Large Lymph Node Metastasis Research Articles

N-cadherin and P-cadherin are biomarkers for invasion, metastasis, and poor prognosis of gallbladder carcinomas

Gallbladder cancer (GBC) is a rare, but highly aggressive cancer. The most common type of gallbladder cancer is adenocarcinoma (AC), while squamous cell/adenosquamous carcinoma (SC/ASC) is a rare type of gallbladder cancer. The clinicopathologic and biological characteristics of SC/ASC have not been well documented. In this study, the protein expression of N-cadherin and P-cadherin in 46 SC/ASCs and 80 ACs was measured using immunohistochemistry. We demonstrated that positive N-cadherin and P-cadherin expression were significantly associated with large tumor size, invasion, and lymph node metastasis of both SC/ASC and AC. In contrast, positive N-cadherin and P-cadherin expression were significantly associated with differentiation and TNM stage in only AC. Univariate Kaplan–Meier analysis showed that positive N-cadherin and P-cadherin expression, differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and surgical curability were significantly associated with overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive N-cadherin and P-cadherin expression are independent poor-prognostic factors in both SC/ASC and AC patients. Our study suggested that positive N-cadherin and P-cadherin expression closely correlated with clinicopathological and biological behaviors, and poor-prognosis of gallbladder cancer.

AGGRESIVE SURGICAL TREATMENT IN CERVICAL TUMOR WITH MULTIPLE LOWER ABDOMINAL DISSEMINATIONS

In cases with advanced cervical cases, with large lymph node metastases or solitary peritoneal masses the patient is candidate rather for debulking surgery than systemic treatments. Several studies have proven that radiotherapy is inefficient for tumoral masses larger than 2 cm. In this case report we present a 55 years old patient with advanced cervical cancer, large lymph node metastasis and a solitary peritoneal mass. A radical hysterectomy with bilateral adnexectomy,lymph node dissection and mesosigmoid mass resection were performed. The patient was addressed to adjuvant chemotherapy.

Clinicopathologic Implications of the BRAFV600E Mutation in Papillary Thyroid Cancer: A Subgroup Analysis of 3130 Cases in a Single Center

The BRAF mutation has been shown to be associated with aggressive clinicopathologic characteristics of papillary thyroid cancer (PTC). However, several studies that analyzed hundreds of patients have not demonstrated any correlation. The objective of this study was to investigate the relationship of the BRAF mutation with clinicopathologic factors in a large group of homogenous PTC patients. We collected data of PTC patients who received curative resection of the thyroid gland and who had undergone BRAF mutation tests of their thyroid cancer tissue. Minor variant PTCs and mixed-type thyroid cancers were excluded in this analysis. Clinicopathologic characteristics, including age, sex, BRAF mutation, tumor histology, size, extrathyroidal extension, tumor margin, lymph node metastasis, multifocality, stage, and associated thyroid disease, were collected. The relationship of the BRAF mutation with clinicopathologic factors was analyzed in each homogenous histologic PTC. There were 3130 PTC patients who met the criteria, and these patients were divided into three major histologic groups: conventional PTC (n = 2947), diffuse sclerosing variant PTC (n = 98), and follicular variant PTC (n = 85). The BRAF mutation was variably detected in 75.3%, 61%, and 40% of patients, respectively. In conventional PTC cases, the BRAF mutation was significantly associated with large tumor size, extrathyroidal extension, and lymph node metastasis. Coexistent chronic lymphocytic thyroiditis was significantly less prevalent in the BRAF mutant group. Age, sex, and tumor margin status were not significantly correlated with the BRAF status. There was no evidence that any clinicopathologic factors were linked with the BRAF mutation status in diffuse sclerosing and follicular variant PTCs. The BRAF mutation was differentially detected in each histologic subtype of PTC and was strongly correlated with pathologic factors, most strongly with no coexistent chronic lymphocytic thyroiditis, in conventional PTC. The BRAF mutation is suggested to be a poor prognostic marker in conventional PTC, and the BRAF mutational analysis may lead to better management for individual PTC patients.

