Unresectable esophageal cancer treated with multiple chemotherapies in combination with chemoradiotherapy: A case report.

BACKGROUND: Definitive chemoradiotherapy (dCRT) using cisplatin plus 5fluorouracil (CF) with radiation is considered the standard treatment for unresectable locally advanced T4 esophageal squamous cell carcinoma (ESCC). Recently, induction chemotherapy has received attention as an effective treatment strategy. CASE SUMMARY: We report a successful case of a 59-year-old female with unresectable locally advanced T4 ESCC treated by two additional courses of chemotherapy with CF after induction chemotherapy with docetaxel, cisplatin and fluorouracil (DCF) followed by dCRT. Initial esophagogastroduodenoscopy (EGD) detected a type 2 advanced lesion located on the middle part of the esophagus, with stenosis. Computed tomography detected the primary tumor with suspected invasion of the left bronchus and 90° of direct contact with the aorta, and upper mediastinal lymph node metastasis. Pathological findings from biopsy revealed squamous cell carcinoma. We initially performed induction chemotherapy using three courses of DCF, but the lesion was still evaluated unresectable after DCF chemotherapy. Therefore, we subsequently performed dCRT treatment (CF and radiation). After dCRT, prominent reduction of the primary tumor was recognized but a residual tumor with ulceration was detected by EGD. Since the patient had some surgical risk, we performed two additional courses of CF and achieved a clinically complete response. After 14 mo from last administration of CF chemotherapy, recurrence has not been detected by computed tomography and EGD, and biopsy from the scar formation has revealed no cancer cells. CONCLUSION: We report successful case with tumor remnants even after DCF and subsequent dCRT, for whom a complete response was finally achieved with two additional courses of CF chemotherapy. Additional CF chemotherapy could be one radical treatment option for residual ESCC after treatment with induction DCF followed by dCRT to avoid salvage surgery, especially for high-risk patients.

Pancreaticoduodenectomy after neoadjuvant chemotherapy for gastric cancer invading the pancreatic head: A case report.

BACKGROUND: Pancreaticoduodenectomy (PD) for advanced gastric cancer is rarely performed because of the high morbidity and mortality rates and low survival rate. However, neoadjuvant chemotherapy for advanced gastric cancer has improved, and chemotherapy combined with trastuzumab may have a preoperative tumor-reducing effect, especially for human epidermal growth factor receptor 2 (HER2)-positive cases. CASE SUMMARY: We report a case of successful radical resection with PD after neoadjuvant S-1 plus oxaliplatin (SOX) and trastuzumab in a patient (66-year-old male) with advanced gastric cancer invading the pancreatic head. Initial esophagogastroduodenoscopy detected a type 3 advanced lesion located on the lower part of the stomach obstructing the pyloric ring. Computed tomography detected lymph node metastasis and tumor invasion to the pancreatic head without distant metastasis. Pathological findings revealed adenocarcinoma and HER2 positivity (immunohistochemical score of 3 +). We performed staging laparoscopy and confirmed no liver metastasis, no dissemination, negative lavage cytological findings, and immobility of the distal side of the stomach due to invasion to the pancreas. Laparoscopic gastrojejunostomy was performed at that time. One course of SOX and three courses of SOX plus trastuzumab were administered. Preoperative computed tomography showed partial response; therefore, PD was performed after neoadjuvant chemotherapy, and pathological radical resection was achieved. CONCLUSION: We suggest that radical resection with PD after neoadjuvant chemotherapy plus trastuzumab is an option for locally advanced HER2-positive gastric cancer invading the pancreatic head in the absence of non-curative factors.

Distal gastric tube resection with vascular preservation for gastric tube cancer: A case report and review of literature.

