Significance of interstitial fibrosis and p16 in papillary thyroid carcinoma.

We enrolled 264 patients with papillary thyroid carcinoma (PTC). We performed immunohistochemical detection of p16 and determined the degree of interstitial fibrosis (IF). The expression of p16 was associated with pathological tumor-node-metastasis (pTNM) stage and age (p < 0.05). The cancer-specific survival (CSS) was longer in p16-negative patients (195.73 vs. 181.78 months, p = 0.007). p16 was significantly related to the degree of IF (r = 0.130, p = 0.035). PTC patients with no or mild fibrosis tended to have a larger tumor (p = 0.045). The degree of fibrosis was related to the proportion of papillary structure components (p = 0.025). Univariate and multivariate survival analyses showed that relapse-free survival (RFS) was longer in patients with moderate/severe IF (p < 0.05). In summary, p16 was correlated with prognosis and IF of PTC. Patients with moderate/severe IF tend to have better prognosis in RFS.

Clinicopathological features of pulmonary artery and vein intimal sarcomas: case series of rare pulmonary vessel intimal sarcoma.

BACKGROUND: Pulmonary vessel intimal sarcoma (IS) is rare. METHODS: We studied gross pathology, microscopic images and immunohistochemistry of 2 pulmonary artery ISs (PAISs) and 2 pulmonary vein ISs (PVISs), followed up the prognosis. The clinical manifestations of IS, imaging examination, electrocardiographic examination and serological examination were also studied. RESULTS: Grossly, the tumors were grayish yellow or grayish-white accompanied by local bleeding, and were manifested as sticky and slippery nodules. PAISs were located in the lumen of the pulmonary trunk or right ventricular outflow tract, and 1 of them had pedicle. PVISs were mainly located in the left atrium. Microscopically, the heteromorphic spindle cells were arranged in lobules and bundles, partially epithelioid, with visible mitotic figures. There were interstitial mucoid degeneration and local hemorrhage and necrosis/infarction. Immunohistochemistry showed that vimentin, h-caldesmon and MDM2 were all positive, SATB2 (+, 3/4); Ki67 proliferation rate was 30-60%; smooth muscle actin, desmin and CD56 were partially positive; cytokeratin and CD34 were locally positive; CD31, FLI-1, and ERG vascular markers were negative; and S-100 was negative. Case 4 showed MDM2 (12q15) amplification. Tumor markers were negative in venous blood; and lactate dehydrogenase increased in 2 cases. 3 patients died after surgery, 1 still survives after 14 months with lung and chest metastases for immunotherapy and 9 courses of chemotherapy. CONCLUSIONS: IS is rare. Microscopically, it is mainly composed of spindle cells (or local epithelioid), along with interstitial mucoid degeneration. IS can differentiate into tumor of fibroblasts, bone, cartilage and smooth muscle, etc. The prognosis is poor.

Impact of the Activation Status of the Akt/mTOR Signalling Pathway on the Clinical Behaviour of Synovial Sarcoma: Retrospective Analysis of 174 Patients at a Single Institution.

PURPOSE: Phosphoinositide 3-kinase (PI3K) and the downstream Akt/mammalian target of rapamycin (mTOR) pathway are central to the control of cell proliferation and survival. Although abnormal activation of this pathway has been well established in a variety of tumours, limited studies are available on synovial sarcoma. The aim of this study was to investigate the expression of several key proteins of those pathways in synovial sarcomas and to correlate the expression of these proteins with clinicopathologic features and prognosis. PATIENTS AND METHODS: A total of 174 patients with synovial sarcomas were recruited for this study. The phosphorylation status of Akt, mTOR, and eukaryotic translation initiation factor 4E binding protein (4E-BP1) was measured by immunohistochemistry assays in formalin-fixed, paraffin-embedded samples. Correlations between the expression levels of these proteins and clinicopathologic features and prognosis were analysed. RESULTS: The positive rates of phosphorylated (p)Akt, pmTOR, p4E-BP1, and CyclinD1 were 62.7%, 55.6%, 47.1%, and 52.6%, respectively. The positive results of pmTOR, pAkt, and downstream p4E-BP1 were correlated with each other. The positive pAkt, pmTOR, p4E-BP1, and CyclinD1 results were more highly expressed in head and neck and visceral tumours, and positive p4E-BP1 results were correlated with larger size and larger areas of necrosis. In multivariate analysis of clinicopathologic factors, head and neck and visceral location, large tumour size, larger areas of necrosis and frequent mitosis were confirmed as risk factors for shorter overall survival. Positive pAkt, pmTOR and p4E-BP1 results were correlated significantly with shorter overall survival, and CyclinD1 was not in the univariate analysis. The positive pmTOR, pAkt, p4E-BP1, and CyclinD1 results were significantly poor prognostic factors for overall survival, and only positive p4E-BP1 results were significantly associated with shorter event-free survival in multivariate analysis. CONCLUSION: This study demonstrated the high expression of pAkt, pmTOR, and p4E-BP1 associated with aggressive clinical behaviour in synovial sarcomas and provided evidence for prognostic evaluation and targeted therapy.