A Noninvasive Encapsulated Macrofollicular Variant of Papillary Thyroid Carcinoma Presenting with Gross Lymph Node Metastasis: A Case Report and Literature Review

Dear Editor:The follicular variant of papillary thyroid carcinoma (FV-PTC) without vascular or capsular invasion is considered tohave virtually no metastatic potential or recurrence risk (1).The macrofollicular variant of papillary thyroid carcinoma(MFV-PTC) is a very rare variant of FV-PTC the behavior ofwhich appears to be similar to FV-PTC (2). However, morerecently, this phenomenon has been challenged by reports ofsystemic metastases and recurrent and fatal cases (3). We re-port a case of encapsulated noninvasive MFV-PTC that pre-sented with gross lymph node metastases, and briefly reviewthe literature. A right thyroid nodule was incidentally foundby a computed tomography scan in an 80-year-old male.Subsequently, a 3.7cm·3.6cm·3.3cm heterogeneous iso- tohyperechogenic thyroid nodule in the right lobe and a2.2cm·2cm·1.3cm right jugular lymph node, both withcalcifications, were detected by ultrasonography. Fine-needleaspiration biopsy of both lesions was performed under ultra-sonography guidance and showed malignant cells consistentwith PTC. The patient underwent a total thyroidectomy withcentral and right (levels 3–4) lymph node dissection. Thethyroidectomy specimen revealed a 3.7cm·3.2cm·2.9cmencapsulated white solid nodule in the right lobe (Fig. 1),which was entirely submitted for histological evaluation. Onhistology, the nodule was completely surrounded by a thickand focally calcified capsule, without evidence of vascular orcapsular invasion. The nodule was predominantly macro-follicular, with minor areas composed of smaller follicles. Thecells lining the macrofollicles were often attenuated withoutsignificant nuclear atypia (Fig. 1). In contrast, the cells liningthe smaller follicles were more cuboidal and had the typicalnuclear features of PTC (Fig. 1). Numerous intratumoral cal-cifications and psammoma bodies were observed (Fig. 1).Insular/solid growth, necrosis, or mitotic activity was notobserved. Two lymph node metastases were found. Thelargest one (2.4cm) was composed predominantly ofmacrofollicles, akin to the primary tumor (Fig. 1). Im-munohistochemistry was supportive of malignancy, withthe tumor cells being diffusely positive for galectin-3, andfocallypositiveforHBME-1(HectorBattiforamesothelin-1)inthe non-macrofollicular areas only. The proliferative index(Ki-67) in the primary tumor and in the larger metastasis wasvery low ( 50%) was composed ofmacrofollicles (>250lm), corresponding to the arbitrarydefinition of an MFV-PTC (2). Interestingly, that feature wasalso retained in the larger lymph node metastasis, but not inthe smaller one. In the literature, although several cases ofMFV-PTC have presented with lymph node metastasis, mostof these cases were either infiltrative and/or associated withvascular invasion (2). In the largest series of MFV-PTC of 29patients, 6 developed lymph node and 2 developed lungmetastasis (2). The metastases occurred in older patients whohad insular components, extrathyroidal extension, and vas-cular invasion. In our case, although the patient was elderly,no other risk factors were identified. To the best of ourknowledge, there are two other documented cases of encap-sulatedMFV-PTCwithoutcapsularorvascularinvasionwithlymph node and/or systemic metastasis (3). In comparison,we found no well-documented cases of conventional encap-sulated noninvasive FV-PTC with lymph node metastases. Inthe study by Liu et al. (1), the only encapsulated FV-PTC withlymph node metastasis had several foci of lymphovascularinvasion. Moreover, observing that most cases of FV-PTCwith metastatic disease had obvious invasion, Lloyd et al. (4)recommend caution in making a diagnosis of FV-PTC in theabsence of the major histopathologic features or obvious

