Metastatic esophageal tumors from distant primary lesions: report of three esophagectomies and study of 1835 autopsy cases

Three cases of esophagectomy for secondary esophageal carcinoma metastasized from the ovary, breast and lung are reported. Long-term survival, 14 and 4 years, after esophagectomy was achieved in two patients. The intervals between surgery for primary cancer and dysphagia onset in these two patients were 16 and 7 years, respectively. An aggressive surgical approach appears to be the therapeutic procedure of choice for metastatic esophageal carcinoma when the primary tumor growth rate is suspected to be slow. Autopsy data on 1835 cases revealed 112 (6.1%) had metastasis to the esophagus. The lung was the most common primary tumor-bearing organ and the diffusely infiltrative type was the most common esophageal tumor observed macroscopically which corresponded to the findings in our three patients. When an esophageal stricture with normal mucosa is encountered, a metastatic tumor must be taken into consideration.     

Increased living donor volunteer rates with a formal recipient family education program

As part of our ongoing studies to characterize molecular alterations in a well-defined series of surgically resected esophageal cancers, we examined the expression of 2 ras-regulated genes, whose products (osteopontin and cathepsin L) previously were shown to be associated with tumor invasion and metastasis. RNA was extracted from primary esophageal tumors (adenocarcinomas, 19; squamous-cell carcinomas, 6) and matched histologically normal esophageal mucosa from the distant resection margin. Northern analysis was used to quantitate RNA, relative to an 18S rRNA control, and immunohistochemistry to assess the tissue distribution of osteopontin. In addition, H-, K- and N-ras mutations were studied in the same tissues using PCR and hybridization with allele (mutant)-specific oligonucleotide probes. We demonstrated a K-ras mutation (codon 12, GTT) in one esophageal adenocarcinoma. The ras-regulated gene osteopontin was over-expressed in 100% of squamous-cell carcinomas and in 58% of adenocarcinomas relative to matched normal esophageal mucosa. Patterns of immunoreactivity for osteopontin protein also varied between squamous-cell carcinomas (tumor cell staining) and adenocarcinomas (predominantly tumor-infiltrating macrophages). Expression of cathepsin L also varied with esophageal tumor histology, with over-expression in 58% of primary esophageal adenocarcinomas and 33% of squamous-cell cancers.     

Characteristics and clinical outcome of proximal-third gastric cancer

BACKGROUND: It is generally accepted that the prognosis of patients with proximal gastric cancer (PGC) is worse than that of patients with more distal gastric cancer. STUDY DESIGN: The aim of this study was to compare the clinical features and outcomes of PGC with those of middle- and distal-third gastric cancers. A total of 646 primary gastric cancers was analyzed as a retrospective study. RESULTS: Proximal gastric cancer occurred in 21.8% of the 646 cancers analyzed, and approximately 21% of PGCs had esophageal invasion. The 5-year survival rate for patients with PGC was significantly lower than that of patients with more distal tumors. When the PGC group was divided into patients with esophageal invasion and without esophageal invasion, patients with esophageal invasion had significantly worse outcomes. When corrected for depth of invasion, lesions with esophageal invasion had significantly worse outcomes than those of other sites in T2 curative cancers. Proximal gastric cancer with esophageal invasion was characterized by a larger tumor, deeper penetration, and a higher incidence of lymph node metastasis compared with tumors in other sites, and in multivariate analysis of all curative cases, these variables were independent prognostic factors for survival. The frequency of positive proximal margins of PGC was higher than those of other sites. CONCLUSIONS: The relatively poor prognosis associated with PGC is mainly from advanced tumor stages of esophageal invasion. Early detection is the most important strategy to improve the survival of patients with PGC. In addition, aggressive lymph node dissection and chemotherapy for esophageal invasion should be considered even if the tumor invasion is moderate (T2 tumor), and a tumor-free margin is important.     

