrypsin, vimentin and progesterone receptor.Accurate diagnosis of pancreatic cystic neoplasms requires correlation of clinical findings, radiologic examination, histologic features and immunostaining results. Pathologic distinction is important because of different prognostic significance. Two-thirds of pancreatic cystic neoplasms are premalignant or malignant and warrant surgical resection, whereas the remaining one-third (including pseudocyst and serous cystadenoma) are benign and can be treated conservatively.

Solitary fibrous tumor of the liver is a rare neoplasm. So far, 23 cases have been described in the English literature. We reported an additional case.A 46-year-old woman presented with abdominal mass for 2 weeks. Both abdominal sonography and CT scan showed a solid mass occupying the right lobe of the liver. Right lobectomy was performed and the tumor was resected.Pathological examination showed spindle cell and fibroblast-like cells within the collagenous troma. On immunohistochemical staining, these spindle tumor cells showed diffusely CD34 positive reactivity. The post-operative course was uneventful. The patient recovered smoothly, and was alive half a year without evidence of disease recurrence.The proper diagnosis was depended on CD34 immunohistochemical study. The number of solitary fibrous tumor of the liver reported to date is too limited to confirm the definite prognosis of the tumor.

Primary pancreatic lymphoma is a rare but treatable malignancy (less than 1% of pancreatic tumors) that may be clinically confused with pancreatic adenocarcinoma.In a patient with upper abdominal pain, ultrasonography and CT detected a mass in pancreatic head, which compressed the common bile duct. The patient received a Whipple's operation and intraoperative frozen sections of the mass showed an anaplastic carcinoma. Immunohistochemical staining was used to indicate the origin and prognosis of tumor.Grossly the tumor involved the pancreatic head, soft in consistence and invaded part of the gastric wall. Histologically, the tumor was composed mainly of large and moderate neoplastic cells, which were diffusely positive for CD20 and Bcl-6 antigens, indicating the features of diffusely large B cell lymphoma.The proper diagnosis of the tumor should be made with CD20 and Bcl-6 immunohistochemical study. Radical surgery is indicated for resectable carcinoma but not for a chemosensitive lymphoma.