Androgen and androgen-metabolizing enzymes in metastasized lymph nodes of breast cancer

Androgen receptor and androgen metabolizing enzymes, 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5) and 5α-reductase1 (5α1), are frequently detected in primary tumor of breast cancer, but their status in metastatic lymph nodes has not been examined. The biological role of androgen in breast cancer and its metastatic process also remain unknown. In this study, we used immunohistochemistry to localize the expression of androgen receptor, 17βHSD5, and 5α1 in primary tumors and paired metastatic lymph nodes and correlated the findings with clinicopathologic factors of individual patients. Approximately 70% of primary tumors and paired metastatic lymph nodes expressed androgen receptor, with significant correlation between both lesions. However, 17βHSD5 and 5α1 immunoreactivity was decreased in metastatic lymph nodes. Alone or in tandem with androgen receptor, 5α1 was associated with significantly lower Ki-67 index, lower pathologic grade, and higher estrogen receptor positivity, but androgen receptor/5α1 double positivity in lymph nodes was associated with larger lymph node metastasis and higher TNM stage. In conclusion, androgen receptor immunoreactivity remained stable during the process of metastasis, whereas androgen-metabolizing enzymes decreased. Although results of our study and previous reports imply additional roles of androgen metabolism in the metastasis process, especially conversion by 5α1, there may be divergence between its effects on primary tumor and those in metastatic lymph nodes.

Role of podoplanin expression in squamous cell carcinoma of upper aerodigestive tract.

Podoplanin, a type-1 transmembrane glycoprotein, was originally named due to its expression in renal podocytes of rats. It was subsequently detected in a variety of normal human tissues, including lymphatic endothelium. Although podoplanin has been identified as the endogenous ligand of C-type lectin-like receptor 2 (CLEC-2) on platelets, its physiological functions and pathways remain largely unknown. A role in lymphangiogenesis has been suggested, since podoplanin-deficient mice were found to die at birth with a phenotype of dilated, malfunctioning lymphatic vessels and lymphedema. Podoplanin is invariably expressed in some tumors, such as lymphangioma, seminoma and follicular dendritic cell tumor, but tumor cell expression of podoplanin is highly variable in squamous cell carcinoma (SCC). It has been found that high podoplanin expression is associated with lymph node metastasis and poor prognosis in SCC of the upper aerodigestive tract. Now there is growing evidence that podoplanin is also involved in carcinogenesis, cell motility, tumor invasiveness, platelet aggregation and hematogenous metastasis. Additionally, animal studies confirmed some in vivo effects of podoplanin-overexpressing tumors, including formation of more tumor lymphatic vessels, larger lymph node metastases, more platelet aggregation, and more pulmonary metastases. Several recently developed anti-podoplanin antibodies, such as NZ-1, P2-0 and hP2-0, have been shown to attenuate podoplanin-induced platelet aggregation and prevent experimental hematogenous metastasis in nude mice. These antibodies may be applied in preclinical and clinical studies to evaluate the possibility of podoplanin-targeted therapy.

Targeting Melanoma Sites in Vivo can Induce Complete Tumor Ablation and Prolong Patient Survival: An Exploratory Study

Dermal and subdermal metastases as well as primary invasive melanoma allow an excellent opportunity to study the effects of intralesional therapy. The therapy consisted of weekly intralesional administration of nontoxic doses of granulocyte-macrophage colony stimulating factor at 500 microgram, and in case of failure to establish complete tumor response at the injection sites in 4-6 weeks; weekly intralesional interleukin-2 at 18 million international units was substituted. The results revealed complete response in patients with multiple small in transit metastases ranging in size from few millimeters to one centimeter (n=4) for over 31-48 months, but not in any of the large sclerotic lesions of 2 centimeter or more (n=3). Complete responses were elicited for 6 months in one of two patients with distant metastases who had palpable subdermal tumors treated with granulacyte-macrophage colony stimulating factor. A patient with primary cutaneous melanoma with a satellite lesion and and a large regional lymph node metastasis received both cytokines in the skin sites, one week prior to surgery, had complete tumor necrosis, intense immune response at the injection sites and at the regional lymph nodes, with over 36 months disease free survival. This could be an affective new approach to tumor-specific adjuvant immunotherapy.

