Staging and prognosis using endosonography in patients with inoperable esophageal carcinoma treated with combined intraluminal and external irradiation.

Brachytherapy and external irradiation combined are an alternative to surgery in the treatment of advanced esophageal cancer. Endosonography has proved to be an accurate method of staging the depth of tumor invasion of esophageal cancer. Sixty-three patients with inoperable esophageal cancer underwent endosonography followed by combined brachytherapy and external irradiation. Staging was incomplete in 31 of 63 patients because of tight stenosis or difficulty in imaging celiac lymph nodes. During follow-up of 23 patients, reduction of tumor thickness and lymph node abnormalities was observed in 16. The median survival was 10.4 months. Survival time was correlated with initial number of metastatic lymph nodes found by endosonography. Paradoxically, the survival of patients with more extensive intra-luminal tumor growth was significantly better than survival of those with less tumor growth. In summary, the response to combined brachytherapy and external irradiation could accurately be assessed with endosonography. Lymph node abnormalities and tumor thickness were closely related to survival rate.

Genetic evidence that Turcot syndrome is not allelic to familial adenomatous polyposis.

Turcot syndrome (TS) is a rare genetic disease in which brain tumors occur in association with colonic polyposis. Since Turcot's original description in 1959, there have been disagreements about the mode of inheritance as well as the clinical expression of this condition. Some investigators maintain that TS is a phenotypic variant of the autosomal dominant familial adenomatous polyposis (FAP), while others observe that there are clinical differences between TS and FAP, and that the pattern of inheritance of TS is autosomal recessive. The distribution of persons with colonic lesions in a family with a patient of colonic polyposis and a brain tumor, described in this report, favored the recessive hypothesis. In this family, the involvement of the FAP gene on chromosome 5q21-q22 could be excluded by a linkage study using a panel of FAP-linked DNA markers. This finding, which indicates the occurrence of another polyposis gene elsewhere in the genome, will have consequences for the presymptomatic diagnosis of FAP by linked DNA markers. We conclude that TS is a distinct clinical-genetical entity with the triad of atypical polyposis coli, CNS tumors, and a recessive mode of inheritance.

The spectrum of gastrointestinal metastases of breast carcinoma: I. Stomach.

In a 15-year period at the Netherlands Cancer Institute, 27 patients were found with breast carcinoma metastatic to the stomach. Presenting symptoms were non-specific, mainly nausea, vomiting, dysphagia, epigastric pain, and melena. Endoscopy, performed in 22 of these patients, yielded a correct diagnosis in 13. Lobular rather than ductal breast carcinoma was the predominant source of gastric metastases in this series. Non-surgical treatment was rewarded by a favorable, palliative response in 32% of cases.

The spectrum of gastrointestinal metastases of breast carcinoma: II. The colon and rectum.

In a 15-year period at the Netherlands Cancer Institute, 17 patients were found with breast carcinoma metastatic to the colon or rectum or both. The presenting symptoms and signs were non-specific and included diarrhea, crampy pain, vomiting, and palpable tumor. Endoscopic examination, possible in only 10 of the 17 patients because of luminal obstruction, yielded a correct diagnosis in seven cases. Biopsy was confirmatory in five cases. Lesions metastatic to the colorectum originated predominantly in lobular carcinoma of the breast. Systemic hormonal or chemotherapy or x-irradiation, either alone or as an adjunct to surgery, produced a favorable response in over half the patients so treated.

Metastatic ovarian or colonic cancer: a clinical challenge.

Clinical problems arise when histology is unable to differentiate between an ovarian carcinoma infiltrating into the rectosigmoid region and a colonic cancer with ovarian metastases. To evaluate the discriminative value of immunohistochemistry we studied four groups: (A) ovarian carcinoma (n = 21), (B) ovarian carcinoma with sigmoid stenosis (n = 18), (C) colonic carcinoma (n = 20) and (D) a group in which the differential diagnosis was a problem (n = 19). Paraffin sections stained with a panel of monoclonal antibodies revealed specific patterns: in group A and B a negative Parlam-4 and positive OC-125; in group C the opposite; in group D the 'colonic' pattern in 15 cases, and the 'ovarian' pattern in only 2. The clinical diagnosis in group D during follow-up was ovarian carcinoma in 7, colonic carcinoma in 8, double tumour in 1 and still unknown in 3. This was based on high levels of serum tumour markers such as carcinoembryonic antigen (n = 5) and CA-125 (n = 4), laparotomy (n = 4), autopsy (n = 1), barium enema and/or endoscopy (n = 5). The response to chemotherapy in group D was extremely poor.

A new deletion polymorphism at D5S71 raises the linkage information on adenomatous polyposis coli: implications for presymptomatic diagnosis.