Prognostic factors in radiation-treated esophageal carcinoma

Prognostic factors in esophageal carcinoma treated with irradiation were examined. The prognosis of 111 patients without metastasis who had received more than 60 Gy was analyzed. Significant associations were found between survival rates and tumor length, stage, radioresponse of the primary tumor and the s.c. X-P classification based on barium contrast radiography; superficial type (tumor limited to the surface of the esophageal wall), tumorous type (solid mass without ulceration), Ul-A type (tumor with shallow ulceration with regular margin), Ul-B type (tumor with deep ulceration or irregular ulcer margin), and funneled type (tumor invading the esophageal wall in a scirrhous pattern). In multiple regression analysis, the X-P classification had the strongest correlation with survival and the survival rates of patients with the superficial type, the tumorous type and the s.c. Ul-A type were significantly higher than those of patients with the other tumor types (p < 0.001).     

TP53 and oesophageal cancer

Mutations of the tumor suppressor gene TP53 have been detected in tumor tissues of a large variety of human malignancies and contribute to the development, progression and probably the prognosis of the disease. The pattern of somatic mutations in the TP53 gene in human tumors most often consists of a point mutation in one allele accompanied by loss or rearrangement of the second allele. Esophageal cancer is one of the most commonly mutated cancer, p53 mutations having an incidence greater than 80% in squamous cell carcinoma. The profile of distribution of these mutations in the TP53 gene is of interest to establish correlation between the exposure to carcinogens responsible for DNA mutations. The other form of esophageal cancer, Barrett's esophageal is a good model to study the role of TP53 in mammalian tumorigenesis.     

Endosonographic features of esophageal granular cell tumors

BACKGROUND AND STUDY AIMS: Granular cell tumors of the esophagus are rare tumors. A definite diagnosis is achieved by endoscopic biopsies in only 50% of cases. Endoscopic ultrasonography (EUS) is the best procedure in the evaluation of upper gastrointestinal tract submucosal tumors. The aim of this study was to describe the endosonographic findings of esophageal granular cell tumors. METHODS: From January 1989 to March 1994, 15 patients with 21 granular cell tumors which had negative biopsies were examined by EUS (Olympus GF UM3 or GF UM20,7,5 and 12 MHz). In five cases, the tumor was also studied with a 20 MHz Olympus miniprobe. The final histological diagnoses were obtained by subsequent endoscopic snare resection in 20 cases and surgically in one case. RESULTS: The endosonographic features (with the GF UM3 or GF UM20) of esophageal granular cell tumors were: a) a tumor size of less than 2 cm in 95% of cases; b) an hypoechoic solid pattern in 100% of cases; c) a tumor arising in the inner layers in 95% (second echo-poor layer n=15; third echo-rich layer n=5). In one case, the endosonographic finding was transmural malignant infiltration of the esophageal wall (histologically confirmed). CONCLUSION: When a granular cell tumor of the esophagus is suspected, EUS can show the inner layer location of the tumor and thus contribute to planning the endoscopic resection or follow up. When the tumor also invades the outer layers, EUS can contribute to planning the surgical resection.     

Upper esophageal stenosis: two case reports

Esophageal stenosis caused by an intrinsic congenital deformity is uncommon in infants and children. The main forms of stenosis are congenital esophageal web congenital stricture caused by tracheobronchial remnants, and congenital idiopathic muscular hypertrophy. The authors report on two patients who were successfully treated and managed after being diagnosed as having upper esophageal stenosis. One patient underwent resection of the web and primary anastomosis of the esophagus and was discharged 6 days after surgery. After 1 year, this patient has had no symptoms of dysphagia or other postoperative difficulties. The second patient underwent balloon dilatation of the esophageal stricture and was discharged on the day of surgery; however, this patient required numerous repeat dilatations.     