Biological effects of ubiquitin-specific peptidase 22 on thyroid papillary cancer cells and its mechanism of action.

BACKGROUND: In this study, ubiquitin-specific peptidase 22 (USP22) was detected in both thyroid papillary cancer-1 (TPC-1) and normal thyroid epithelial cell lines (HT-ori3), and its biological function was analyzed. METHOD: Cell culture, resuscitation, and passage, Western blot, and real-time polymerase chain reaction were used. RESULTS: The expression of USP22 was found to be significantly higher in TPC-1 cancer cells than in normal cells. After silencing of the USP22 gene in TPC-1 cells, the levels of USP22 gene and protein expression were significantly decreased. After 6 h with silencing of the USP22 gene, the migration rate was lower and the cells had become smaller than in the control group (P<0.05). At 24 h, the number of invasive cells was significantly lower than in the control group (P<0.05). A cell viability test showed that the differences between the groups increased on days 4 and 5 (P<0.05). The number of colony-forming cells had also decreased significantly after 10 days (P<0.05) in the USP22-siRNA1 group. Compared with the control group, the protein levels of USP22, cyclin D2, and Bmi-1 were significantly decreased (P<0.05). The decrease of USP22 was positively correlated with the decrease of Bmi-1 and cyclin D2. After silencing of the USP22 gene in normal HT-ori3 cells, the USP22 gene and protein expressions decreased significantly (P<0.05). A cell viability test showed that the difference had increased (P<0.01), and the number of cloned cells had significantly decreased than that in negative group (P<0.01). CONCLUSIONS: In conclusion, the USP22 gene plays a key role in the growth, proliferation, invasion, and migration of papillary thyroid cancer cells. USP22 possibly exerts its effect in TPC through the Bmi-1 and cyclin D2 pathways. USP22 also plays a crucial role in the growth of normal thyroid cells.

Overexpression of Forkhead box Q1 correlates with poor prognosis in papillary thyroid carcinoma.

OBJECTIVE: Forkhead box Q1 (FOXQ1), a member of the forkhead transcription factor family, plays important parts in cell cycle, apoptosis, metabolism, immunology and tumour genesis. Its expression has been associated with poor clinical prognosis in various tumours. However, the clinical significance of FOXQ1 in papillary thyroid carcinoma (PTC) has not been fully studied. The purpose of this study was to investigate whether FOXQ1 is correlated with poor prognosis in PTC. DESIGN/METHODS: We performed a retrospective study of 136 PTCs. Immunohistochemistry (IHC) was used to examine the expression of FOXQ1 in 136 PTCs and 47 nodular goitre specimens. Rank-sum test, chi-square test, Kaplan-Meier survival analysis, univariate and multivariate Cox analyses were used to investigate the clinical and prognostic significance of FOXQ1 expression in PTC. RESULTS: The comparison of PTC specimens with nodular goitre with papillary hyperplasia specimens revealed an upregulation of FOXQ1 in PTC. Overexpression of FOXQ1 was observed in 63.24% of PTC and correlated with classic variant, tall variant, distant metastasis, AJCC stage and recurrence. FOXQ1-positive expression was associated with shorter disease-free survival: median disease-free survival of FOXQ1-positive patients was 23 months compared with 128 months for FOXQ1-negative patients (Log-rank χ2  = 12.31, P = 0.00045). Additional independent risk factors in this study were multifocality (recurrence-free survival [RFS]: hazard ratio [HR] = 2.391, P < 0.05), extrathyroidal extension (RFS: HR = 3.906, P < 0.05) and positive expression of FOXQ1 (RFS: HR = 6.385, P < 0.01). CONCLUSIONS: Our results indicated that FOXQ1 may be a useful additional biomarker to evaluate the progression of PTC and to predict likely relapse of disease.

