Risk factors for lymph node metastasis in submucosal invasive colorectal cancer.

BACKGROUND: Recent studies have shown a 7-15% lymph node (LN) metastasis rate in submucosal invasive colorectal cancer (SICC). Identifying risk factors for LN metastasis is crucial in selecting therapeutic modalities for SICC. We assessed the possibility of and the risk factors for LN metastasis in SICC. METHODS: We performed a retrospective study on 168 SICC patients who underwent curative resection between June 1989 and December 2004 at Asan Medical Center. The level of submucosal invasion was classified into upper third (sm1), middle third (sm2), and lower third (sm3). The following carcinoma-related variables were assessed: tumor size, tumor location, depth of submucosal invasion, cell differentiation, lymphovascular invasion, neural invasion, and tumor cell dissociation (TCD). RESULTS: The overall LN metastasis rate was 14.3%. Significant predictors of LN metastasis both univariately and multivariately were sm3 (p = 0.039), poorly differentiated cancer (p = 0.028), and TCD (p = 0.045). Lymphovascular invasion was a risk factor for LN metastasis in univariate analysis (p = 0.019); however, in multivariate analysis, lymphovascular invasion could not predict LN metastasis. No statistical difference was observed in the risk of LN metastasis with regard to tumor location, size, and neural invasion. CONCLUSION: The depth of submucosal invasion, cell differentiation, and tumor cell dissociation were significant pathologic predictors of LN metastasis in SICC. Because SICC is associated with a considerable risk of LN metastasis, local excision may be performed carefully in SICC without adverse features.

Intraductal papillary mucinous neoplasm of the pancreas: clinical characteristics and treatment outcomes of 118 consecutive patients from a single center.

BACKGROUND/PURPOSE: Appropriate surgical treatment strategies based on clinicopathological findings are unavailable for intraductal papillary mucinous neoplasm (IPMN) of the pancreas. We investigated the clinical features of pancreatic IPMN in a single-center database in order to design an optimal surgical strategy. METHODS: The medical records of 118 consecutive patients who had undergone surgical resection between August 1994 and December 2004, in whom IPMN was histologically confirmed, were reviewed retrospectively for radiological and pathological findings. RESULTS: Most of the invasive carcinomas in these patients were detected as the main-duct type (88.5%). The type of tumor (main-duct type vs branched-duct type), the tumor size, and the dilated duct size were significant predictive factors associated with malignancy. The relative risk of malignancy was greatest at 13-mm or more ductal dilation in the main-duct type (Odds ratio, 4.1), at 35-mm or more tumor size (Odds ratio, 7.6), and for main-duct type (Odds ratio, 3.9). Major pancreatic resections such as total pancreatectomy and pancreatoduodenectomy were performed in 14.5% and 69% of the patients, respectively. There was a 19.5% rate of incomplete resection, with these patients having a positive resection margin. However, significant recurrence did not occur in patients with a benign IPMN lesion which remained at the resection margin. The overall postoperative survival rate at 5 years was 98.2% for benign IPMN and 65.3% for malignant IPMN. CONCLUSIONS: Function-preserving strategies, based on the clinical status of the patient, are necessary in order to avoid possible severe metabolic complications following extended pancreatectomy in patients with benign IPMN because of the low recurrence rate and good prognosis of this entity, irrespective of margin status.

Individual tumorigenesis pathways of sporadic colorectal adenocarcinomas are associated with the biological behavior of tumors.

Clinicopathologic features of sporadic colorectal adenocarcinomas were compared using integrated data from 224 [corrected] patients subjected to curative resection. Individual steps in the tumorigenesis pathway, that is, adenomatosis polyposis coli (APC), Wnt-activated, base excision repair mutations, mismatch repair defects, RAF-mediated, transforming growth factor (TGF)-beta-suppressed, bone morphogenic protein (BMP)-suppressed, and p53 alterations, were examined in terms of genetic and epigenetic changes, as well as protein expression. Genetic and molecular alterations of right colon cancers were distinct from those of left colon and rectal cancers. Rectal cancers showed the attenuated phenotype of left colon cancers. Tumors most frequently displayed either TGF-beta- or BMP-suppressed alterations (81.2%), followed by RAF-mediated alterations (78.6%), and mismatch repair defects (38.4%), constituting a total of 24 integrated pathways. Tumors lacking APC mutations or carrying the RAF alteration (V600E) were frequently associated with lymphovascular invasion and lymph node metastasis (P < 0.05). Poorly differentiated or mucinous adenocarcinomas were generally associated with high level microsatellite instability, Axin2 suppression, TGF-beta1 or BMPR1A suppression, loss of heterozygosity of D18S46 or D18S474, and absence of base excision repair mutations (P < 0.0001-0.05). Early tumor recurrence was significantly correlated with lack of APC mutations (P = 0.036). Moreover, tumors that concurrently displayed APC/Wnt-activated, TGF-beta/BMP-suppressed, and p53 alterations were significantly predisposed to early recurrence (P = 0.026). Our data clearly indicate that particular steps or pathways of colorectal tumorigenesis are closely associated with characteristic clinicopathologic features that, in turn, determine biological behavior, such as tumor growth, invasion, and recurrence.