Micrometastasis and tumor cell microinvolvement of lymph nodes from esophageal squamous cell carcinoma: frequency, associated tumor characteristics, and impact on prognosis

BACKGROUND: The purpose of this study was to investigate micrometastasis (MM) and tumor cell microinvolvement (TCM) in the regional lymph nodes of patients with esophageal squamous cell carcinoma (SCC). METHODS: MM was defined as individual tumor cells or tumor cell clusters <0.5 mm in greatest dimension with a surrounding stromal reaction. TCM was defined as individual tumor cells or tumor cell clusters without a surrounding stromal reaction. One thousand nine hundred and fifty-four lymph nodes were dissected from 69 complete (R0) resection specimens of TNM classified pT1-3, pN0 or pN1, and M0 esophageal SCC. These lymph nodes were examined immunohistochemically using the monoclonal antibody cocktail AE1/AE3 for cytokeratins. The primary tumors were immunostained with an anti-E-cadherin monoclonal antibody. RESULTS: MM +/- TCM was found in 13 cases (31.7%) and TCM alone in 2 cases (4.9%) of the 41 pN0 cases. The pN0 patients with MM (but not TCM) had the same shorter survival as the original pN1 cases (P < 0.05). Of the 69 primary tumors, 49 (71.0%) had reduced or negative E-cadherin expression that showed a correlation with the occurrence of lymph node metastases (original pN1), MM, and TCM, but not prognosis. CONCLUSIONS: The results of the current study show that, in SCC of the esophagus, MM, but not TCM, in the regional lymph nodes is prognostically equivalent to metastasis and should be examined by immunohistochemistry to classify these cases correctly as pN1.     

Antioxidant systems in rat epididymal spermatozoa

Down-regulation of KAI1 mRNA expression has been shown to be associated with the formation of metastases or disease progression in pancreatic cancer. Whether KAI1 possesses similar characteristics in other malignancies of the gastrointestinal tract is not known. Here, we compared the patterns of KAI1 mRNA expression in 41 esophageal cancers and 35 stomach cancers to assess whether KAI1 might also be of biological relevance in the metastatic ability of these tumors. By Northern blot analysis, KAI1 mRNA levels ranged widely in both normal and cancerous esophageal and gastric tissue samples, with no statistical differences. No association between KAI1 mRNA expression and tumor stage or tumor differentiation was seen in these tumors. In addition, KAI1 mRNA expression was similar in primary esophageal and gastric cancer samples with or without metastases. By in situ hybridization, KAI1 mRNA expression was evident in the cytoplasm of most squamous epithelial cells in the normal esophagus and in nonmucosal epithelial cells of the normal stomach. The staining intensity in the esophageal and gastric cancer cells was similar to that in the normal controls. This differential pattern of KAI1 mRNA expression in esophageal and gastric cancers in comparison to pancreatic cancer indicates that KAI1 seems to influence the potential of gastrointestinal cancer cells to metastasize differently. In esophageal and gastric cancers, the formation of metastases is not dependent on the reduction of KAI1 in the cancer cells.     

Combined lung resection for advanced thoracic esophageal carcinoma

We performed lung resection together with esophagectomy in 2 patients with advanced thoracic esophageal cancer. Both patients survived more than 2 years with no evidence of disease. The first case was a 60-year-old man who had a cancer lesion in middle of the intra-thoracic esophagus (Im) and the right lower lobe of the lung was involved. In March 1989, right lower lobectomy of the lung was performed with esophagectomy. Pathologic examination showed well differentiated squamous cell carcinoma invading the lung parenchyma and intrapulmonary lymph node. Postoperatively, 44 Gy of radiation and Peplomycin cancer chemotherapy was performed. The patient survived 51 months after surgery and died of chronic myelogenous leukemia. The second case was a 60-year-old man who underwent thoracic esophagectomy with resection of the involved pericardium and right lung in February 1992. Pathologic examination showed N3 lymph node metastasis. Postoperatively, the patient received 48 Gy of radiation and was free from cancer after 30 months. In conclusion, better surgical results are expected in cases of advanced thoracic esophageal cancer with lung involvement which can be completely resected en bloc with the primary tumor even in a3 cases than in those with aortic or tracheobronchial involvement.     