Clinicopathological features of low-grade malignant endolymphatic sac tumors.

BACKGROUND: Low-grade malignant endolymphatic sac tumor (ELST) is a rare neoplasm, occurring in the inner ear and invading the temporal bone. This study aims to investigate the clinicopathological features of low-grade malignant ELSTs. METHODS: The clinicopathological data of 21 patients with low-grade malignant ELSTs were collected and analyzed. RESULTS: The patients were aged 16-71 years, with an average age of 40.3 years and a median age of 39 years, and the male to female ratio was 1:1.6. There were 13 cases (61.9%) of ELSTs occurring on the left side, 7 cases (33.3%) on the right side, and 1 case (4.8%) on both sides. Blood types O and B were noted in 71.4% of the patients. Immunohistochemistry showed that CK, EMA and Vim were all positive, and S-100 (71.4%, 10/14), CD56 (75.0%, 9/12), NSE (50.0%, 2/4), and GFAP (11.1%, 1/9) were also positive, while Syn, CgA, TTF-1, TG, CD34, and calcitonin were negative. The Ki-67 index was 4.3% on average. Histologically, cells were arranged in a papillary shape often with branches and abundant fibrous axial vessel. Some cells had an expanded different-sized thyroid-follicle-like structure, with the follicles containing red-stained colloids and scallop-like secretary vacuoles. There were expanded cavities. Some cases were in a glandular arrangement, and a few in a nest-like, gland-cystoid arrangement. Most tumors were coated with a monolayer of cubic epithelium, a few cells were flat or columnar, with translucent cytoplasm and light staining. The nuclei were oval, nucleolus was not obvious, chromatin was delicate, and a few nucleoli were small. The tissue was prone to bleeding, with fresh and old bleeding. Approximately half of the patients had necrotic bones, and in some cases the tumor tissue had destroyed the surrounding bone. The background fibrous tissue showed hyperplasia with hyaline degeneration, some had calcification and formation of sandy-gravel bodies. The clinical manifestations were hearing reduction or loss, followed by tinnitus, and accompanied by varying degrees of cranial nerve injury. No patients died during follow-up. CONCLUSIONS: Low-grade malignant ELSTs occur most frequently on the left side, with a female preponderance. The disease progressed slowly, with no death, and but relapse in two patients in this series. These tumors are often misdiagnosed.

Clinicopathological features of myeloid sarcoma: Report of 39 cases and literature review.

OBJECTIVE: To explore the clinicopathological features of myeloid sarcoma (MS). METHODS: We retrospectively analyzed the clinicopathological features of patients with MS and reviewed the relevant literature. RESULTS: There were 39 patients (20 male and 19 female, with a ratio of 1.1:1) aged 2-62 years (median: 33 years; mean: 33.4 years), with 53.9% patients in the 21-50 years age group. The clinical manifestations varied and were dependent on the lesion location. Immunohistochemistry and special staining showed that the positive rates for myeloperoxidase, CD43, CD34, CD117, CD68, Lysozyme, CD99, and naphthol AS-D chloroacetate esterase were 92.1% (35/38), 91.3% (21/23), 44.8% (13/29), 42.3% (11/26), 61.1% (11/18), 100.0% (5/5), 78.6% (11/14), and 55.6% (10/18), respectively. Histologically, the cells were predominantly arranged diffusely, and the solitary infiltrating cells may show an acinus-like arrangement, while some cells were arranged in linear or "Indian file" pattern. Obvious small nucleoli were seen in most cases. The nuclei were predominantly round or oval, although eccentric, kidney-shaped, and lobulated nuclei were also observed. A varied number of eosinophilic granulocytes were found in most cases. The "starry sky" appearance was observed in a few patients. Among 18 patients, the survival rate was 38.9% and the median survival time was 28 months. MS occurred following allogeneic stem cell transplantation in 5 cases. There were 14 de-novo (45.2%,14/31) and 17 secondary MS (54.8%, 17/31). As for de-novo MS, female rates was higher (64.3% vs. 29.4%), older average years (41.4 vs. 31.1 years), older middle years (47.5 vs.32 years). CONCLUSIONS: The combined application of morphology, immunohistochemistry, and special staining may facilitate the diagnosis of this malignancy. Surgery plus chemotherapy remains the most common treatment for MS. The prognosis of MS was bad.