BACKGROUND: Survival rates in patients with esophageal cancer undergoing esophagectomy have improved, but the prevalence of gastric tube cancer (GTC) has also increased. Total resection of the gastric tube with lymph node dissection is considered a radical treatment, but GTC surgery is more invasive and involves a higher risk of severe complications or death, particularly in elderly patients. CASE SUMMARY: We report an elderly patient with early GTC that had invaded the duodenum who was successfully treated with resection of the distal gastric tube and Roux-en-Y (R-Y) reconstruction. The tumor was a type 0-IIc lesion with ulcer scars surrounding the pyloric ring. Endoscopic submucosal resection was not indicated because the primary lesion was submucosally invasive, was undifferentiated type, surrounded the pyloric ring, and had invaded the duodenum. Resection of distal gastric tube with R-Y reconstruction was safely performed, with preservation of the right gastroepiploic artery (RGEA) and right gastric artery (RGA). CONCLUSION: Distal resection of the gastric tube with preservation of the RGEA and RGA is a good treatment option for elderly patients with cT1bN0 GTC in the lower part of the gastric tube.

A Rare Solitary Fibrous Tumor Originating From the Distal Aortic Arch.

We report a 68-year-old man who presented with a well-circumscribed 6.9 × 6.5 × 3.6-cm tumor with a feeding vessel from the thyrocervical trunk in his left pleural cavity. The tumor was attached to the distal aortic arch, so he underwent a tumor resection with prosthetic graft replacement of the distal aortic arch. Pathological examination revealed a solitary fibrous tumor with potentially malignant features. To our knowledge, this is the first case of a solitary fibrous tumor arising from the aortic adventitia reported in the literature.

Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer.

PURPOSE: Cyclooxygenase-2 (COX-2; PTGS2) is considered to play an important role in colorectal carcinogenesis and is often up-regulated in colon cancers. However, previous data on the influence of COX-2 expression on patient outcome have been conflicting. EXPERIMENTAL DESIGN: Using 662 colon cancers (stage I-IV) in two independent prospective cohorts (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected COX-2 overexpression in 548 (83%) tumors by immunohistochemistry. Cox proportional hazards models were used to compute hazard ratios (HR) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and related molecular events, including the CpG island methylation phenotype, microsatellite instability, and p53, CIMP, KRAS, and BRAF mutations. RESULTS: During follow-up of the 662 cases, there were 283 deaths, including 163 colon cancer-specific deaths. Patients with COX-2-positive tumors showed a trend towards an inferior colon cancer-specific mortality [HR, 1.37; 95% confidence interval (95% CI), 0.87-2.14], which became significant after adjusting for tumor stage and other predictors of clinical outcome (multivariate HR, 1.70; 95% CI, 1.06-2.74; P = 0.029). Notably, the prognostic effect of COX-2 expression might differ according to p53 status (Pinteraction = 0.04). Compared with tumors with both COX-2 and p53 negative, COX-2-positive tumors were significantly associated with an increased cancer-specific mortality (multivariate HR, 2.12; 95% CI, 1.23-3.65) regardless of p53 status. A similar trend was observed when overall mortality was used as an outcome. CONCLUSION: COX-2 overexpression is associated with worse survival among colon cancer patients. The effect of COX-2 on clinical outcome may be modified by p53 status.

Increased nuclear expression of growth hormone receptor in uterine cervical neoplasms of women under 40 years old.

There has been an increased incidence of cervical cancer among young women, and they tend to have a poor prognosis due to unknown reasons. We hypothesize growth hormone (GH) receptor (GHR) may be involved in the proliferation of cervical carcinoma, because GH-related neoplasms arise in various organs and the amount of GH secretion may be different according to age. GHR is normally expressed in the cell membrane and cytoplasm, while the nuclear distribution of GHR has been considered to reflect high proliferative activity of cells. We analyzed the subcellular localization of GHR by immunohistochemistry in cervical neoplasms of 55 patients (38.6 +/- 13.9 years old): 33 patients (< 40 years) and 22 patients (>or= 40 years). Nuclear expression of GHR was detected in more than 50% of neoplastic cells present in the tissue samples derived from 20 patients under 40 years (20/33, 61%), whereas less than 25% of neoplastic cells expressed GHR in their nuclei in 17 patients over 40 years (17/22, 77%). In contrast, more than 75% of neoplastic cells showed cytoplasmic GHR expression in the tissues derived from both age groups. Furthermore, the population of cells with nuclear GHR expression was high in the squamous epithelium and the stromal cells of patients under 40, but low in patients over 40. The GH-GHR signal may act at the nuclear level to promote the proliferation of uterine cervical neoplasms in young patients. We suggest the involvement of GHR in progression of uterine cervical carcinoma.