Biopsy-negative malignant esophageal stricture: diagnosis by endoscopic ultrasound

Endoscopic ultrasound (EUS) of the esophagus has been used primarily in staging biopsy-proven cancers. Its use as a primary diagnostic modality for esophageal malignancy has not been previously described. We report our recent experience in four patients with dysphagia and endoscopic biopsies negative for malignancy, including one patient with clinical and manometric features suggestive of achalasia. In all cases, EUS revealed a large infiltrating tumor invading through the esophageal wall into the surrounding tissues, and in one case into the aorta. Computed tomography suggested the possibility of a tumor in only one of the cases. Two patients underwent esophagectomy and were found to have adenocarcinoma. Two patients underwent repeat biopsy with alternative aggressive biopsy techniques and were found to have squamous cell carcinoma. We conclude that EUS is useful in the diagnosis of esophageal cancer and should be performed in selected patients with esophageal strictures whose biopsies are negative for malignancy; i.e., those with suspicious endoscopic or radiographic appearance, atypical presentation (e.g., profound weight loss, short duration of symptoms, or advanced age), and failure to respond to treatment.     

The invasion-MTT assay as a predictor of liver metastasis using human gastrointestinal carcinomas transplanted in nude mice

The invasion-3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay, which evaluates invasive potential into the reconstituted basement membrane, Matrigel, was performed on 49 human gastrointestinal carcinomas transplanted in nude mice. There were 19 colorectal carcinomas, 10 pancreatic carcinomas, 10 gastric carcinomas, 8 esophageal carcinomas, and 2 bile duct carcinomas. The percent invasion (PI) value of each tumor by the invasion-MTT assay expresses the invasive rate of tumor cells into the Matrigel as a percentage. There were no significant differences in correlations between the PI values and primary tumor site, clinicopathological findings, tumor doubling time, or DNA index; however, the PI values of primary tumors and lymph nodes with liver metastases were significantly higher than those of primary tumors without liver metastasis (P < 0.05). Furthermore, the primary tumors with synchronous (P < 0.05) or asynchronous (P < 0.01) liver metastases showed significantly higher PI values compared with the primary tumors without liver metastases. These results suggest that PI is not only an independent factor to predict liver metastasis, but it also correlates closely with liver metastasis. Thus, the invasion-MTT assay for primary tumors might be clinically useful to predict liver metastasis in patients following surgery for gastrointestinal carcinomas.     

A resected case of esophageal leiomyoma with 15 cm in long diameter, diagnosed by transesophageal ultrasonic endoscopy

A 28-year-old man whose chest X-ray film showed a mass on the right upper mediastinum was admitted. Preoperative examination, including CT, MRI, esophagogram, did not make it possible to determine clinically from which organ the tumor originated. On diagnosing with transesophageal ultrasonic endoscopy (TUE) the tumor was found to originate in the esophageal submucosa, with no involvement of the mediastinal organ apparent. Esophageal sub-mucosal tumor enucleation was performed. The resected tumor was 15 cm in long diameter and weighed 125 g. We therefore believe that TUE is clinically useful in diagnosing the tumor originating in the esophageal wall or adjoining esophageal wall.     

Variations in nucleolar organizer regions during 9-10 dimethyl1-2 benzanthracene induced tongue carcinogenesis in rats

BACKGROUND: Many studies have reported the increased expression of epidermal growth factor receptor (EGFR) in various human malignancies and its association with the biologic behavior of the tumors. METHODS: We performed an immunohistochemical analysis of the EGFR in 217 cases of human esophageal squamous cell carcinoma, 161 lymph node metastases and 23 foci of squamous dysplasias. The findings were correlated with clinicopathologic features, including the clinical outcome. Southern blot analysis was performed in 42 cases for the detection of DNA amplification of the EGFR gene and subsequently was correlated with EGFR immunoreactivity. RESULTS: Epidermal growth factor receptor overexpression was detected in 71% of primary tumors and 88% of lymph node metastases, as compared to nonpathologic adjacent esophageal epithelium. Statistically significant correlations were observed between EGFR overexpression and sex, age, histologic type, and the presence of invasion. Tumor staining was classified into two patterns, homogeneous and heterogeneous, based on the distribution of EGFR-positive cells. The immunostaining patterns of primary tumors had a statistically significant correlation with histologic type, the presence of adventitial invasion, histologic stage and lymph node metastasis. There was a tendency toward a worse prognosis for those patients with EGFR overexpression in the primary tumor. Greater than 90% of the foci of squamous dysplasia demonstrated homogeneous EGFR overexpression. DNA amplification of the EGFR was observed in 21% of primary tumors, and all demonstrated immunohistochemical overexpression. CONCLUSIONS: Immunohistochemical overexpression of the EGFR, which was more frequent than EGFR DNA amplification, appears to play an important role in biologic behavior of human esophageal squamous cell carcinomas.     