Esophageal granular cell tumors: Case report and literature review.

We reported 5 cases of granular cell tumors (GCTs) of esophagus and reviewed the literature. There were 4 females and 1 male with a median age of 43 years and an average age of 44 years. All of the cases had solitary tumors. Tumor size was 0.4-2.5 cm in diameter. Gastroscopy revealed that 2 cases were located in the middle esophagus, 1 case in the upper esophagus, and 2 cases in the distal one. Five cases displayed gray-white, pink, yellow mucosal uplifts of esophagus, 3 cases had smooth surface, 1 case was slightly concave, and the biggest tumor had erosion. Tumor cells were large and polygonal with rich granular and eosinophilic cytoplasm, and small oval nuclei. Cells were arranged in nest or aciniform. Immunohistochemistry and histochemistry staining showed S-100+, neuron specific enolase+, Vim+, CD68+, smooth muscle actin-, Des-, CK-, CD117-, CD34-, Ki67-or ≤ 5%+. Periodic acid-Schiff reaction and epithelial membrane antigen were both weakly positive. GCTs of esophagus are rare and most of the cases have good prognosis.

The regulatory role of activating transcription factor 2 in inflammation.

Activating transcription factor 2 (ATF2) is a member of the leucine zipper family of DNA-binding proteins and is widely distributed in tissues including the liver, lung, spleen, and kidney. Like c-Jun and c-Fos, ATF2 responds to stress-related stimuli and may thereby influence cell proliferation, inflammation, apoptosis, oncogenesis, neurological development and function, and skeletal remodeling. Recent studies clarify the regulatory role of ATF2 in inflammation and describe potential inhibitors of this protein. In this paper, we summarize the properties and functions of ATF2 and explore potential applications of ATF2 inhibitors as tools for research and for the development of immunosuppressive and anti-inflammatory drugs.

[Expression of the LC3A protein in prostate cancer and its implications].

OBJECTIVE: To investigate the expression of the LC3A protein in prostate cancer (PCa) and its clinicopathological significance. We detected the expression of the LC3A protein by immunohistochemistry in 54 cases of PCa and 14 cases of benign prostatic hyperplasia (BPH), and analyzed the correlation between the LC3A expression and the clinicopathological parameters in PCa. The positive signals of the LC3A protein were located in the cytoplasm and/or cell nuclei. The rate of its strongly positive expression was 90.7% in PCa, significantly higher than 14.3% in BPH (P < 0.01). The LC3A expression was also found in the cell nuclei of 22 cases of PCa, with no significant correlation to that in the cytoplasm (P > 0.05). The expression of LC3A was significantly correlated with Gleason scores (r = 0.297, P = 0.029 in cytoplasm; r = 0.288, P = 0.034 in cell nuclei), but not with the clinical stage, patient's age, androgen receptor (AR) level and preoperative levels of serum PSA and cPSA (all P > 0.05). LC3A was also expressed in the fibrocytes and smooth muscle cells in PCa and BPH. The positive rate of AR was 74.1% (40/54) in PCa and 64.3% (9/14) in BPH, with no significant difference between the two groups (P > 0.05). CONCLUSION: The expression of the LC3A protein might be involved in the development, differentiation, and prognosis of prostate cancer.

Solitary necrotic nodule of the liver: a report of two cases and review of the literature.

