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1.  Prognostic role of lymph node metastasis in early gastric cancer 
Objective
To clarify the relationship between clinicopathological features and lymph node metastasis and to propose the potential indications of lymph node metastasis for prognosis in early gastric cancer (EGC) patients.
Methods
We retrospectively observed 226 EGC patients with lymph node resection, and analyzed the associations between lymph node metastasis and clinicopathological parameters using the chi-square test in univariate analysis and logistic regression analysis in multivariate analysis. Overall survival analysis was determined using the Kaplan-Meier and log-rank test. We conducted multivariate prognosis analysis using the Cox proportional hazards model.
Results
Of all the EGC patients, 7.5% (17/226) were histologically shown to have lymph node metastasis. The differentiation, lymphovascular invasion and depth of invasion were independent risk factors for lymph node metastasis in EGC. The 5- and 10-year survival rates were significantly lower in patients with lymph node metastasis than in those without and the patients also had shorter progress-free survival time. Lymph node metastasis and tumor size were independent prognostic factors for EGC. The status of the lymph nodes was a significant factor in predicting recurrence or metastasis after surgery.
Conclusions
The undifferentiated carcinoma and lymphovascular and/or submucosal invasion were associated with a higher incidence of lymph node metastasis in EGC patients, whom need to perform subsequent D2 lymphadenectomy or laparoscopic lymph node dissection and more rigorous follow-up or additional chemotherapy/radiation after D2 gastrectomy for poor prognosis and high recurrence/metastasis rate.
doi:10.3978/j.issn.1000-9604.2014.04.06
PMCID: PMC4000899  PMID: 24826060
Early gastric cancer (EGC); lymph node metastasis; prognosis; recurrence
2.  Indication for Endoscopic Resection of Submucosal Colorectal Carcinoma: Special Reference to Lymph Node Metastasis 
We investigated the relationship between histological factors and lymph node metastasis in 77 lesions with submucosally invasive colorectal carcinomas to establish useful criteria for lesions in which endoscopic treatment alone results in cure of malignancy. There were positive correlations between histological factors, including the level of invasion, the histologic grade, presence or absence of lymphatic invasion, presence or absence of budding, and lymph node metastasis (p < 0.05, p < 0.05, p < 0.005, p < 0.01). The presence or absence of venous invasion did not influence lymph node metastasis. Laparoscopic surgery involving lymph node dissection should be indicated for sm1 carcinoma lesions with unfavorable histological factors. In lesions diagnosed as sm2 or sm3 prior to resection, intestinal resection involving lymph node dissection by laparoscopic surgery should be directly performed without endoscopic resection.
In treating submucosally invasive colorectal carcinomas, the level of invasion can be clinically diagnosed, consequently endoscopic resection should be initially performed when lesions are evaluated as sm1 prior to resection. When histological investigation reveals sm1 carcinoma with histologic grade I (well-differentiated) or II (moderately-differentiated), and the absence of lymphatic invasion and budding, endoscopic treatment alone is sufficient.
doi:10.1155/DTE.6.101
PMCID: PMC2362745  PMID: 18493513
3.  Tumour budding at the deepest invasive margin correlates with lymph node metastasis in submucosal colorectal cancer detected by anticytokeratin antibody CAM5.2 
British Journal of Cancer  2006;94(2):293-298.
In the past few years, tumour budding at the invasive margin has been reported as a new risk factor for lymph node metastasis in advanced colorectal cancers, but it is sometimes difficult to detect tumour budding in submucosal colorectal cancer by haematoxylin and eosin staining. We immunohistochemically examined tumour budding at the deepest invasive margin of 56 surgically resected submucosal colorectal carcinomas using anticytokeratin antibody CAM5.2, furthermore checked by AE1/AE3, and determined the relation between tumour budding and clinicopathological factors. Moreover, we used the monoclonal antibody D2-40 for immunohistochemistry to detect lymphatic involvement. Tumour budding was detected in 42 cases (75.0%), and the budding-positive group showed a significantly higher rate of lymph node metastasis (including isolated tumour cells) (16/42 vs 0/14; P=0.004) than the budding-negative group. The sensitivity and negative predictive value of tumour budding alone for lymph node metastasis were superior to those of lymphatic invasion alone. Furthermore, the specificity and positive predictive value of the combination of either lymphatic invasion or tumour budding were superior to those of lymphatic invasion alone. Tumour budding detected immunohistochemically by using CAM5.2 is a newly found risk factor for lymph node metastasis and may help to avoid oversurgery in the future.
doi:10.1038/sj.bjc.6602927
PMCID: PMC2361114  PMID: 16404429
tumour budding; micrometastasis; isolated tumour cells; CAM5.2; D2-40
4.  Treatment of colorectal carcinoids: A new paradigm 
It is often difficult to evaluate the grade of malignancy and choose an appropriate treatment for colorectal carcinoids in clinical settings. Although tumor size and depth of invasion are evidently not enough to stratify the risk of this rare tumor, the present guidelines or staging systems do not mention other clinicopathological variables. Recent studies, however, have shed light on the impact of lymphovascular invasion on the outcome of colorectal carcinoids. It has been revealed that the presence of lymphovascular invasion was among the strongest risk factors for metastasis along with tumor size and depth of invasion. Furthermore, tumors smaller than 1 cm, within submucosal invasion and without lymphovascular invasion, carry minimal risk for metastasis with 100% 5-year survival in the studies from Japan as well as from the USA. This would suggest that these tumors could be curatively treated by endoscopic resection or transanal local excision. On the other hand, colorectal carcinoids with either lymphovascular invasion or tumor size larger than 1 cm carry the risk for metastasis equivalent to adenocarcinomas. Therefore, it should be emphasized that histological examination of lymphovascular invasion is mandatory in the specimens obtained by endoscopic resection or transanal local excision, as this would provide useful information for determining the need for additional radical surgery with regional lymph node dissection. Although the present guidelines or TNM staging system do not mention the impact of lymphovascular invasion, this would be among the next promising targets in order to establish better guidelines and staging systems, particularly in early-stage colorectal carcinoids.
doi:10.4240/wjgs.v2.i5.153
PMCID: PMC2999232  PMID: 21160865
Lymphovascular invasion; Neuroendocrine tumor; Carcinoid; Colorectal cancer
5.  Predictive Factors for Lymph Node Metastasis in Signet Ring Cell Gastric Cancer and the Feasibility of Endoscopic Submucosal Dissection 
Journal of Gastric Cancer  2013;13(2):93-97.