Clinically significant, isolated metastatic disease to the thyroid gland

Despite being second only to the adrenal glands in terms of relative vascular perfusion, the thyroid gland is a rare site of metastatic disease; but when thyroid metastases occur, long-term survival has been reported to be dismal. To determine the incidence and management of isolated, metastatic disease to the thyroid, we reviewed our clinical experience. Between June 1986 and August 1994 ten patients underwent thyroidectomy for isolated, metastatic disease of nonthyroidal origin (mean +/- SD age 58 +/- 6 years, 30% female). The primary tumors were renal cell carcinomas (RCCs) (n = 5), esophageal adenocarcinoma (n = 1), pulmonary squamous cell carcinoma (n = 1), gastric leiomyosarcoma (n = 1), lingual squamous cell carcinoma (n = 1), and parotid gland carcinoma (n = 1). Three patients underwent preoperative fine-needle aspiration (FNA), all of which were suggestive of metastatic disease. The mean time from resection of the primary tumor to thyroid metastases was 3.5 +/- 6.0 years (range 0-19.5 years). Total thyroidectomy (n = 5) or lobectomy (n = 5) was performed without morbidity or mortality. After a median follow-up of 5.2 years six patients are alive and two are free of disease. Moreover, no patients have had recurrent disease in the neck. Thus carcinomas metastatic to the thyroid represent a rare cause of clinically significant thyroid disease, with RCCs comprising 50%. Most thyroid metastases (80%) present within 3 years of primary tumor resection, but with RCC they can occur as late as 19 years. The diagnosis of metastatic disease should be suspected in patients with even a remote history of cancer, especially RCC, and an FNA revealing clear cell or spindle cell carcinoma. Contrary to previous reports, long-term survival can be achieved after resection of the metastatic tumor. Furthermore, thyroidectomy may also palliate/prevent the potential morbidity of tumor recurrence in the neck.     

Significance of routine annual esophagram for early detection of carcinoma of the esophagus

BACKGROUND/AIMS: In order to achieve increased survival rates for patients with carcinoma of the esophagus, early detection of the disease is vital. Serial esophagrams were evaluated to clarify which interval would be effective for early detection of carcinoma of the esophagus during routine examination. MATERIALS AND METHODS: One hundred eighty-nine patients with carcinoma of the esophagus were grouped into three, according to the experience and the time of the previous roentgenograms before the definite diagnosis. RESULTS: Five patients were in Group 1, in which roentgenographic examination had been done within 12 months prior to the diagnosis. Retrospective observation revealed a slight but certain abnormal shadow at the same location as the esophageal tumor seen on the second films. In Group 2, seven had received an esophagram between 12 and 24 months before the diagnosis. In contrast to Group 1, neither abnormality nor findings indicating esophageal tumors were detected on the former x-ray films, in all seven cases. Group 2 was characterized by relatively small tumors and low stage of the disease. Mean tumor length was 4.1 +/- 2.9 cm, and three of seven were classified as Stage I and two as Stage IIA. On the other hand, most of the 177 patients in Group 3, with no previous examination of the esophagus within 24 months before the diagnosis, had far advanced disease. Mean tumor length was 6.3 +/- 2.6 cm. Only nine (5.1%) were classified as Stage I, whereas 115 (65.0%) were classified as Stage III or IV. CONCLUSION: In light of these data, for populations in which esophageal cancer frequently occurs, esophageal examination every 12 months will no doubt contribute towards the early detection of lesions.     

