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1.  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.
PMCID: PMC3505024  PMID: 22627741
superficial cancer; esophageal cancer; squamous cell carcinoma; endoscopic resection; lymph node metastasis
2.  Prognostic role of lymph node metastasis in early gastric cancer 
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.
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.
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.
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.
PMCID: PMC4000899  PMID: 24826060
Early gastric cancer (EGC); lymph node metastasis; prognosis; recurrence
3.  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.
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
4.  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.
PMCID: PMC2362745  PMID: 18493513
5.  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.
PMCID: PMC2999232  PMID: 21160865
Lymphovascular invasion; Neuroendocrine tumor; Carcinoid; Colorectal cancer
6.  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.
PMCID: PMC2361114  PMID: 16404429
tumour budding; micrometastasis; isolated tumour cells; CAM5.2; D2-40
7.  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.
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.
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.
Endoscopic submucosal dissection can be performed on patients with early signet ring cell carcinoma limited to the mucosa and less than 15 mm.
PMCID: PMC3705138  PMID: 23844323
Stomach neoplasms; Carcinoma, signet ring cell; Endoscopic submucosal dissection; Lymph node metastasis; Predictive factor
8.  Tumor Budding as a Strong Prognostic Indicator in Invasive Ampullary Adenocarcinomas 
Prognostication of invasive ampullary adenocarcinomas (AACs) and their stratification into appropriate management categories have been highly challenging owing to a lack of well-established predictive parameters. In colorectal cancers, recent studies have shown that tumor budding confers a worse prognosis and correlates significantly with nodal metastasis and recurrence; however, this has not been evaluated in AAC.
To investigate the prevalence, significance, and clinical correlations of tumor budding in AAC, 244 surgically resected, stringently defined, invasive AAC were analyzed for tumor budding—defined as the presence of more than or equal to 5 isolated single cancer cells or clusters composed of fewer than 5 cancer cells per field measuring 0.785 mm2 using a 20 × objective lens in the stroma of the invasive front. The extent of the budding was then further classified as “high” if there were greater than or equal to 3 budding foci and as “low” if there were <3 budding foci or no budding focus.
One hundred ninety-four AACs (80%) were found to be high-budding and 50 (20%) were low-budding. When the clinicopathologic features and survival of the 2 groups were compared, the AACs with high-budding had larger invasion size (19 mm vs. 13 mm; P<0.001), an unrecognizable/absent pre-invasive component (57% vs. 82%; P<0.005), infiltrative growth (51% vs. 2%; P<0.001), nonintestinal-type histology (72% vs. 46%; P<0.001), worse differentiation (58% vs. 10%; P<0.001), more lymphatic (74% vs. 10%; P<0.001), and perineural invasion (28% vs. 2%; P<0.001); more lymph node metastasis (44% vs. 17%; P<0.001), higher T-stage (T3 and T4) (42% vs. 10%; P<0.001), and more aggressive behavior (mean survival: 50 mo vs. 32 mo; 3-year and 5-year survival rates: 93% vs. 41% and 68% vs. 24%, respectively; P<0.001). Furthermore, using a multivariable Cox regression model, tumor budding was found to be an independent predictor of survival (P = 0.01), which impacts prognosis (hazard ratio: 2.6) even more than T-stage and lymph node metastasis (hazard ratio: 1.9 and 1.8, respectively).
In conclusion, tumor budding is frequently encountered in AAC. High-budding is a strong independent predictor of overall survival, with a prognostic correlation stronger than the 2 established parameters: T-stage and lymph node metastasis. Therefore, budding should be incorporated into surgical pathology reports for AAC.
PMCID: PMC3163902  PMID: 20871215
ampulla; ampullary; carcinoma; tumor; budding; prognostic parameter
9.  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.
To evaluate the histopathological risk factors for lymph node metastasis in cases of pedunculated or semipedunculated submucosal invasive colorectal carcinoma (SICC).
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.
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.
Results indicate that tumour budding is a useful risk factor for predicting lymph node metastasis in cases of pedunculated or semipedunculated SICC.
PMCID: PMC1994481  PMID: 16997919
colorectal carcinoma; pedunculated; lymph node metastasis; risk factors; tumour budding
10.  Clinicopathological features associated with lymph node metastasis in early gastric cancer: Analysis of a single-institution experience in China 
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.
To evaluate the clinicopathological features associated with lymph node metastasis of early gastric cancer in patients from a single institution in China.
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.
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.
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
11.  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.
PMCID: PMC3484351  PMID: 23155323
Endoscopic submucosal dissection; Neuroendocrine tumor; Foregut
12.  Clinical Outcomes of Gastrectomy after Incomplete EMR/ESD 
Journal of Gastric Cancer  2011;11(3):162-166.