Purpose
Endoscopic submucosal dissection has recently been practiced on a differentiated type of early gastric cancer. However, there is no clear evidence for endoscopic treatments of signet ring cell carcinoma. The aim of this study is to identify the predictive clinicopathological factors for lymph node metastasis in signet ring cell carcinoma for assisting endoscopic submucosal dissection trials.
Materials and Methods
A total of 186 patients with early signet ring cell carcinoma who underwent radical curative gastrectomy between January 2001 and September 2009 were enrolled in this study. Retrospective reviews of their medical records are being conducted. Several clinicopathologic factors were being investigated in order to identify predictive factors for lymph nodes metastasis: age, gender, tumor size, type of operation, tumor location, gross type, ulceration, Lauren's classification, depth of invasion, and lymphatic invasion.
Results
The lymph node metastasis rate for signet ring cell carcinoma was 4.3% (n=8). Of the 186 lesions with early signet ring cell carcinoma, 91 (48.9%) tumors were larger than 15 mm in size and 40 (21.5%) showed submucosal invasions in the resection specimens. In multivariate analysis, only the lymphatic invasion (P<0.0001) showed an association with lymph node metastasis. To evaluate cutoff values for tumor sizes in the presence of lymph node metastasis, early signet ring cell carcinomas with lymphatic invasions were excluded. In the absence of lymphatic invasion, mucosal cancer with tumor sizes <15 mm had no lymph node metastasis.
Conclusions
Endoscopic submucosal dissection can be performed on patients with early signet ring cell carcinoma limited to the mucosa and less than 15 mm.
doi:10.5230/jgc.2013.13.2.93
PMCID: PMC3705138  PMID: 23844323
Stomach neoplasms; Carcinoma, signet ring cell; Endoscopic submucosal dissection; Lymph node metastasis; Predictive factor
6.  Parameters predicting lymph node metastasis in patients with superficial esophageal squamous cell carcinoma 
Endoscopic resection is a less invasive treatment than esophagectomy for superficial esophageal squamous cell carcinoma, but patients with lymph node metastasis need additional treatment after endoscopic resection. The purpose of this study was to establish a set of indicators to identify superficial esophageal squamous cell carcinoma patients at a high risk of metastasis. 271 superficial esophageal squamous cell carcinoma esophagectomy cases were reviewed retrospectively. The relationships between clinicopathological parameters and immunohistochemical findings (p53, Cyclin D1, EGFR and VEGF) on tissue microarrays, on the one hand, and lymph node metastasis were assessed by univariate and multivariate logistic regression analyses. Patients with intraluminal masses and ulcerated masses had a high risk of lymph node metastasis. Patients with superficial esophageal squamous cell carcinoma 1) thinner than 1200µm; 2) confined to the mucosa; 3) with submucosal invasion <250µm; 4) with submucosal invasion ≥250µm but with negative VEGF expression and well/moderately differentiated or basaloid histology; or 5) with submucosal invasion ≥250µm but with weak VEGF expression and well differentiated histology had almost no risk of lymph node metastasis. We recommend endoscopic resection for all erosive, papillary and plaque-like superficial esophageal squamous cell carcinomas where endoscopic resection is clinically feasible, and esophagectomy for all other erosive, papillary and plaque-like cases and all intraluminal masses and ulcerated tumors. No additional treatment is needed for endoscopic resection cases with superficial esophageal squamous cell carcinoma 1) thinner than 1200µm; 2) confined to the mucosa; 3) with submucosal invasion <250µm; 4) with submucosal invasion ≥250µm but with negative VEGF expression and well/moderately differentiated or basaloid histology; or 5) with submucosal invasion ≥250µm but with weak VEGF expression and well differentiated histology. These clinical and pathological criteria should enable more accurate selection of patients for these procedures.
doi:10.1038/modpathol.2012.89
PMCID: PMC3505024  PMID: 22627741
superficial cancer; esophageal cancer; squamous cell carcinoma; endoscopic resection; lymph node metastasis
7.  Histopathological risk factors for lymph node metastasis in submucosal invasive colorectal carcinoma of pedunculated or semipedunculated type 
Journal of Clinical Pathology  2006;60(8):912-915.
Aims
To evaluate the histopathological risk factors for lymph node metastasis in cases of pedunculated or semipedunculated submucosal invasive colorectal carcinoma (SICC).
Methods
A total of 48 patients with non‐sessile SICC who underwent systematic lymph node dissection were included. Tumour size, histological grade, angiolymphatic invasion, tumour budding, dedifferentiation, objective submucosal invasion depth from the identified muscularis mucosa, relative invasion depth of the submucosal layer, and depth of stalk invasion were investigated histopathologically.
Results
Lymph node metastasis was observed in seven cases (14.6%). Univariate analysis showed angiolymphatic invasion and tumour budding to be significantly associated with lymph node metastasis. Multivariate analysis showed that tumour budding was the only independent factor associated with lymph node metastasis in cases of non‐sessile SICC.
Conclusions
Results indicate that tumour budding is a useful risk factor for predicting lymph node metastasis in cases of pedunculated or semipedunculated SICC.
doi:10.1136/jcp.2006.043539
PMCID: PMC1994481  PMID: 16997919
colorectal carcinoma; pedunculated; lymph node metastasis; risk factors; tumour budding
8.  Endoscopic and surgical resection of T1a/T1b esophageal neoplasms: A systematic review 
AIM: To investigate potential therapeutic recommendations for endoscopic and surgical resection of T1a/T1b esophageal neoplasms.
METHODS: A thorough search of electronic databases MEDLINE, Embase, Pubmed and Cochrane Library, from 1997 up to January 2011 was performed. An analysis was carried out, pooling the effects of outcomes of 4241 patients enrolled in 80 retrospective studies. For comparisons across studies, each reporting on only one endoscopic method, we used a random effects meta-regression of the log-odds of the outcome of treatment in each study. “Neural networks” as a data mining technique was employed in order to establish a prediction model of lymph node status in superficial submucosal esophageal carcinoma. Another data mining technique, the “feature selection and root cause analysis”, was used to identify the most important predictors of local recurrence and metachronous cancer development in endoscopically resected patients, and lymph node positivity in squamous carcinoma (SCC) and adenocarcinoma (ADC) separately in surgically resected patients.