BAL fluid contains detectable superoxide dismutase 1 activity

We retrospectively analyzed the prognostic significance of angiogenesis and the relationships between tumor angiogenesis and clinopathological variables in a series of 127 patients with primary esophageal squamous cell carcinoma which were curatively resected. Vessels were stained with anti-factor VIII polyclonal antibody and areas with the highest number of microvessels were counted in a x400 field. Microvessel counts were significantly correlated with pN category, pM category, venous invasion and recurrence (p=0.002, p=0.040, p=0.016 and p=0.0013, respectively). The proportion of patients with recurrence increased in proportion to the number of microvessels. multivariate analysis using Cox's proportional hazard modelling showed angiogenesis assessed by microvessel count affected the poorer prognosis of patients with esophageal squamous cell carcinoma (hazard ratio, 1.03; 95%CI, 1.00-1.07), although it was not a significant independent prognostic factor (P=0.088). This study suggest that angiogenesis assessed by microvessel count is a marker for relapse and prognosis in patients with esophageal squamous cell carcinoma.     

A novel amplicon at 8p22-23 results in overexpression of cathepsin B in esophageal adenocarcinoma

Cathepsin B (CTSB) is overexpressed in tumors of the lung, prostate, colon, breast, and stomach. However, evidence of primary genomic alterations in the CTSB gene during tumor initiation or progression has been lacking. We have found a novel amplicon at 8p22-23 that results in CTSB overexpression in esophageal adenocarcinoma. Amplified genomic NotI-HinfI fragments were identified by two-dimensional DNA electrophoresis. Two amplified fragments (D4 and D5) were cloned and yielded unique sequences. Using bacterial artificial chromosome clones containing either D4 or D5, fluorescent in situ hybridization defined a single region of amplification involving chromosome bands 8p22-23. We investigated the candidate cancer-related gene CTSB, and potential coamplified genes from this region including farnesyl-diphosphate farnesyltransferase (FDFT1), arylamine N-acetyltransferase (NAT-1), lipoprotein lipase (LPL), and an uncharacterized expressed sequence tag (D8S503). Southern blot analysis of 66 esophageal adenocarcinomas demonstrated only CTSB and FDFT1 were consistently amplified in eight (12.1%) of the tumors. Neither NAT-1 nor LPL were amplified. Northern blot analysis showed overexpression of CTSB and FDFT1 mRNA in all six of the amplified esophageal adenocarcinomas analyzed. CTSB mRNA overexpression also was present in two of six nonamplified tumors analyzed. However, FDFT1 mRNA overexpression without amplification was not observed. Western blot analysis confirmed CTSB protein overexpression in tumor specimens with CTSB mRNA overexpression compared with either normal controls or tumors without mRNA overexpression. Abundant extracellular expression of CTSB protein was found in 29 of 40 (72. 5%) of esophageal adenocarcinoma specimens by using immunohistochemical analysis. The finding of an amplicon at 8p22-23 resulting in CTSB gene amplification and overexpression supports an important role for CTSB in esophageal adenocarcinoma and possibly in other tumors.     

Diet supplemented with yoghurt or milk fermented by Lactobacillus casei DN-114 001 stimulates growth and brush-border enzyme activities in mouse small intestine

Adjuvant and neoadjuvant therapeutic principles have in recent years received increasing attention in the management of patients with carcinoma of the upper gastrointestinal tract. A series of randomized prospective trials has demonstrated that adjuvant postoperative radiation or chemotherapy does not result in a convincing survival advantage after complete tumor resection in gastric or esophageal cancer. The available data on the role of neoadjuvant preoperative therapy in these patients as yet permit no conclusion. While neoadjuvant therapy may reduce the tumor mass in a substantial portion of patients, a series of randomized controlled trials has shown that, compared to primary resection, a multimodal approach does not result in a survival benefit in patients with loco-regional, i.e. potentially resectable, tumors. In contrast, in patients with locally advanced tumors, i.e. tumors for which complete removal with primary surgery appears unlikely, neoadjuvant therapy increases the chance for complete tumor resection on subsequent surgery. However, only patients with objective histopathologic response to preoperative therapy appear to benefit from this approach. Compared to preoperative chemotherapy alone, combined radio-chemotherapy increases the rate of response, particularly in squamous cell esophageal cancer, but may also increase postoperative morbidity and mortality. Neoadjuvant therapy should therefore currently only be performed in experienced centers within the context of prospective clinical trials. The identification of factors that would allow prediction of response to neoadjuvant or adjuvant therapy is the focus of ongoing studies.