Overexpression of ubiquitin-specific protease 22 predicts poor survival in patients with early-stage non-small cell lung cancer

Ubiquitin-specific protease 22 (USP22), a novel ubiquitin hydrolase, has been implicated in oncogenesis and cancer progression in various types of human cancer. However, the clinical significance of USP22 expression in non-small cell lung cancer (NSCLC) has not been determined. In the present study, USP22 messenger RNA (mRNA) and protein levels were analyzed by quantitative real-time polymerase chain reaction (PCR) and western blot analysis in 30 cases of NSCLC and in corresponding non-tumor tissue samples. Furthermore, immunohistochemistry was performed to detect USP22 protein expression in 86 primary tumor tissues derived from clinically annotated NSCLC cases at stage I-II. In our analysis we found that both USP22 mRNA and protein levels in NSCLC tissues were significantly higher than those in corresponding non-tumor tissues and that there was a significant correlation between the expression of USP22 mRNA and protein (P=0.000, κ=0.732). In addition, a high-level of USP22 expression was observed in 53.3% (39 out of 86) cases and it was correlated with large tumor size (P=0.029) and lymph node metastasis (P=0.026). Patients with tumors displaying a high-level of USP22 expression showed significantly shorter survival (P=0.006, log-rank test). Importantly, multivariate analysis showed that high USP22 protein expression was an independent prognostic factor for NSCLC patients (P=0.003). In sum, our data suggest that USP22 plays an important role in NSCLC progression at the early stage, and that overexpression of USP22 in tumor tissues could be used as a potential prognostic marker for patients with early clinical stage of NSCLC.

The Impact of Preoperative Lymph Node Size on Long-Term Outcome Following Curative Gastrectomy for Gastric Cancer

Multidetector-row computed tomography (MDCT) is widely used to predict pathological nodal status. However, an appropriate nodal size cutoff value to predict pathological nodal status has not been determined, and the impact of preoperative lymph node size on long-term outcomes is unclear. This study included 137 gastric cancer patients with nodal involvement who underwent R0 gastrectomy between September 2002 and December 2006. Lymph nodes with a short-axis diameter of 10 mm or more as measured by MDCT were regarded as metastasized. An appropriate cutoff value with a high positive predictive value (PPV) and high specificity also was identified, and the subsequent clinicopathological characteristics and long-term outcomes were investigated. A cutoff value of 15 mm was found to be appropriate for grouping patients into large (≥15 mm) and small (<15 mm) lymph node metastasis (LLNM and SLNM) groups, with a high PPV (98.6 %) and specificity (99.8 %). There were no differences in clinicopathological characteristics between the groups except for pathological nodal status. In the LLNM group, the 5-year survival rate was 55 %, which was significantly lower than in the SLNM group (73.2 %; P = 0.008). After stratification by tumor depth, the same trend was observed in patients with pT3 disease (46.8 % vs. 72.7 %; P = 0.015) and those with pT4 disease (14.3 % vs. 64.8 %; P = 0.035). Gastric cancer patients with lymph nodes measuring 15 mm or more preoperatively have worse long-term outcomes. These patients would therefore be suitable candidates for future clinical trials investigating the efficacy of neoadjuvant chemotherapies.