RESULTS: Endoscopically resected patients: Low grade dysplasia was observed in 4% of patients, high grade dysplasia in 14.6%, carcinoma in situ in 19%, mucosal cancer in 54%, and submucosal cancer in 16% of patients. There were no significant differences between endoscopic mucosal resection and endoscopic submucosal dissection (ESD) for the following parameters: complications, patients submitted to surgery, positive margins, lymph node positivity, local recurrence and metachronous cancer. With regard to piecemeal resection, ESD performed better since the number of cases was significantly less [coefficient: -7.709438, 95%CI: (-11.03803, -4.380844), P < 0.001]; hence local recurrence rates were significantly lower [coefficient: -4.033528, 95%CI: (-6.151498, -1.915559), P < 0.01]. A higher rate of esophageal stenosis was observed following ESD [coefficient: 7.322266, 95%CI: (3.810146, 10.83439), P < 0.001]. A significantly greater number of SCC patients were submitted to surgery (log-odds, ADC: -2.1206 ± 0.6249 vs SCC: 4.1356 ± 0.4038, P < 0.05). The odds for re-classification of tumor stage after endoscopic resection were 53% and 39% for ADC and SCC, respectively. Local tumor recurrence was best predicted by grade 3 differentiation and piecemeal resection, metachronous cancer development by the carcinoma in situ component, and lymph node positivity by lymphovascular invasion. With regard to surgically resected patients: Significant differences in patients with positive lymph nodes were observed between ADC and SCC [coefficient: 1.889569, 95%CI: (0.3945146, 3.384624), P < 0.01). In contrast, lymphovascular and microvascular invasion and grade 3 patients between histologic types were comparable, the respective rank order of the predictors of lymph node positivity was: Grade 3, lymphovascular invasion (L+), microvascular invasion (V+), submucosal (Sm) 3 invasion, Sm2 invasion and Sm1 invasion. Histologic type (ADC/SCC) was not included in the model. The best predictors for SCC lymph node positivity were Sm3 invasion and (V+). For ADC, the most important predictor was (L+).
CONCLUSION: Local tumor recurrence is predicted by grade 3, metachronous cancer by the carcinoma in-situ component, and lymph node positivity by L+. T1b cancer should be treated with surgical resection.
doi:10.3748/wjg.v19.i9.1424
PMCID: PMC3602502  PMID: 23539431
Superficial esophageal cancer; Endoscopic resection; Mucosal infiltration; Submucosal involvement; Recurrent tumor; Controversies in treatment; Squamous cell carcinoma; Adenocarcinoma; Lymphatic invasion; Vascular invasion; Submucosal layer; Superficial submucosal layer; Middle third submucosal layer; Deep third submucosal layer; Esophageal cancer; Endoscopic gastrointestinal surgical procedures; Endoscopic gastrointestinal surgery; Lymph node dissection; Dysplasia
9.  Clinicopathological features associated with lymph node metastasis in early gastric cancer: Analysis of a single-institution experience in China 
BACKGROUND:
An accurate assessment of potential lymph node metastasis is an important issue for the appropriate treatment of early gastric cancer. Minimizing the number of invasive procedures used in cancer therapy is critical for improving the patient’s quality of life.
OBJECTIVE:
To evaluate the clinicopathological features associated with lymph node metastasis of early gastric cancer in patients from a single institution in China.
METHODS:
A retrospective review of data from 410 patients surgically treated for early gastric cancer at the First Affiliated Hospital (Nanjing, China) between 1998 and 2007, was conducted. The clinicopathological variables associated with lymph node metastasis were evaluated.
RESULTS:
Lymph node metastasis was observed in 12.20% of patients. The macroscopic type, tumour size, location in the stomach, depth of gastric carcinoma infiltration, and presence of vascular or lymphatic invasion showed a positive correlation with the incidence of lymph node metastasis by univariate analysis. Multivariate analyses revealed histological classification, macroscopic type, tumour size, depth of gastric carcinoma infiltration, and the presence of vascular or lymphatic invasion to be significantly and independently related to lymph node metastasis. The depth of gastric carcinoma infiltration was the strongest predictive factor for lymph node metastasis. For intramucosal cancer, tumour size was the unique risk factor for lymph node metastasis. For submucosal cancer, histological classification and tumour size were independent risk factors for lymph node metastasis.
CONCLUSIONS:
Histological classification, macroscopic type, tumour size, depth of gastric carcinoma infiltration, and the presence of vascular or lymphatic invasion are independent risk factors for lymph node metastasis in patients with early gastric cancer in China. Minimal invasive treatment, such as endoscopic mucosal resection, may be possible for highly selected cancers.
PMCID: PMC2706748  PMID: 19440566
China; Early gastric cancer; Lymph node metastasis; Risk factor
10.  The clinical significance of subcarinal lymph node dissection in the radical resection of oesophageal cancer 
OBJECTIVES
To explore the rule of subcarinal lymph node metastasis in thoracic oesophageal cancer and its clinical significance in the radical resection of oesophageal cancer.
METHODS
We retrospectively analysed 2223 patients with oesophageal cancer who were admitted to Henan Cancer Hospital during 2004–2011 and underwent surgery as the first treatment option. Routine subcarinal lymph node dissections were performed, and the sections from the resected lymph nodes were embedded in paraffin for routine pathological examination.
RESULTS
Subcarinal lymph node metastasis was observed in 200 patients (9%). Logistic regression analysis identified the following risk factors (P < 0.05): tumour location, depth of invasion into the oesophageal wall, tissue type, number of lymph node metastases, paraoesophageal lymph node metastasis (level 8 lymph nodes), left gastric cardiac lymph node metastasis. Unpaired t-test and χ2-test showed that more lymph node metastases, longer tumour length, deeper tumour invasion, middle oesophageal cancer, squamous-cell carcinoma, lower degree of differentiation, paraoesophageal lymph node metastasis and left gastric cardiac lymph node metastasis were associated with a higher frequency of subcarinal lymph node metastases (P < 0.05). Using the Kaplan–Meier method, recurrence and metastasis were shown to be more likely with solitary subcarinal lymph node metastasis than with solitary paraoesophageal lymph node metastasis (P = 0.001).