Endoscopic resection is widely accepted as standard treatment for early gastric cancer (EGC) without lymph node metastasis. The procedure is minimally invasive, safe, and convenient. However, surgery is sometimes needed after endoscopic mucosal resection/endoscopic submucosal dissection endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD) due to perforation, bleeding, or incomplete resection. We evaluated the role of surgery after incomplete resection.
Materials and Methods
We retrospectively studied 29 patients with gastric cancer who underwent a gastrectomy after incomplete EMR/ESD from 2006 to 2010 at Korea University Hospital.
There were 13 incomplete resection cases, seven bleeding cases, three metachronous lesion cases, three recurrence cases, two perforation cases, and one lymphatic invasion case. Among the incomplete resection cases, a positive vertical margin was found in 10, a positive lateral margin in two, and a positive vertical and lateral margin in one case. Most cases (9/13) were diagnosed as mucosal tumors by endoscopic ultrasonography, but only three cases were confirmed as mucosal tumors on final pathology. The positive residual tumor rate was two of 13. The lymph node metastasis rate was three of 13. All lymph node metastasis cases were submucosal tumors with positive lymphatic invasion and no residual tumor in the gastrectomy specimen. No cases of recurrence were observed after curative resection.
A gastrectomy is required for patients with incomplete resection following EMR/ESD due to the risk of residual tumor and lymph node metastasis.
PMCID: PMC3204469  PMID: 22076221
Stomach neoplasms; EMR/ESD; Gastrectomy
13.  The clinical significance of subcarinal lymph node dissection in the radical resection of oesophageal cancer 
To explore the rule of subcarinal lymph node metastasis in thoracic oesophageal cancer and its clinical significance in the radical resection of oesophageal cancer.
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.
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).
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.
PMCID: PMC3653481  PMID: 23475120
Oesophageal cancer; Oesophageal surgery; Subcarinal lymph node dissection
14.  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.
PMCID: PMC2362570  PMID: 18493439
15.  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.
PMCID: PMC3921521  PMID: 24574813
Endoscopic submucosal dissection; Epstein-Barr virus; Lymph node; Lymphoepithelioma-like gastric carcinoma; Prognosis
16.  The Natural History of pT1 Colorectal Cancer 
Colorectal carcinoma invading the submucosa but not the muscular layer (pT1, early invasive cancer) represents the earliest form of clinically relevant colorectal cancer in most patients. Neoplastic invasion of the submucosa, in fact, opens the way to metastasis via the lymphatic and blood vessels, and the choice between surveillance and major surgery will turn on its metastatic potential. The following histological features predict the risk of metastasis and the different clinical outcomes: grade of differentiation of carcinoma, lymphovascular invasion, state of the resection margin. Microstaging of invasive cancer, namely the width and the depth of submucosal invasion, together with tumor budding at the advancing edge allow the metastatic risk to be further stratified in minimal, low, and high. Different, although morphologically undistinguishable, tumorigenic pathways are supposed to lead to the malignant transformation of colonic mucosa and subsequently to drive the progression from early to advanced cancer: new biomarkers are needed to identify progressive and non-progressive pT1 neoplasia.
PMCID: PMC3355924  PMID: 22649781
colon; early cancer; cancerised adenoma
17.  Impact of tumor chronology and tumor biology on lymph node metastasis in breast cancer 
SpringerPlus  2013;2:480.
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.
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.
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.
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.
According to our data variables of tumor chronology and tumor biology have a similar impact on the presence of lymph node metastasis.
PMCID: PMC3786086  PMID: 24083118
Tumor chronology; Tumor biology; Lymph node; Metastasis; Breast cancer
18.  Process of distant lymph node metastasis in colorectal carcinoma: Implication of extracapsular invasion of lymph node metastasis 
BMC Cancer  2011;11:216.
We previously demonstrated that extracapsular invasion (ECI) at a metastatic sentinel node was significantly associated with the presence of positive non-sentinel nodes in patients with breast cancer. However, the mechanism of metastatic spreading of tumor cells to distant lymph nodes in patients with colorectal carcinoma is not fully understood. In this study, we investigated the factors that may determine the likelihood of additional regional lymph node metastasis when metastasis is found in nodes at the N1 site in colorectal cancer, especially focusing on the presence of ECI.
Two hundred and twenty-eight consecutive patients who underwent colorectal resection were identified for inclusion in this study, of which 37 (16.2%) had positive lymph nodes at the N1 site. Six of these 37 cases had additional metastasis in N2 site lymph nodes. We reviewed the clinicopathological features of these cases and performed statistical analysis of the data.
In the univariate analysis ECI at the N1 site was the only factor significantly associated with the presence of cancer cells in the N2 site. Other factors, including number of positive lymph nodes, lymphovascular invasion of the primary tumor, tumor size and tumor depth of invasion, were not associated with metastatic involvement at the N2 site.