To investigate the clinicopathological characteristics and possible causes of solitary necrotic nodule of the liver (SNN), two cases of SNN of the liver were studied with clinicopathological data, immunohistochemistry, and histochemistry staining. The patients had no specific symptoms, with negative results for the serum tumor markers. CT and ultrasound all showed low-density lesion. Morphologically, there was isolate, single necrosis tubercle of the liver. It was composed of a central necrotic core and a peripheral fibrotic capsule with inflammatory cells, including histiocytes, plasma cells, lymphocytes, and so forth. The staining result of PAS, acid-fast, and iron was all negative, and AG + VG staining showed that the outline of reticular fibers and collagen was intact. Vimtin was positive for necrotic tissue and surrounding fibrous tissue. CD34 and CD68 was both positive for case 1. CK was negative in case 2 but positive for a few residual cells in case 1. SNN of the liver is a rare nonmalignant disease with a good prognosis. Hemangioma and fatty liver might be ones of the causes of SNN.

[Expression of a novel metastasis-inducing protein human anterior gradient-2 (AGR2) in breast cancer and its clinical and prognostic significance].

OBJECTIVE: To investigate the expression of a novel metastasis-inducing protein human anterior gradient-2 (AGR2) in breast cancer and its clinical and prognostic significance. METHODS: AGR2 expression was assessed in 160 cases of breast cancer and 20 cases of benign breast diseases by immunohistochemistry using tissue chip technology. In addition the expression of ERa, PR and c-erbB-2 in breast cancer was also evaluated. Follow-up information of 5-year duration was available in 127 patients with breast cancer. Kaplan-Meier analysis and COX regression model were used to analyze the correlation between AGR2 expression and the follow-up clinical data. RESULTS: The expression of AGR2 was significantly higher in breast cancers than that in benign diseases (68.3% vs. 25.0% , P < 0.01). There was a negative correlation between AGR2 expression and the histological grade of breast cancer (P <0.05) , whereas positive correlations was found between the expression of AGR2 and ERalpha (P <0.05), and between the expression of AGR2 and PR (P <0.01). In the subgroup of ERalpha-positive breast cancer, Logistic regression model demonstrated AGR2 and TNM stage were important factors affecting lymph node metastasis (both P < 0.01). Kaplan-Meier analysis demonstrated that a positive expression of AGR2 was associated with poor overall survival and relapse-free survival (both P <0.01). Moreover, COX regression model confirmed the expression of AGR2 as an independent prognostic factor among patients with ERa-positive breast cancer (P <0.01). CONCLUSIONS: The abnormal expression of AGR2 may play a role in the pathogenesis and progression of breast cancer. The metastasis-inducing capability of AGR2 may be partly regulated through the ER pathway. Therefore, AGR2 may be a useful molecular marker for prognostication for patient with hormone-responsive breast cancer.

Prognostic significance of MMP-9 and TIMP-1 serum and tissue expression in breast cancer.

Tumor progression and metastasis contribute to the great majority of breast cancer deaths. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to be involved in tumor progression and metastasis. Thus, we determined whether the expression of MMP-9 and TIMP-1 is associated with prognosis in breast cancer patients. We measured serum MMP-9 and TIMP-1 by enzyme-linked immunosorbent assay in 60 breast cancer patients, 18 benign breast disease patients and 15 healthy controls. We also evaluated the expression of MMP-9 and TIMP-1 protein and mRNA in paraffin-embedded tumor tissues from the 60 breast cancer patients by immunohistochemistry and in situ hybridization. We then correlated serum and tissue levels of MMP-9 and TIMP-1 in breast cancer samples and their expression with patients' clinicopathologic characteristics. We found that serum levels of MMP-9 and TIMP-1 were significantly higher in breast cancer patients than in benign breast disease and in healthy controls. High serum levels of MMP-9 and TIMP-1 were associated with lymph node metastasis, higher tumor stage and lower relapse-free and overall survival (OS) rates. Compared to low expression, high tissue expression of MMP-9 protein was associated with lymph node metastasis and higher tumor stage; and high tissue expression of TIMP-1 was associated with a lower OS rate. Our findings suggest that MMP-9 and TIMP-1 may further be evaluated as biomarkers for predicting progression and prognosis of breast cancer.