CONCLUSIONS
Tumour location, depth of invasion, pathological type, degree of differentiation and other factors are closely associated with subcarinal lymph node metastasis. Recurrence and metastasis after oesophageal dissection are more likely with subcarinal lymph node metastasis.
doi:10.1093/icvts/ivt070
PMCID: PMC3653481  PMID: 23475120
Oesophageal cancer; Oesophageal surgery; Subcarinal lymph node dissection
11.  Impact of tumor chronology and tumor biology on lymph node metastasis in breast cancer 
SpringerPlus  2013;2:480.
Synopsis
The significance of nodal metastasis in breast cancer is under discussion. We investigated the impact of variables of tumor chronology and tumor biology on the presence of lymph node metastases.
Purpose
Lymph node involvement is the main prognostic factor in breast cancer. However, it is under discussion whether nodal metastasis in breast cancer only reflects the chronological age of the tumor or whether it is also a marker of tumor biology. The goal of our study was to investigate the impact of variables of tumor chronology and biology on the presence of lymph node metastases.
Methods
We performed a retrospective analysis of data from 3002 patients with an early invasive breast carcinoma. All patients underwent primary surgery at the University Hospitals Leuven between 2001 and 2009. First, the impact of tumor size on the presence of lymph node metastasis was evaluated as the chronological age of a tumor is supposed to be reflected in its size. Next, the impact of tumor grade, lymphovascular invasion and the hormone receptor status, which are all variables of tumor biology, was studied. Logistic regression analyses were performed and the area under the ROC curve (AUC) was calculated as a measure of discrimination between logistic regression models.
Results
Using pathological tumor size the AUC of prediction was 0.67. Based on variables of tumor biology, axillary lymph node positivity could be predicted with an AUC of 0.68. Combining variables of tumor chronology and biology an AUC of 0.74 for the prediction of axillary lymph node (ALN) positivity was calculated.
Conclusions
According to our data variables of tumor chronology and tumor biology have a similar impact on the presence of lymph node metastasis.
doi:10.1186/2193-1801-2-480
PMCID: PMC3786086  PMID: 24083118
Tumor chronology; Tumor biology; Lymph node; Metastasis; Breast cancer
12.  Factors predicting survival in patients with proximal gastric carcinoma involving the esophagus 
AIM: To investigate the clinicopathologic features which predict surgical overall survival in patients with proximal gastric carcinoma involving the esophagus (PGCE).
METHODS: Electronic pathology database established in the Department of Pathology of the Nanjing Drum Tower Hospital was searched for consecutive resection cases of proximal gastric carcinoma over the period from May 2004 through July 2009. Each retrieved pathology report was reviewed and the cases with tumors crossing the gastroesophageal junction line were selected as PGCE. Each tumor was re-staged, following the guidelines on esophageal adenocarcinoma, according to the 7th edition of the American Joint Commission on Cancer Staging Manual. All histology slides were studied along with the pathology report for a retrospective analysis of 13 clinicopathologic features, i.e., age, gender, Helicobacter pylori (H. pylori) infection, surgical modality, Siewert type, tumor Bormann’s type, size, differentiation, histology type, surgical margin, lymphovascular and perineural invasion, and pathologic stage in relation to survival after surgical resection. Prognostic factors for overall survival were assessed with uni- and multi-variate analyses.
RESULTS: Patients’ mean age was 65 years (range: 47-90 years). The male: female ratio was 3.3. The 1-, 3- and 5-year overall survival rates were 87%, 61% and 32%, respectively. By univariate analysis, age, male gender, H. pylori, tumor Bormann’s type, size, histology type, surgical modality, positive surgical margin, lymphovascular invasion, and pT stage were not predictive for overall survival; in contrast, perineural invasion (P = 0.003), poor differentiation (P = 0.0003), > 15 total lymph nodes retrieved (P = 0.008), positive lymph nodes (P = 0.001), and distant metastasis (P = 0.005) predicted poor post-operative overall survival. Celiac axis nodal metastasis was associated with significantly worse overall survival (P = 0.007). By multivariate analysis, ≥ 16 positive nodes (P = 0.018), lymph node ratio > 0.2 (P = 0.003), and overall pathologic stage (P = 0.002) were independent predictors for poor overall survival after resection.
CONCLUSION: Patients with PGCE showed worse overall survival in elderly, high nodal burden and advanced pathologic stage. This cancer may be more accurately staged as gastric, than esophageal, cancer.
doi:10.3748/wjg.v18.i27.3602
PMCID: PMC3400864  PMID: 22826627
Cancer; Esophagus; Gastroesophageal junction; Staging; Stomach
13.  Clinical Pathological Analysis of Surgically Resected Superficial Esophageal Carcinoma to Determine Criteria for Deciding on Treatment Strategy 
We performed a clinical pathological study of conventionally resected superficial esophageal carcinomas since this type of lesion has been increasing, in order to develop criteria of determination for therapeutic strategies. Pathological studies were performed on specimens obtained by radical surgical resection in 133 cases of superficial esophageal cancer. Evaluation was performed in terms of the gross classification of the lesion type, depth of invasion, lymph node metastasis, vascular invasion, size of the lesion, outcome, etc. In 0-I, 0-IIc+0-IIa, and 0-III type submucosal cancer lesions the rate of metastasis to lymph nodes was more than 40%, but in 0-IIa and 0-IIb mucosal cancer cases no lymph node metastasis was observed. 0-IIc type lesions showed a wide range of invasiveness, ranging from m1 to sm3. In cases with m1 or m2 invasion, no lymph node or lymph-vessel invasion was recognized, but in m3, sm1, sm2, and sm3 cases lymph node metastasis was recognized in 12.5%, 22.2%, 44.0% and 47.4%, respectively. In 47% of lesions with a greatest dimension of less than 30 mm invasion was limited to the mucosa. Seventy-two percent of m1 and m2 cases were 30 mm in size or less. Lymph node metastasis was recognized in only 16.7% of cases less than 30 mm in size, but in cases of lesions 30 mm or more the rate of lymph node metastasis was 35.8%. 0-IIb and 0-IIa type lesions are indications for endoscopic esophageal mucosal resection (EEMR), while 0-I, 0-IIc+0-IIa, and 0-III lesions should be candidates for radical surgical resection. In the 0-IIc category, lesions in which the depression is relatively flat and with a finely granular surface are indications for EEMR, but those cases in which the surface of depression shows granules of varying sizes should be treated with radical surgical resection. Cases of 0-IIa type 30 mm or larger in greatest dimension which have a gently sloping protruding margin shoulder or reddening should be treated with caution, but EEMR can be performed first and subsequent therapeutic strategy decided on, based on the pathological findings of the specimen.