Our results suggest that the presence of ECI at metastatic lymph nodes at the N1 site is correlated with further metastasis at the N2 site. These findings imply the possibility that ECI might indicate the ability of colorectal tumor cells to disseminate to distant lymph nodes.
PMCID: PMC3118198  PMID: 21635742
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.
PMCID: PMC3499485  PMID: 23162621
rectal carcinoid; metastasis; Ki-67; lymphovascular invasion
20.  Fascin expression in colorectal carcinomas 
Clinics  2010;65(2):157-164.
The purpose of this study was to investigate the significance of fascin expression in colorectal carcinoma.
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.
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).
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.
PMCID: PMC2827702  PMID: 20186299
Colorectal carcinoma; Fascin; Prognosis; Tumor
21.  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.
PMCID: PMC3400864  PMID: 22826627
Cancer; Esophagus; Gastroesophageal junction; Staging; Stomach
22.  The extramural metastasis might be categorized in lymph node staging for colorectal cancer 
BMC Cancer  2011;11:414.
The objective of this study is to assess the clinical significance and prognostic impact of extramural metastasis in colorectal carcinoma and establish an optimal categorization in the staging system.
To determine the frequency and prognostic significance of extramural metastasis, from 2000 to 2005, a total of 1,215 patients with colorectal cancer who underwent surgical resection were recruited into this study. Individual demographic and clinicopathologic data were collected including tumor stage, nodal stage, tumor histology, degree of tumor differentiation, and presence of lymphovascular invasion. After surgery, all patients received standard treatments and follow-up, which were closed in April 2010.
EM was detected in 167 (13.7%) patients and in 230 (1.8%) of the 12,534 nodules retrieved as 'lymph nodes'. The incidence of extramural metastasis was significantly higher in patients with large tumors, deeper invasive depth and more lymph node metastasis (P < 0.001). After curative operation, overall survival was significantly worse for patients with extramural metastasis than those without (P < 0.001). Multivariate analysis identified extramural metastasis as an independent prognostic factor (RR = 2.1, 95%CI:1.5-3.0). By using the Akaike information criterion (AIC), N staging was capable of predicting survival outcome with the highest accuracy when both nodal involvement and extramural metastasis were treated together as N factors(AIC = 1025.3).
Extramural metastasis might be diagnosed as replaced lymph nodes in the process of classification, thus forming a new categorization.
PMCID: PMC3190391  PMID: 21943144
extramural metastasis; staging; colorectal cancer
23.  Clinical Implications of Microsatellite Instability in T1 Colorectal Cancer 
Yonsei Medical Journal  2014;56(1):175-181.
The estimation of regional lymph node metastasis (LNM) risk in T1 colorectal cancer is based on histologic examination and imaging of the primary tumor. High-frequency microsatellite instability (MSI-H) is likely to decrease the possibility of metastasis to either regional lymph nodes or distant organs in colorectal cancers. This study evaluated the clinical implications of MSI in T1 colorectal cancer with emphasis on the usefulness of MSI as a predictive factor for regional LNM.
Materials and Methods
A total of 133 patients who underwent radical resection for T1 colorectal cancer were included. Genomic DNA was extracted from normal and tumor tissues and amplified by polymerase chain reaction (PCR). Five microsatellite markers, BAT-25, BAT-26, D2S123, D5S346, and D17S250, were used. MSI and clinicopathological parameters were evaluated as potential predictors of LNM using univariate and multivariate analyses.
Among 133 T1 colorectal cancer patients, MSI-H, low-frequency microsatellite instability (MSI-L), and microsatellite stable (MSS) colorectal cancers accounted for 7.5%, 6%, and 86.5%, respectively. MSI-H tumors showed a female predominance, a proximal location and more retrieved lymph nodes. Twenty-two patients (16.5%) had regional LNM. Lymphovascular invasion and depth of invasion were significantly associated with LNM. There was no LNM in 10 MSI-H patients; however, MSI status was not significantly correlated with LNM. Disease-free survival did not differ between patients with MSI-H and those with MSI-L/MSS.
MSI status could serve as a negative predictive factor in estimating LNM in T1 colorectal cancer, given that LNM was not detected in MSI-H patients. However, validation of our result in a different cohort is necessary.
PMCID: PMC4276753  PMID: 25510762
Microsatellite instability; lymph node metastasis; early colorectal cancer; T1; prognosis
24.  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.
PMCID: PMC2795176  PMID: 20014453
Colorectal cancer; Prognosis; Tumor invasive front; Tumor budding; Tumor growth pattern; Tumor infiltrating lymphocytes; Tumor immunity; Microsatellite instability
25.  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.
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

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