Correlation of beta-catenin localization with cyclooxygenase-2 expression and CpG island methylator phenotype (CIMP) in colorectal cancer.

The WNT/beta-catenin (CTNNB1) pathway is commonly activated in the carcinogenic process. Cross-talks between the WNT and cyclooxygenase-2 (COX-2 or PTGS2)/prostaglandin pathways have been suggested. The relationship between beta-catenin activation and microsatellite instability (MSI) in colorectal cancer has been controversial. The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer, which is associated with MSI-high. However, no study has examined the relationship between beta-catenin activation and CIMP status. Using 832 population-based colorectal cancer specimens, we assessed beta-catenin localization by immunohistochemistry. We quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A(p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). MSI-high, CIMP-high, and BRAF mutation were associated inversely with cytoplasmic and nuclear beta-catenin expressions (i.e., beta-catenin activation) and associated positively with membrane expression. The inverse relation between beta-catenin activation and CIMP was independent of MSI. COX-2 overexpression correlated with cytoplasmic beta-catenin expression (even after tumors were stratified by CIMP status), but did not correlate significantly with nuclear or membrane expression. In conclusion, beta-catenin activation is inversely associated with CIMP-high independent of MSI status. Cytoplasmic beta-catenin is associated with COX-2 overexpression, supporting the role of cytoplasmic beta-catenin in stabilizing PTGS2 (COX-2) mRNA.

The development of high-grade serous carcinoma from atypical proliferative (borderline) serous tumors and low-grade micropapillary serous carcinoma: a morphologic and molecular genetic analysis.

Recently, we have proposed a model for the development of ovarian surface epithelial tumors. In this model, all histologic types of surface epithelial tumors are divided into 2 categories designated type I and type II which correspond to 2 pathways of tumorigenesis. Type I tumors include low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, malignant Brenner tumor, and clear cell carcinoma which develop slowly in a stepwise fashion from well-recognized precursors, namely atypical proliferative (borderline) tumors. Type II tumors are high-grade, rapidly growing tumors that typically have spread beyond the ovaries at presentation. They include high-grade serous carcinoma ("moderately" and "poorly" differentiated), malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinoma. These tumors are rarely associated with morphologically recognizable precursor lesions and it has been proposed that they develop "de novo" from ovarian inclusion cysts. This model implies that the pathogenesis of type I and type II tumors are separate and independent but it is not clear whether some type II tumors develop from type I tumors. In this study, we attempted to address this issue by determining the clonality of 6 cases of high-grade serous carcinomas that were closely associated with atypical proliferative serous (borderline) tumors and invasive low-grade micropapillary serous carcinomas. We reviewed 210 ovarian serous tumors from the surgical pathology files of the Johns Hopkins Hospital and identified 3 high-grade serous carcinoma that were directly associated with atypical proliferative serous (borderline) tumors and 3 that were associated with invasive low-grade micropapillary serous carcinomas. A morphologic continuum between the high-grade carcinoma and the low-grade tumors was observed in 4 cases whereas in the remaining 2 cases the high-grade and low-grade components were separate. Mutational analyses for KRAS, BRAF, and p53 genes were performed on microdissected samples from the high-grade and low-grade tumor areas for each case. All 6 tumors demonstrated wild-type BRAF and p53 genes. Only 2 of the 6 cases were informative from a molecular genetic standpoint. In those 2 cases we found the same mutations of KRAS in both the atypical proliferative serous (borderline) tumor and the high-grade serous carcinoma component of the tumor, indicating a clonal relationship. The above results suggest that the majority of high-grade and low-grade carcinomas develop independently but in rare cases, a high-grade serous carcinoma may arise from an atypical proliferative serous (borderline) tumor.

Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation.

The infrequent association of serous borderline tumors (SBTs) with invasive serous carcinoma has led to the view that SBTs are unrelated to invasive serous carcinoma. Nonetheless, mortality associated with SBTs is generally attributed to malignant transformation, and traditionally these tumors have been designated as "carcinomas of low malignant potential." Previous immunohistochemical studies evaluating p53 expression and molecular genetic studies evaluating mutational status have reported that p53 overexpression and mutations are infrequent in SBTs and occur in as many as 50% to 80% of invasive serous carcinomas. The different methodologies for determining p53 status and the failure to correlate the findings with tumor grade make these studies difficult to interpret. The current study was undertaken to overcome these deficiencies and to reconcile the relationship of SBTs to invasive serous carcinoma by performing a morphologic, immunohistochemical, and molecular genetic analysis comparing SBTs with low- and high-grade serous carcinoma. The molecular genetic analysis used a highly stringent, carefully designed nucleotide-sequencing method. A total of 96 sporadic serous tumors including 25 SBTs (11 atypical proliferative serous tumors and 14 intraepithelial low-grade serous carcinomas [noninvasive micropapillary serous carcinomas, MPSCs]), 12 low-grade serous carcinomas (invasive MPSCs), and 59 high-grade serous carcinomas were analyzed for their p53 mutational status of exons 5 to 9. Functional mutations, defined as mutations resulting in the alteration of the structure of the encoded protein, were detected in 30 of 59 (50.8%) high-grade serous carcinomas and 1 (8.3%) of 12 low-grade invasive serous carcinomas compared with 2 (8%) of 25 SBTs, both of these in intraepithelial low-grade serous carcinomas (noninvasive MPSCs). The similar frequency of p53 mutations in SBTs and low-grade invasive serous carcinomas in contrast to the significantly higher frequency of p53 mutations in high-grade serous carcinomas (P < 0.0005) suggests a common lineage for SBTs and low-grade invasive serous carcinomas and supports the view that SBTs are unrelated to the usual type of invasive serous carcinoma, which is a high-grade neoplasm. Mutational status was also correlated with p53 immunoreactivity. Although p53 immunoreactivity is generally higher in those specimens containing mutant p53, immunostaining is neither sufficiently specific nor sensitive enough to predict p53 mutations. The molecular genetic findings confirm our hypothesis of dual pathways of serous carcinogenesis based on previous analyses of KRAS and BRAF mutations on the same set of cases in which KRAS and BRAF mutations were found in 60% of SBTs and low-grade serous carcinoma but not in high-grade serous carcinomas. Based on these studies, we have proposed a model of serous carcinogenesis in which SBTs are the precursors of low-grade serous carcinomas whereas the usual type of invasive serous carcinoma is a high-grade neoplasm that develops "de novo" from in situ alterations in epithelial inclusion cysts.

Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors.

Molecular genetic changes that are associated with the initiating stage of tumor development are important in tumorigenesis. Ovarian serous borderline tumors (SBTs), putative precursors of low-grade serous carcinomas, are among the few human neoplasms with a high frequency of activating mutations in BRAF and KRAS genes. However, it remains unclear as to how these mutations contribute to tumor progression. To address this issue, we compared the mutational status of BRAF and KRAS in both SBTs and the adjacent epithelium from cystadenomas, the presumed precursor of SBTs. We found that three of eight SBTs contained mutant BRAF, and four SBTs contained mutant KRAS. All specimens with mutant BRAF harbored wild-type KRAS and vice versa. Thus, seven (88%) of eight SBTs contained either BRAF or KRAS mutations. The same mutations detected in SBTs were also identified in the cystadenoma epithelium adjacent to the SBTs in six (86%) of seven informative cases. As compared to SBTs, the cystadenoma epithelium, like ovarian surface epithelium, lacks cytological atypia. Our findings provide cogent evidence that mutations of BRAF and KRAS occur in the epithelium of cystadenomas adjacent to SBTs and strongly suggest that they are very early events in tumorigenesis, preceding the development of SBT.