Two independent study-groups, one in Britain and the other in the United States, were the first to report linkage between APC and a TaqI restriction fragment length polymorphism (RFLP) at D5S71 (probe C11p11) on chromosome 5q. They found no recombinants in about 50 informative meioses. The same TaqI RFLP was found to be uninformative for linkage in 15 Dutch polyposis families. The recently reported four base-pair deletion polymorphism (DEL1) at D5S71 has raised the polymorphism information content of this marker from 0.17 to 0.40 in the Dutch population. Seven of 20 polyposis families screened for the DEL1 as well as the TaqI polymorphism gave a combined peak lod score of 5.68 with no recombinants in 37 informative meioses. These data, together with those so far reported in the literature, raise the peak lod score to 17.09 at a recombination fraction of 0.05, the 95% upper confidence limit being 0.09. In combination with the use of another informative marker, D5S81 (probe YN5.48) closely mapping on the other side of APC, the presymptomatic diagnosis of the disease can be made with more than 99.9% certainty. It has to be stressed, however, that the the possible existence of more than one polyposis locus cannot, as yet, be excluded.

Preoperative TNM classification of esophageal carcinoma by endosonography.

Endosonography was performed preoperatively in 111 patients with an esophageal carcinoma. The results were correlated with the histology of resected specimens employing the new (1987) TNM classification. Endosonography was accurate in assessing the depth of tumor infiltration (overall accuracy: 89%). Early carcinomas could be distinguished from advanced cancer. Extensive stenosis preventing the passage of the instrument was a limiting factor prior to the availability of a small-caliber catheter echoprobe (25% of cases). Endosonography was helpful for diagnosing lymph node metastasis, but was less accurate in defining non-metastatic enlarged lymph nodes (accuracy: 81%, sensitivity 95% and specificity 50%). The incidence of lymph node metastasis increased with the progression of tumor infiltration. Endosonography was also less accurate for diagnosing liver metastases and peritoneal dissemination because of the low depth of penetration of ultrasound. Technical improvements such as a reduction in the diameter of the instrument will further enhance the accuracy of endosonography. Moreover, ES-guided cytology may become helpful for confirming the ES diagnosis of lymph node metastasis.

The tumour spectrum in hereditary non-polyposis colorectal cancer: a study of 24 kindreds in the Netherlands.

The hereditary colonic cancer syndrome without polyposis, hereditary non-polyposis colorectal cancer (HNPCC), is usually divided into 2 main categories: hereditary site-specific colorectal cancer (Lynch syndrome I) and colorectal cancer in association with other forms of cancer (Lynch syndrome II). One problem associated with Lynch II is the uncertainty as to which types of cancer form part of the hereditary tumour spectrum. The present study was performed to obtain more information about the tumour spectrum of HNPCC. In the 24 HNPCC families studied, 104 patients had colorectal cancer (mean age at diagnosis: 46 years) and in 4 of the families this was the only type of cancer to occur. Sixty-five extra-colonic tumours were diagnosed in 20 families. Endometrial carcinoma was found in 16 patients belonging to 12 families. Cancer of the stomach occurred in 10 patients representing 5 families, and mainly in the older generations. Urinary-tract tumours were found in 8 patients from 4 families. Second primary tumours were diagnosed in 13 of the 16 patients with endometrial cancer, in 4 of the 10 patients with stomach cancer and in 7 of the 8 patients with a urinary-tract tumour. Many other types of carcinoma were found as well, but less frequently. In our families, the trait appears to be transmitted by patients with cancer of the stomach, endometrium or urinary tract, because some of their children have developed colorectal cancer. The findings suggest that, in these 24 HNPCC families, carcinomas of the endometrium, stomach and urinary tract belong to the hereditary tumour spectrum. Definite assignment of tumours to this spectrum will become possible only after a sensitive and specific biomarker becomes available. The screening programme should depend on which and how many extra-colonic tumours occur in a family.

Endoscopic ultrasonography for the evaluation of smooth muscle tumors in the upper gastrointestinal tract: an experience with 42 cases.

Before surgery, 12 patients with suspected leiomyoma and 12 patients with suspected leiomyosarcoma were studied by endoscopic ultrasonography (EUS), computed tomography (CT), endoscopy, and barium swallow. The results were correlated with surgery and histology. Ten leiomyomas, one benign gastric ulcer, one carcinoid metastasis, eight leiomyosarcomas, two leiomyoblastomas, one mucus secreting adenocarcinoma, and one bronchial carcinoma were diagnosed. Eighteen additional patients suspected to have benign submucosal lesions by endoscopy and barium meal were treated non-surgically, and studied by EUS and CT. EUS was superior to other imaging techniques in the detection, staging, and follow-up of submucosal smooth muscle tumors because of clear imaging of the intramural abnormality and adjacent lymph nodes.