Early Recurrence in Sentinel Lymph Node Positive Stage III Melanoma Patients

Patients with sentinel lymph node (SLN) positive melanoma have a significant recurrence risk. We sought to examine variables associated with development of early recurrence. A prospective institutional review board-approved database of cutaneous melanoma patients treated from 2003 to 2010 was used to identify SLN positive stage III patients with 1 year of follow-up. The Kaplan-Meier method, and logistic regression were used to evaluate variables associated with early recurrence. Seventy-four patients were identified. Twenty-four (32%) had an early recurrence. Five variables were highly significantly associated with early recurrence: location of head/neck, Breslow depth greater than two, ulceration, number of lymph nodes positive ≥ 2, and largest lymph node metastasis > 1 mm. Using these five variables, a numerical risk score was created from 0 to 5 to determine if an early recurrence occurred as the number of risk factors increased. The proportion of patients with early recurrence increased in linear fashion with increasing risk score (P < 0.0001). These data suggest that SLN positive stage III melanoma patients have a significant risk of early recurrence, which is associated with several defined variables and increases with the number of risk factors present. These data may be useful in stratifying patients to level of recurrence risk and adjusting follow-up schedules.

Amyloid precursor protein as a potential marker of malignancy and prognosis in papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) is the most common carcinoma of the thyroid gland and has a relatively favorable prognosis. However, it is important to identify PTC characteristics that indicate a high risk for recurrence and metastasis. Recent data indicate that the amyloid precursor protein (APP) is involved in cell adhesion, motility and proliferation. At present, the expression levels of APP and their prognostic significance in PTC have not been studied. In the present study, the APP gene expression in 10 PTCs and their adjacent thyroid tissue samples was analyzed using quantitative real time-PCR. Tissue array blocks were obtained from 90 PTC cases. Tumor regions and their adjacent non-tumor regions were analyzed in tissue array blocks and immunohistochemistry was conducted using sectioned slides. Semi-quantitative scores were correlated with the clinicopathological factors of 90 PTC patients. APP-specific mRNA was increased 50-fold in PTC samples compared with their adjacent thyroid tissue. The immunohistochemistry results showed APP expression levels to be significantly increased in PTC samples compared with their adjacent non-tumor thyroid tissue (p<0.001). High APP scores were significantly correlated with large tumor size, extracapsular invasion and lymph node metastasis. The amyloid precursor protein was overexpressed in PTC and a high APP expression was associated with high malignant potential. Therefore, APP may serve as a prognostic marker and potential novel therapeutic target in PTC.

Prognostic Factors for Recurrence of Papillary Thyroid Carcinoma in the Lymph Nodes, Lung, and Bone: Analysis of 5,768 Patients with Average 10‐year Follow‐up

Papillary thyroid carcinoma (PTC) frequently recurs to the lymph nodes, which may not be fatal immediately but is a stressor for physicians and patients. Recurrence to the distant organs, although less frequent, is often life-threatening, and the lung and bone are organs to which PTC is likely to recur. In the present study we investigated factors predicting recurrence of PTC to the lymph nodes, lung, and bone in a large number of patients undergoing long-term follow-up. A total of 5,768 PTC patients (608 males and 5,159 females) without distant metastasis at diagnosis who underwent initial surgery between 1987 and 2004 in Kuma Hospital were enrolled in this study. The postoperative follow-up ranged from 12 to 280months, and was 129months (10.8years) on average. To date, node, lung, and bone recurrences have been detected in 389 (7%), 118 (2%), and 33 patients (0.6%), respectively, and 57 patients (1%) have died of PTC. We examined the prognostic significance of the tumor size (T), extrathyroid extension (Ex), age 55years or older (Age), male gender (Gender), clinical node metastasis (N), and extranodal tumor extension (LN-Ex) for each outcome on multivariate analysis. Age, Gender, T>2cm, N, and Ex were independent predictors of lymph node recurrence. Age, Ex, T>2cm, and N were independent prognostic factors for lung recurrence. Ex, T>4cm, and N independently predicted bone recurrence. Of these, N≥3cm had the strongest prognostic value for lymph node, lung, and bone recurrences. In contrast, Age was the strongest predictor for carcinoma death. LN-Ex also had a prognostic value for carcinoma death, although it was not a predictor of carcinoma recurrence. Ex, N≥3cm, and T>2cm also had a prognostic impact on carcinoma death. Large lymph node metastasis showed a strong prognostic impact on carcinoma recurrence not only to the lymph nodes but also to the lung and bone, and carcinoma death. Extrathyroid extension also independently predicted these recurrences and carcinoma death, although hazard ratios were lower than for large node metastasis. Age 55years or older, in contrast, was the strongest predictor of carcinoma death. Extranodal tumor extension did not independently affect recurrence, but it had prognostic significance for carcinoma death. These findings suggest that recurring PTC lesions of older patients and/or extranodal tumor extensions are difficult to control and very progressive.