doi:10.1155/DTE.3.211
PMCID: PMC2362570  PMID: 18493439
14.  Epstein-Barr virus-associated lymphoepithelioma-like early gastric carcinomas and endoscopic submucosal dissection: Case series 
Epstein-Barr virus (EBV)-associated lymphoepithelioma-like gastric carcinoma (LELC) is characterized by a lower lymph node (LN) metastasis rate and a higher survival rate than other forms of gastric cancer. Although current prognosis for LELC is favorable, the most common approach is radical gastrectomy involving an extensive D2 lymph node dissection. Here, we report four cases of EBV-associated early LELC that were treated by an alternative approach, endoscopic submucosal dissection (ESD). The long-term outcome of this procedure is discussed. All patients were treated by ESD en bloc, and all ESD specimens showed tumor-free lateral resection margins. None of the lesions showed lymphovascular invasion. A pathological examination of ESD specimens revealed submucosal invasion of more than 500 μm in all four cases. One patient underwent additional radical surgery post-ESD; no residual tumor or LN metastasis was noted in the surgical specimen. The other three patients did not undergo additional surgery, either because of severe comorbidity or their refusal to undergo operation, but were subjected to medical follow-up. None of the ESD-treated patients reported local recurrence or distant metastases during the 27-32 mo of follow-up after ESD.
doi:10.3748/wjg.v20.i5.1365
PMCID: PMC3921521  PMID: 24574813
Endoscopic submucosal dissection; Epstein-Barr virus; Lymph node; Lymphoepithelioma-like gastric carcinoma; Prognosis
15.  Invasive front of colorectal cancer: Dynamic interface of pro-/anti-tumor factors 
Tumor-host interaction at the invasive front of colorectal cancer represents a critical interface encompassing a dynamic process of de-differentiation of colorectal carcinoma cells known as epithelial mesenchymal transition (EMT). EMT can be identified histologically by the presence of “tumor budding”, a feature which can be highly specific for tumors showing an infiltrating tumor growth pattern. Importantly, tumor budding and tumor border configuration have generated considerable interest as additional prognostic factors and are also recognized as such by the International Union Against Cancer. Evidence seems to suggest that the presence of tumor budding or an infiltrating growth pattern is inversely correlated with the presence of immune and inflammatory responses at the invasive tumor front. In fact, several tumor-associated antigens such as CD3, CD4, CD8, CD20, Granzyme B, FOXP3 and other immunological or inflammatory cell types have been identified as potentially prognostic in patients with this disease. Evidence seems to suggest that the balance between pro-tumor (including budding and infiltrating growth pattern) and anti-tumor (immune response or certain inflammatory cell types) factors at the invasive front of colorectal cancer may be decisive in determining tumor progression and the clinical outcome of patients with colorectal cancer. On one hand, the infiltrating tumor border configuration and tumor budding promote progression and dissemination of tumor cells by penetrating the vascular and lymphatic vessels. On the other, the host attempts to fend off this attack by mounting an immune response to protect vascular and lymphatic channels from invasion by tumor buds. Whereas standard pathology reporting of breast and prostate cancer involves additional prognostic features, such as the BRE and Gleason scores, the ratio of pro- and anti-tumor factors could be a promising approach for the future development of a prognostic score for patients with colorectal cancer which could complement tumor node metastasis staging to improve the clinical management of patients with this disease.
doi:10.3748/wjg.15.5898
PMCID: PMC2795176  PMID: 20014453
Colorectal cancer; Prognosis; Tumor invasive front; Tumor budding; Tumor growth pattern; Tumor infiltrating lymphocytes; Tumor immunity; Microsatellite instability
16.  Lymph node staging in colorectal cancer: Old controversies and recent advances 
Outcome prediction based on tumor stage reflected by the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor node metastasis (TNM) system is currently regarded as the strongest prognostic parameter for patients with colorectal cancer. For affected patients, the indication for adjuvant therapy is mainly guided by the presence of regional lymph node metastasis. In addition to the extent of surgical lymph node removal and the thoroughness of the pathologist in dissecting the resection specimen, several parameters that are related to the pathological work-up of the dissected nodes may affect the clinical significance of lymph node staging. These include changing definitions of lymph nodes, involved lymph nodes, and tumor deposits in different editions of the AJCC/UICC TNM system as well as the minimum number of nodes to be dissected. Methods to increase the lymph node yield in the fatty tissue include methylene blue injection and acetone compression. Outcome prediction based on the lymph node ratio, defined as the number of positive lymph nodes divided by the total number of retrieved nodes, may be superior to the absolute numbers of involved nodes. Extracapsular invasion has been identified as additional prognostic factor. Adding step sectioning and immunohistochemistry to the pathological work-up may result in higher accuracy of histological diagnosis. The clinical value of more recent technical advances, such as sentinel lymph node biopsy and molecular analysis of lymph nodes tissue still remains to be defined.
doi:10.3748/wjg.v19.i46.8515
PMCID: PMC3870496  PMID: 24379568
Colon cancer; Rectum cancer; Tumor staging; Lymph node metastasis; Prognosis; Sentinel lymph node; Lymph node ratio; Extracapsular invasion; Immunohistochemistry; Molecular analysis
17.  Preoperative carcinoembryonic antibody is predictive of distant metastasis in pathologically T1 colorectal cancer after radical surgery 
AIM: To identify the predictors of distant metastasis in pathologically T1 (pT1) colorectal cancer (CRC) after radical resection.
METHODS: Variables including age, gender, preoperative carcinoembryonic antibody (CEA) level, tumor location, tumor size, lymph node status, and histological grade were recorded. Patients with and without metastasis were compared with regard to age, gender, CEA level and pathologic tumor characteristics using the independent t test or χ2 test, as appropriate. Risk factors were determined by logistic regression analysis.