Villotrophoblastic pulmonary nodule with implantation site intermediate trophoblasts after induced abortion.

We describe a case of villotrophoblastic pulmonary nodule with a hitherto unrecognized implantation site intermediate trophoblasts (ISITs) in an asymptomatic 19-year-old woman, who had an induced abortion 1 month before the discovery of a pulmonary nodule. This 8-mm-sized nodule was incidentally identified on chest computed tomography during routine postoperative follow-up for osteosarcoma, for which she was treated with surgery and chemotherapy 3 years previously. The nodule was located in the subpleural lung parenchyma and was composed histologically of a few chorionic villi and trophoblasts surrounded by fibrinoid materials, with individually scattered intermediate trophoblasts at the periphery of the nodule. The intermediate trophoblasts were strongly immunopositive for cytokeratin, human placental lactogen, and Mel-CAM (CD146), but immunonegative for human chorionic gonadotropin and p63, characteristic features of ISITs. Our case indicates that villotrophoblastic pulmonary emboli have the potential to implant after migration from their original sites through the invasive property of ISITs.

Additional lymph node examination from entire submission of residual mesenteric tissue in colorectal cancer specimens may not add clinical and pathologic relevance.

The examination of lymph nodes in colorectal cancer is a critical procedure for determining the stage, which determines prognosis and need for adjuvant therapy. The current recommendation is to harvest at least 12 lymph nodes by conventional manual node dissection (MND). Recent studies have suggested that all lymph nodes in mesenteric tissue should be retrieved using a special method such as the entire submission of residual mesenteric tissue (ESMT) after MND. We investigated the efficacy of ESMT with its potential impact on the pN stage. After an MND in 48 consecutive colorectal cancer resection specimens, the residual mesenteric tissues were entirely submitted for routine histologic examination by ESMT. After initial MND, 933 (mean, 19.4) lymph nodes were found, and there were 29 pN0, 10 pN1, and 9 pN2 cases. By ESMT after MND, 1132 (mean, 23.6) additional lymph nodes were found. Most (88.6%) of them were 2.0 mm or less in maximum dimension, and of the 1132 additional lymph nodes, 14 (1.2%) lymph nodes revealed tumor metastases. Although there was no additional nodal metastasis in any of the initial 29 pN0 cases, additional nodal metastases were found in 10 of the original 19 node-positive cases. Two of the 10 cases with additional positive nodes identified would be upstaged from pN1 to pN2. Both of these cases had fewer than 12 nodes identified by MND but had 1 and 2 additional nodes identified by ESMT. Our study demonstrated that MND seems to be accurate and efficient in evaluating tumors with pN stage of pN0. Although ESMT may be useful to assess the correct pN stage in pN1 cases with fewer than 12 lymph nodes in MND, it may not add any additional information in pN0 cases or in node-positive cases with 12 or more lymph nodes found by MND.

MYH, OGG1, MTH1, and APC alterations involved in the colorectal tumorigenesis of Korean patients with multiple adenomas.

This study was done to characterize base excision repair (BER) genes and adenomatous polyposis coli (APC) alterations in the tumorigenesis of multiple colorectal adenomas in Korean patients. In total, 217 adenomas (mean number = 10) and 117 cancers were available from 143 patients. The heterozygous genotype of OGG1 c.1-18G>T was closely associated with multiple adenoma families (P < 0.001), while MYH A359V mutation exhibited a tendency (P = 0.053). MYH R170G mutation was exclusively identified in one patient. The G:C>T:A transversion or attenuated familial adenomatous polyposis (AFAP) mutations of APC was identified in the specific genotypes of BER variants. Tubular adenomas or adenomas with none-to-mild dysplasia were significantly associated with polymorphic genotypes of OGG1 IVS4-15 and S326C. In addition, large and pedunculated adenomas were more frequent in patients with G:C>T:A transversion and AFAP mutations of APC, respectively. However, BER variants were not associated with mismatch repair or altered p53 protein expression. Conclusively, two novel mutations of MYH and a novel OGG1 polymorphism seemed to be associated with multiple colorectal adenomas in Korean families, differing from those in other ethnic groups. Some BER variants involved in specific APC mutations are associated with characteristics of histogenesis other than altered mismatch repair or p53 pathway.