Radical prostatectomy reporting: consensus and controversy

Standardisation of the reporting of prostate cancer in radical prostatectomy (RP) specimens has resulted from the development of synoptic reporting protocols by groups in the US, Canada, UK and the RCPA. The recommendations for this were informed by the International Society of Urological Pathology Consensus Conference convened in 2009 which made a comprehensive series of recommendations regarding sampling and reporting. From this conference it was recommended that the weight of the prostate without seminal vesicles should be recorded. It was also agreed that the apical and basal excision margins should be examined by the cone method and that, while total sampling of the prostate was preferred, partial sampling was acceptable. For RPs without carcinoma on initial evaluation, a formal protocol was developed. It was agreed at the Conference that pT2 substaging was, in its present form, illogical and its use should be optional. It was similarly agreed that morphometric measurement of tumour volume should be optional, although some assessment of tumour volume should be provided. Infiltration of extraprostatic fat or desmoplastic bulging of the prostatic contour was considered diagnostic of extraprostatic extension of tumour. There was less agreement regarding the features of extraprostatic extension at the prostatic apex or bladder neck, although infiltration of an inked margin was considered positive by a majority of respondents. It was agreed that the site of positive surgical margin(s) should be provided and that the extent of the positive margin involvement should be measured in millimetres. There was agreement that all lymph nodes from any associated pelvic lymph node dissection should be blocked and an attempt made to quantify the proportion of positive nodes. In response to recent prognostic evidence it was also agreed that the diameter of the largest lymph node metastasis should be measured. There was consensus that lymphovascular invasion should be reported, although there was debate regarding the significance of presence of lymphovascular invasion within the seminal vesicle, with 56% reporting this as pT3b. Muscular infiltration of the extraprostatic, but not intraprostatic seminal vesicle, was considered by a majority to be diagnostic of pT3b tumours.

Prognosis and prognostic factors of patients with papillary thyroid carcinoma requiring resection of recurrent laryngeal nerve due to carcinoma extension

The recurrent laryngeal nerve (RN) is one of the most common organs to which papillary thyroid carcinoma (PTC) extends. However, the prognosis and prognostic factors for patients with PTC extending to the RN remain unclear. In this study, we investigated this issue in 298 patients who underwent initial and locally curative surgery for PTC requiring RN resection due to carcinoma extension. Preoperative vocal cord paralysis was detected in 179 patients (60.1%), and directly linked to significant extension to other organs, large tumor size, and advanced age. However, it did not have a significant prognostic impact on uni- or multivariate analyses. On multivariate analysis, independent prognostic factors were large node metastasis and advanced age for lymph node recurrence, significant extension to other organs for distant recurrence, and significant extension to other organs, large node metastasis, extranodal tumor extension, and advanced age for carcinoma death, respectively. Most prognostic factors identified in the entire series of patients also had a strong prognostic impact on the subset of patients requiring RN resection, together with significant extension to other organs. Preoperative vocal cord paralysis reflected the aggressive characteristic of PTC to some extent, but did not have a significant prognostic value.

Prognostic factors of papillary and follicular carcinomas in Japan based on data of kuma hospital.