RESULTS: Metastasis occurred in 6 (3.8%) of the 159 patients during a median follow-up of 67.0 (46.5%) mo. The rates of distant metastasis in patients with pT1 cancer of the colon and rectum were 6.7% and 2.9%, respectively (P < 0.001). The rates of distant metastasis between male and female patients with T1 CRC were 6.25% and 1.27%, respectively (P < 0.001). The most frequent site of distant metastasis was the liver. Age (P = 0.522), gender (P = 0.980), tumor location (P = 0.330), tumor size (P = 0.786), histological grade (P = 0.509), and high serum CEA level (P = 0.262) were not prognostic factors for lymph node metastasis. Univariate analysis revealed that age (P = 0.231), gender (P = 0.137), tumor location (P = 0.386), and tumor size (P = 0.514) were not risk factors for distant metastasis after radical resection for T1 colorectal cancer. Postoperative metastasis was only significantly correlated with high preoperative serum CEA level (P = 0.001). Using multivariate logistic regression analysis, high preoperative serum CEA level (P = 0.004; odds ratio 15.341; 95%CI 2.371-99.275) was an independent predictor for postoperative distant metastasis.
CONCLUSION: The preoperative increased serum CEA level is a predictive risk factor for distant metastasis in CRC patients after radical resection. Adjuvant chemotherapy may be necessary in such patients, even if they have pT1 colorectal cancer.
doi:10.3748/wjg.v19.i3.389
PMCID: PMC3554824  PMID: 23372362
Colorectal cancer; Risk factor; Metastasis; Pathologically T1; Carcinoembryonic antigen
18.  Fascin expression in colorectal carcinomas 
Clinics  2010;65(2):157-164.
PURPOSE
The purpose of this study was to investigate the significance of fascin expression in colorectal carcinoma.
METHODS
This is a retrospective study of 167 consecutive, well-documented cases of primary colorectal adenocarcinoma for which archival material of surgical specimens from primary tumor resections were available. We chose a representative tissue sample block and examined fascin expression by immunohistochemistry using a primary antibody against “fascin”. We calculated the “immunohistochemical score (IHS)” of fascin for each case, which was calculated from the multiplication of scores for the percentage of stained cells and the staining intensity.
RESULTS
Fascin immunoreactivity was observed in 59 (35.3%) of all cases with strong reactivity in 24 (14.4%), moderate reactivity in 25 (14.9%) and weak reactivity in 10 (6.0%) cases. Strong/moderate immunoreactivities were mostly observed in invasive fronts of the tumors or in both invasive and other areas. Fascin immunoreactivity scores were significantly higher in tumors with lymph node metastasis (p:0.002) and advanced stage presentation (p:0.007). There was no relation between fascin expression and age, gender, depth of invasion, distant metastasis or histological grade (p>0.05). There was a higher and statistically significant correlation between fascin immunoreactivity in the invasive borders of tumors and lymph node metastasis (r:0.747, p:0.005). In stage III/IV tumors, two-year survival was 92.2% in tumors without fascin immunoreactivity, and only 60.0% in tumors with a fascin IHS>10 (p:0.003).
CONCLUSION
These findings suggest that fascin is heterogeneously expressed in approximately one third of colorectal carcinomas with a significant association with lymph node metastasis, tumor stage and location. Moreover, these results indicate that fascin may have a role in the lymph node metastasis of colorectal carcinomas.
doi:10.1590/S1807-59322010000200007
PMCID: PMC2827702  PMID: 20186299
Colorectal carcinoma; Fascin; Prognosis; Tumor
19.  Clinicopathological characteristics of rectal carcinoid patients undergoing surgical resection 
Oncology Letters  2012;4(5):910-914.
The aim of this study was to clarify the clinical aspects, histopathological features and prognosis of patients with rectal carcinoids, focusing on properties associated with metastasis, in order to gain insights into appropriate management. A total of 20 patients (15 males, 5 females; mean age, 54.9 years; range, 23–71) who underwent surgery for rectal carcinoid tumors at the Department of Colorectal Surgery, Hyogo College of Medicine, between May 2000 and January 2011 were analyzed. Ki-67 immunostaining was performed in 13 cases with available tumor tissue specimens. Of the 20 patients, a radical operation including rectal resection with a lymphadenectomy was performed in 16. The mean tumor size was 11.9 mm (3–25 mm) and lymph node metastasis was confirmed in 9 cases, including 3 with lesions no greater than 7 mm in diameter. Overall, 16 (80%) of the tumors were localized in the submucosal layer and 4 (20%) involved the proper muscle layer. Ki-67 labeling index and lymphovascular invasion were shown to be associated with lymph node and/or distant metastasis by multiple logistic regression analysis, but were not statistically significant in ANOVA findings. Lymph node metastasis from rectal carcinoids, even those smaller than 10 mm in diameter, was not a rare event. More attention should be given to decision-making, including the possibility of endoscopic resection for the treatment of rectal carcinoid tumors regardless of size.
doi:10.3892/ol.2012.868
PMCID: PMC3499485  PMID: 23162621
rectal carcinoid; metastasis; Ki-67; lymphovascular invasion
20.  Can serum interleukin-2 receptor alpha predict lymph node metastasis in early gastric cancer? 
Purpose
Although local resection like endoscopic mucosal resection for early gastric cancer is accepted as a treatment option, one of the most important drawbacks of such an approach is the inability to predictlymph node metastasis. The aim of this study was to evaluate the serum soluble receptor alpha for interleukin-2 (IL-2Rα) level as a predictor of lymph node metastasis in the patients with early gastric cancer.
Methods
Assessment of pre-operative serum IL-2Rα levels was performed on 86 patients with early gastric cancer treated by gastrectomies combined with D2 lymph node resections and 20 healthy controls at Samsung Medical Center. Data on patient age and gender, tumor size, depth of invasion, histologic differentiation, and endoscopic findings were reviewed post-operatively. The submucosal lesions were divided into three layers (sm1, sm2, and sm3) in accordance with the depth of invasion.
Results
Lymph node metastasis was observed in 16 patients (18.6%). Statistically, the serum IL-2Rα level was an important predictive factor of lymph node metastasis in undifferentiated gastric cancer, and the cut-off point for the predictive value of serum IL-2Rα level was 200 U/mL.
Conclusion
The serum IL-2Rα level might be a good predictor of lymph node metastasis in undifferentiated early gastric cancer.
doi:10.4174/jkss.2012.82.3.143
PMCID: PMC3294107  PMID: 22403747
Stomach neoplasms; Lymphatic metastasis; Serum marker; Prediction
21.  Endoscopic submucosal dissection for foregut neuroendocrine tumors: An initial study 
AIM: To evaluate the feasibility and efficacy of endoscopic submucosal dissection (ESD) for foregut neuroendocrine tumors (NETs).