Efficacy of 3-dimensional endorectal ultrasonography compared with conventional ultrasonography and computed tomography in preoperative rectal cancer staging.

BACKGROUND: This study was performed to verify reports of the decreased accuracy of endorectal ultrasonography (EUS) in preoperative staging of rectal cancer, and to compare the efficacy of 3-dimensional (3D) EUS with that of 2-dimensional (2D) EUS and computed tomography (CT). METHODS: Eighty-six consecutive rectal cancer patients undergoing curative surgery were evaluated by 2D EUS, 3D EUS, and CT scan. RESULTS: The accuracy in T-staging was 78% for 3D EUS, 69% for 2D EUS, and 57% for CT (P < .001-.002), whereas the accuracy in evaluating lymph node metastases was 65%, 56%, and 53%, respectively (P < .001-.006). Examiner errors were the most frequent cause of misinterpretation, occurring in 47% of 2D EUS examinations and in 65% of 3D EUS examinations. By eliminating examiner errors, the accuracy rates in T-staging and lymph node evaluation could be improved to 88% and 76%, respectively, for 2D EUS, and to 91% and 90%, respectively, for 3D EUS. Conical protrusions along the deep tumor border on 3D images were correlated closely with infiltration grade, advanced T-stage, and lymph node metastasis. CONCLUSIONS: We found that 3D EUS showed greater accuracy than 2D EUS or CT in rectal cancer staging and lymph node metastases. Concrete 3D images based on tumor biology appear to provide more accurate information on tumor progression.

Invasive colorectal micropapillary carcinoma: an aggressive variant of adenocarcinoma.

Micropapillary carcinoma (MC) has been well described in other organs, including breast, urinary bladder, lung, ovary, and salivary gland, but has not been described in the large intestine. We compared the clinicopathologic and immunohistochemical findings of MC with those of conventional adenocarcinoma in the large intestine. Fifty-five cases of adenocarcinoma with an MC component were identified among 585 consecutive cases of colorectal cancer at the Asan Medical Center between January 2003 and June 2004 and were compared with 119 cases of conventional adenocarcinoma of colorectum without an MC component. Arrayed tissue blocks were constructed and immunostained for cytokeratin 7 and 20 and CDX2. We also compared the results of MLH-1, MSH-2, p53, and carcinoembryonic antigen immunostainings between the 2 groups. The grade of both MC and conventional adenocarcinoma was mostly moderately differentiated. The proportion of MC ranged from 5% to 80%. The presence but not extent of MC in the primary tumors was associated with more frequent lymphovascular invasion and lymph node (LN) metastases, a greater mean number of positive LNs, and a higher tumor stage with more frequent distant metastases, compared with conventional adenocarcinoma (P < .05). Cytokeratin 7 staining was occasionally observed in both MC (9.1%, 5/55 cases) and conventional adenocarcinoma (13.4%, 16/119 cases). Although MLH-1 and CDX2 expression tended to be lower in conventional adenocarcinoma, none of the immunohistochemical results was significantly different between 2 groups. Recognition of MC component is important as MC appeared to be an aggressive variant of colonic adenocarcinoma and presented at a higher stage, with frequent lymphovascular invasion, LN metastasis, and distant metastasis, compared with conventional adenocarcinoma. The proportion of MC component did not impact the prognosis, and the immunoprofiles of MC were not significantly different from those of conventional adenocarcinoma.

Multiple gastrointestinal stromal tumors with a germline c-kit mutation.

Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder; thus far, only seven families have been reported with c-kit germline mutations. Presented herein is a case of multiple intestinal GIST in a 38-year-old man with a germline mutation of the c-kit gene. Operative specimens of the jejunal segment and multiple wedge resection specimens included approximately 30 masses, ranging in size from 1.0 to 6.0 cm. Microscopically, the tumors were composed of CD117-positive spindle/epitheloid cells with variable numbers of mitotic counts, a characteristic of GIST. The mitotic rate increased to more than 5/50 high-power fields. Interestingly, marked hypertrophy of the myenteric plexus with CD117-positive cells was identified in the intestinal segment. By polymerase chain reaction-single-strand conformation polymorphism analysis and direct DNA sequencing, a heterozygous c-kit missense mutation at nucleotide 1676 of codon 559 (T --> C, Val --> Ala), part of the juxtamembrane domain, was detected in the normal tissue. The same mutation was homozygous in the tumor samples. The present case is the first proven case of multiple GIST with a c-kit germline mutation in Korea and is distinguishable from other reported germ-line c-kit mutations because the same 1676 T --> C missense mutation occurs in the normal allele as well as the affected allele, although the significance of the identical mutations remains to be investigated.