There are some important prognostic factors for papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). In this paper, clinicopathological features significantly affecting patient prognosis are described based on our data as well as others. Distant metastasis at diagnosis is the most important prognostic factor for both PTC and FTC. Other than that, preoperative and intraoperative findings are important to evaluate the biological behavior of PTC. Extrathyroid extension, large lymph-node metastasis, and extranodal tumor extension that can be evaluated preoperatively or intraoperatively are significant prognostic factors for PTC patients. In contrast, pathological findings are important not only for diagnosis of FTC, but also for the evaluation of its biological character. Grade of invasiveness (minimally or widely invasive) and degree of differentiation (well differentiated or including a poorly differentiated component) greatly affect the prognosis of FTC patients.

A rare angiosarcoma: retiform haemangioendothelioma

We report the case of a rare angiosarcoma, retiform haemangioendothelioma, in an 18-year-old young man, which presented as a recurrent ulcerating lesion of the left pinna. Case report and literature review of retiform haemangioendothelioma. This is a low grade angiosarcoma with a high local recurrence rate and low metastasis rate, and was first described in 1994 by Calonje et al. This patient represents only the third report of lymph node metastasis in a case of retiform haemangioendothelioma. To date, 31 cases of the tumour have been reported. Histological diagnosis of this group of vascular neoplasms can be challenging, as their histopathological appearance is intermediate between haemangioma and angiosarcoma. Surgical excision remains the primary treatment modality, with adjuvant radiotherapy recommended in patients with large tumour size, local recurrence and lymph node metastasis, as seen in this case.

Early gastric cancer of signet ring cell carcinoma is more amenable to endoscopic treatment than is early gastric cancer of poorly differentiated tubular adenocarcinoma in select tumor conditions

Recently, endoscopic submucosal dissection has been carefully applied in early gastric cancer (EGC) with undifferentiated type. However, there are no individual guidelines for endoscopic treatment of EGCs with poorly differentiated tubular adenocarcinoma or signet ring cell carcinoma. The aim of this study was to investigate and compare the clinicopathologic features of these two types of EGC to guide the application of endoscopic treatment. Patients to undergo radical gastrectomy for the treatment of EGC were selected for inclusion in this study. Histology was classified according to the Japanese Gastric Cancer Association. Between January 2005 and December 2008, 288 patients with poorly differentiated EGC and 419 patients with signet ring cell EGC were enrolled. Their medical records were reviewed retrospectively. Compared with signet ring cell EGC, poorly differentiated EGC had higher rates of male gender, old age (≥45years), large tumor length (>20mm), ulcer, submucosal invasion, lymphovascular invasion, and lymph node metastasis. In the multivariate analyses, poorly differentiated EGC was significantly associated with ulcer (odds ratio [OR]: 2.4, 95% confidence interval [CI]: 1.5-3.8), submucosal invasion (OR: 3.6, 95% CI: 2.6-5.1) and lymphovascular invasion (OR: 2.0, 95% CI: 1.1-3.6) with a reference of signet ring cell EGC. The independent risk factors for lymph node metastasis were large tumor length, submucosal invasion, and lymphovascular invasion in both types of EGC. Young age was an independent risk factor of lymph node metastasis only in poorly differentiated EGC. Poorly differentiated EGC has clinicopathologic features that are less favorable to endoscopic treatment than are those of signet ring cell EGC. Therefore, these two types of EGC should be approached separately, not as a united type of undifferentiated histology, during the planning of endoscopic treatment.