METHODS: From April 2008 to December 2010, patients with confirmed histological diagnosis of foregut NETs were included. None had regional lymph node enlargement or distant metastases to the liver or lung on preoperative computerized tomography scanning or endoscopic ultrasonography (EUS). ESD was attempted under general anesthesia. After making several marking dots around the lesion, a mixture solution was injected into the submucosa. The mucosa was incised outside the marking dots. Dissection of the submucosal layer beneath the tumor was performed under direct vision to achieve complete en bloc resection of the specimen. Tumor features, clinicopathological characteristics, complete resection rate, and complications were evaluated. Foregut NETs were graded as G1, G2, or G3 on the basis of proliferative activity by mitotic count or Ki-67 index. All patients underwent regular follow-up to evaluate for any local recurrence or distant metastasis.
RESULTS: Those treated by ESD included 24 patients with 29 foregut NETs. The locations of the 29 lesions are as follows: esophagus (n = 1), cardia (n = 1), stomach (n = 23), and duodenal bulb (n = 4). All lesions were found incidentally during routine upper gastrointestinal endoscopy for other indications, and none had symptoms of carcinoid syndrome. Preoperative EUS showed that all tumors were confined to the submucosa. Among the 24 gastric lesions, 16 lesions in 11 patients were type I gastric NETs arising in chronic atrophic gastritis with hypergastrinemia, while the other 8 solitary lesions were type III because of absence of atrophic gastritis in these cases. All of the tumors were removed in an en bloc fashion. The average maximum diameter of the lesions was 9.4 mm (range: 2-30 mm), and the procedure time was 20.3 min (range: 10-45 min). According to the World Health Organization 2010 classification, histological evaluation determined that 26 lesions were NET-G1, 2 gastric lesions were NET-G2, and 1 esophageal lesion was neuroendocrine carcinoma (NEC). Complete resection was achieved in 28 lesions (28/29, 96.6%), and all of them were confined to the submucosa in histopathologic assessment with no lymphovascular invasion. The remaining patient with NEC underwent additional surgery because the resected specimens revealed angiolymphatic and muscularis invasion, as well as incomplete resection. Delayed bleeding occurred in 1 case 3 d after ESD, which was managed by endoscopic treatment. There were no procedure-related perforations. During a mean follow-up period of 24.4 mo (range: 12-48 mo), local recurrence occurred in only 1 patient 7 mo after initial ESD. This patient successfully underwent repeat ESD. Metastasis to lymph nodes or distal organs was not observed in any patient. No patients died during the study period.
CONCLUSION: ESD appears to be a safe, feasible, and effective procedure for providing accurate histopathological evaluations and curative treatment for eligible foregut NETs.
doi:10.3748/wjg.v18.i40.5799
PMCID: PMC3484351  PMID: 23155323
Endoscopic submucosal dissection; Neuroendocrine tumor; Foregut
22.  Ex vivo localization and immunohistochemical detection of sentinel lymph node micrometastasis in patients with colorectal cancer can upgrade tumor staging 
Diagnostic Pathology  2012;7:71.
Background
It is not clear if sentinel lymph node (SLN) mapping can improve outcomes in patients with colorectal cancers. The purpose of this study was to determine the prognostic values of ex vivo sentinel lymph node (SLN) mapping and immunohistochemical (IHC) detection of SLN micrometastasis in colorectal cancers.
Methods
Colorectal cancer specimens were obtained during radical resections and the SLN was identified by injecting a 1% isosulfan blue solution submucosally and circumferentially around the tumor within 30 min after surgery. The first node to stain blue was defined as the SLN. SLNs negative by hematoxylin and eosin (HE) staining were further examined for micrometastasis using cytokeratin IHC.
Results
A total of 54 patients between 25 and 82 years of age were enrolled, including 32 males and 22 females. More than 70% of patients were T3 or above, about 86% of patients were stage II or III, and approximately 90% of patients had lesions grade II or above. Sentinel lymph nodes were detected in all 54 patients. There were 32 patients in whom no lymph node micrometastasis were detected by HE staining and 22 patients with positive lymph nodes micrometastasis detected by HE staining in non-SLNs. In contrast only 7 SLNs stained positive with HE. Using HE examination as the standard, the sensitivity, non-detection rate, and accuracy rate of SLN micrometastasis detection were 31.8% (7/22), 68.2% (15/22), and 72.2%, respectively. Micrometastasis were identified by ICH in 4 of the 32 patients with HE-negative stained lymph nodes, resulting in an upstaging rate 12.5% (4/32). The 4 patients who were upstaged consisted of 2 stage I patients and 2 stage II patients who were upstaged to stage III. Those without lymph node metastasis by HE staining who were upstaged by IHC detection of micrometastasis had a significantly poorer disease-free survival (p = 0.001) and overall survival (p = 0.004).
Conclusion
Ex vivo localization and immunohistochemical detection of sentinel lymph node micrometastasis in patients with colorectal cancer can upgrade tumor staging, and may become a factor affecting prognosis and guiding treatment.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1350200526694475.
doi:10.1186/1746-1596-7-71
PMCID: PMC3472318  PMID: 22726450
Colorectal carcinoma; Sentinel lymph node; Micrometastasis; Prognosis
23.  Factors that predict lymph node status in clinical stage T1aN0M0 lung adenocarcinomas 
Background
To identify patients in whom systematic lymph node dissection would be suitable, preoperative diagnosis of the biological invasiveness of lung adenocarcinomas through the classification of these T1aN0M0 lung adenocarcinomas into several subgroups may be warranted. In this retrospective study, we sought to determine predictive factors of lymph node status in clinical stage T1aN0M0 lung adenocarcinomas.
Methods
We retrospectively reviewed the records of 273 consecutive patients undergone surgical resection of clinical stage T1aN0M0 lung adenocarcinomas at Shanghai Chest Hospital, from January 2011 to December 2012. Preoperative computed tomography findings of all 273 patients were reviewed and their tumors categorized as pure GGO, GGO with minimal solid components (<5 mm), part-solid (solid parts >5 mm), or purely solid. Relevant clinicopathologic features were investigated to identify predictors of hilar or mediastinal lymph node metastasis using univariate or multiple variable analysis.