Insulin-like growth factor II mRNA-binding protein 3 expression promotes tumor formation and invasion and predicts poor prognosis in oral squamous cell carcinoma

Insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3), an oncofetal RNA-binding protein, has been implicated in the enhancement of proliferation and invasion in various cancers. This study aimed to investigate the clinical significance and functional role of IGF2BP3 expression in oral squamous cell carcinoma (OSCC). IGF2BP3 expression in 93 OSCC patients was investigated using immunohistochemical staining and correlated with clinical parameters and patients' survival. The effect of IGF2BP3 on cell invasion ability was evaluated by RNA interference in OSCC cell line. High expression of IGF2BP3 in OSCC was significantly correlated with large tumor size and lymph node metastasis. Kaplan-Meier analysis revealed that oral cancer patients with high IGF2BP3 expression had a significantly lower 5-year survival (P = 0.0017). Multivariate analysis of clinical samples demonstrated IGF2BP3 to be an independent prognosis factor (P = 0.003). Moreover, the IGF2BP3 shRNA significantly suppressed the invasion ability of OSCC in vitro, and the knockdown of endogenous IGF2BP3 expression also inhibited tumor formation in vivo. IGF2BP3 enhances cell invasion ability and tumorigenicity in human OSCC in vitro and in vivo. IGF2BP3 is an independent prognostic factor in patients with OSCC. Targeting of IGF2BP3 could potentially suppress the tumor growth and metastasis to improve the outcome of patients with OSCC.

Nodal metastasis in well-differentiated follicular carcinoma of the thyroid: Its incidence and clinical significance

The clinical significance of nodal metastasis in well-differentiated follicular carcinoma (WD-FC) of the thyroid remains a controversial issue. This study aimed to clarify clinical and pathological characteristics of WD-FC with nodal metastasis, based on the new WHO classification. We examined 249 WD-FC cases diagnosed between 1983 and 2004 in our hospital. Poorly differentiated follicular carcinoma was not included in this study. Of the 249 WD-FC cases, 9 (3.6%) revealed nodal metastasis. The incidences of nodal metastasis in minimally invasive and widely invasive cases were 2.0 and 9.8%, respectively. In four patients, nodal metastasis was detected in the ipsilateral lymph nodes during the initial surgery. A total of 6 patients presented with nodal metastasis 2-10 years after the initial operation, and 3 patients with bilateral and large nodal metastases were relatively young. No patients succumbed to the carcinoma. Primary lesions of WD-FC with nodal metastasis were microscopically conventional, and there were no findings predicting nodal metastasis. We hypothesized that the incidence of nodal metastasis in WD-FC, based on the new WHO classification, was lower compared with previous reports. Younger individuals may be at a higher risk of large bilateral nodal metastasis. The presence of nodal metastasis did not affect the long-term outcome of follicular carcinoma.

Association between polymorphisms in interleukin‐17A and interleukin‐17F genes and risks of gastric cancer

Chronic inflammation is the hallmark of the pathogenesis of Helicobacter pylori-induced gastric cancer. Interleukin (IL)-17A and IL-17F are inflammatory cytokines expressed by a novel subset of CD4+ Th cells and play critical function in inflammation and probably in cancer. We conducted a case-control study including 1,010 gastric cancer patients and 800 healthy controls to assess the association between IL-17A G197A and IL-17F A7488G polymorphisms and risk of gastric cancer. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. Logistic regression and Cox-proportional hazards analyses were used to evaluate the associations between polymorphisms and gastric cancer susceptibility, clinicopathological features and survival. After adjusted for age and gender, IL-17F 7488GA and GG genotypes were associated with an increased risk of gastric cancer compared with AA genotype [OR 1.51, 95% confidence interval (CI): 1.22-1.87 for GA; OR 1.61, 95% CI: 1.03-2.51 for GG]. Further stratification analyses indicated that the effect of IL-17F 7488GA genotype was noteworthy in gastric cancer patients of noncardia, intestinal type, poorly and moderately differentiated, age older than 40, large tumor size and lymph node metastasis. IL-17A 197AG genotype was associated with increased risk of poorly differentiated, TNM I/II, age of 40-65-year subtypes of gastric cancer, but not with total gastric cancer risk (p = 0.098). No significant relationship was observed between polymorphisms and survival of gastric cancer patients. These findings suggest that polymorphism of IL-17F 7488 involved in susceptibility to gastric cancer, which also influenced certain subtypes according to clinicopathological features, whereas IL-17A 197 may be less relevant.