Results
Among the 273 eligible clinical stage T1aN0M0 lung adenocarcinomas examined on thin-section CT, 103 (37.7%) were pure GGO, 118 (43.2%) GGO with minimal solid components, 13 (4.8%) part-solid (solid parts >5 mm, five GGO predominant and eight solid predominant), and 39 (14.3%) pure solid. There were 18 (6.6%) patients with lymph node metastasis. Incidence of N1 and N2 nodal involvement was 11 (6.6%) and seven (2.6%) patients, respectively. All patients with pure GGO and GGO with minimal solid components (<5 mm) tumors were pathologically staged N0. Multivariate analyses showed that the following factors significantly predicted lymph node metastasis for T1a lung adenocarcinomas: symptoms at presentation, GGO status, and abnormal carcinoembryonic antigen (CEA) titer. Multivariate analyses also showed that the following factors significantly predicted lymph node metastasis for pure solid tumors: air bronchogram sign, tumor size, symptoms at presentation, and abnormal CEA titer.
Conclusions
The patients of clinical stage T1aN0M0 lung adenocarcinomas with pure GGO and GGO with minimal solid components tumors were pathologically staged N0 and systematic lymph node dissection should be avoided. But systematic lymph node dissection should be performed for pure solid tumors or part-solid, especially in patients with CEA greater than 5 ng/mL or symptoms at presentation, because of the high possibility of lymph node involvement.
doi:10.1186/1477-7819-12-42
PMCID: PMC3945801  PMID: 24559138
Lymph node; Lung adenocarcinomas; Stage small non-small cell lung cancer
24.  Tumor budding is a significant indicator of a poor prognosis in lung squamous cell carcinoma patients 
Molecular Medicine Reports  2012;6(5):937-943.
Lung cancer is a leading cause of cancer mortality worldwide and patients occasionally develop local recurrence or distant metastasis soon after curative resection. Reports of new therapeutic strategies for lung squamous cell carcinoma (SqCC) are extremely rare, while selective anticancer therapy has been reported for lung adenocarcinoma. The aim of this study was to identify clinicopathological prognostic factors for SqCC. We analyzed tumor budding and infiltrative patterns (INF) in 103 cases of surgically-resected SqCC. Tumor infiltrative patterns were classified into three groups (INFa, b and c) and INFc was infiltrative growth at the tumor invasive front. The cases with an INFc component [INFc(+)]were significantly associated with venous invasion (P=0.014) and the scirrhous stromal type (P<0.001). The overall survival rate of patients with INFc(+) was significantly lower than that of patients without the INFc component [INFc(−); P=0.003]. Tumor budding was defined as a single cancer cell or a small nest of up to four cancer cells within stromal tissue. The cases with tumor budding [Bud(+)] were significantly associated with lymph node metastasis (P=0.001), lymphatic invasion (P=0.002), INFc(+) (P<0.001) and the scirrhous stromal type (P=0.014). Patients with the Bud(+) type had a lower overall survival rate than patients with the Bud(−) type (P<0.001). Multivariate analysis demonstrated that tumor budding [hazard ratio (HR), 2.766; 95% confidence interval (CI), 1.497–5.109] and lymph node metastasis (HR, 1.937; 95% CI, 1.097–3.419) were independent predictors of mortality. In conclusion, tumor budding is a significant indicator of a high malignant potential and poor prognosis in SqCC of the lung.
doi:10.3892/mmr.2012.1048
PMCID: PMC3493086  PMID: 22940760
lung cancer; squamous cell carcinoma; patient prognosis; tumor budding
25.  Radical lymph node dissection and assessment: Impact on gallbladder cancer prognosis 
AIM: To investigate the lymph node metastasis patterns of gallbladder cancer (GBC) and evaluate the optimal categorization of nodal status as a critical prognostic factor.
METHODS: From May 1995 to December 2010, a total of 78 consecutive patients with GBC underwent a radical resection at Liaocheng People’s Hospital. A radical resection was defined as removing both the primary tumor and the regional lymph nodes of the gallbladder. Demographic, operative and pathologic data were recorded. The lymph nodes retrieved were examined histologically for metastases routinely from each node. The positive lymph node count (PLNC) as well as the total lymph node count (TLNC) was recorded for each patient. Then the metastatic to examined lymph nodes ratio (LNR) was calculated. Disease-specific survival (DSS) and predictors of outcome were analyzed.
RESULTS: With a median follow-up time of 26.50 mo (range, 2-132 mo), median DSS was 29.00 ± 3.92 mo (5-year survival rate, 20.51%). Nodal disease was found in 37 patients (47.44%). DSS of node-negative patients was significantly better than that of node-positive patients (median DSS, 40 mo vs 17 mo, χ2 = 14.814, P < 0.001), while there was no significant difference between N1 patients and N2 patients (median DSS, 18 mo vs 13 mo, χ2 = 0.741, P = 0.389). Optimal TLNC was determined to be four. When node-negative patients were divided according to TLNC, there was no difference in DSS between TLNC < 4 subgroup and TLNC ≥ 4 subgroup (median DSS, 37 mo vs 54 mo, χ2 = 0.715, P = 0.398). For node-positive patients, DSS of TLNC < 4 subgroup was worse than that of TLNC ≥ 4 subgroup (median DSS, 13 mo vs 21 mo, χ2 = 11.035, P < 0.001). Moreover, for node-positive patients, a new cut-off value of six nodes was identified for the number of TLNC that clearly stratified them into 2 separate survival groups (< 6 or ≥ 6, respectively; median DSS, 15 mo vs 33 mo, χ2 = 11.820, P < 0.001). DSS progressively worsened with increasing PLNC and LNR, but no definite cut-off value could be identified. Multivariate analysis revealed histological grade, tumor node metastasis staging, TNLC and LNR to be independent predictors of DSS. Neither location of positive lymph nodes nor PNLC were identified as an independent variable by multivariate analysis.
CONCLUSION: Both TLNC and LNR are strong predictors of outcome after curative resection for GBC. The retrieval and examination of at least 6 nodes can influence staging quality and DSS, especially in node-positive patients.
doi:10.3748/wjg.v19.i31.5150
PMCID: PMC3746389  PMID: 23964151
Gallbladder neoplasms; Lymphatic metastasis; Lymph node excision; Lymph node ratio; Prognosis

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