Rectosigmoid obstruction caused by ovarian cancer.

Out of a total of 379 patients with ovarian carcinoma a rectosigmoid stenosis was detected in 44 (12%). A barium enema was available in 27 cases, which revealed a severe stenosis (less than 1/2 lumen open) in 23, with an average length of 17 cm (5-40 cm). Five characteristic types of stenosis were found: solitary stenosis (n = 6), large spherical impression (n = 6), multiple stenoses (n = 4), long narrow tract (n = 6) and a total obstruction (n = 5). Desmoplastic reaction with tethering and/or parallel folds (n = 16) or fixation and/or angulation (n = 18) were frequently found, but tumour invasion was rare (n = 3). A sigmoid resection (n = 1) or colostomy (n = 3) was seldom needed, due to beneficial response to combined therapy.

The value of screening and central registration of families with familial adenomatous polyposis. A study of 82 families in The Netherlands.

In 1984 a national registry of families with familial adenomatous polyposis was set up in The Netherlands to promote screening in those families. Eight-two families had been registered by the end of 1988. Analysis of the pedigrees showed that 204 family members at risk had not yet been screened. The diagnosis of familial adenomatous polyposis was histologically confirmed in 230 patients. These patients were subdivided into two groups. Group A comprised patients with familial adenomatous polyposis referred because they were symptomatic, and Group B relatives of these patients who were found by screening to have familial adenomatous polyposis. The authors compared these groups with respect to the occurrence of colorectal carcinoma. Fifty-four patients were found to have a colorectal carcinoma at the time of diagnosis of familial adenomatous polyposis, i.e., 49 of the 104 patients in Group A (47 percent) and five of the 126 patients in Group B (4 percent). The average age at diagnosis of the 104 patients in Group A was 35 years (range, 13 to 66 years) and that of the 126 patients in Group B was 24 years (range, 8 to 59 years). By the age of 40 years, 90 percent of the patients in group B had been diagnosed. Late onset of familial adenomatous polyposis was found in four families. Endoscopy and/or radiography of the upper digestive tract were (was) performed in 44 of the 230 patients. Nineteen patients (43 percent) were found to have polyps in the stomach or duodenum, or both. In our series, only one patient died from cancer of the upper digestive tract (ampullary carcinoma). These results show conclusively that screening leads to the early detection of familial adenomatous polyposis. The value of a national registry is proved by the finding of many at-risk family members who had not previously been screened. Screening should start between the ages of 10 and 12 and should continue up to the age of 50. In the rare cases of families with an apparently late onset of familial adenomatous polyposis, screening should be continued up to age 60. More studies are needed to determine the natural history of polyps in the upper digestive tract.

Presymptomatic diagnosis of familial adenomatous polyposis by bridging DNA markers.

Familial adenomatous polyposis (FAP) is a disorder with autosomal dominant inheritance, which predisposes to colorectal adenocarcinoma. The gene causing the disorder has been assigned to chromosome 5 by means of a polymorphic DNA marker called C11p11. An informative Dutch pedigree showed that two other linked polymorphic DNA markers, Pi227 and YN5.48, closely flank the FAP locus, one on either side. This finding will allow prenatal and presymptomatic diagnosis of FAP, with more than 99.9% reliability in the majority of families, by means of already available markers.

Late radiation injury of the rectum and sigmoid colon: barium enema findings in 92 patients.

We reviewed the findings on 169 contrast enema examinations in 92 patients with late radiation injury of the rectum and sigmoid colon, encountered over an 11-year period. The diagnosis was made by rectosigmoidoscopy in all patients. The limitations and pitfalls of both examinations were studied. The mean interval between radiotherapy and diagnosis was 1.7 years and the mean follow-up period was 3.5 years. The main radiological features varied from normal findings (15% of the initial examinations) to decreased distensibility of the bowel wall, intestinal fixation, mucosal and contour abnormalities, ulceration, stenoses and fistula formation. During follow-up, the number of all pathological findings increased. Pre-stenotic dilatation of the descending colon was always absent. The contrast enema examinations and endoscopies were found to be complementary. The barium enema showed the extent of the disease and accurately identified stenoses and fistulas, but underdiagnosed ulceration and overdiagnosed malignancy. Endoscopy allowed unequivocal detection of mucosal damage, especially ulceration, and was accurate in showing stenoses but sometimes failed to demonstrate fistulas. Moreover, in 25% of examinations it was impossible to examine the entire abnormal area.

Endosonography and computed tomography of esophageal carcinoma. Preoperative classification compared to the new (1987) TNM system.

Transesophageal endosonography and computed tomography were performed preoperatively in 74 patients with an esophageal carcinoma. The results were correlated with the histology of resected specimens according to the new (1987) TNM classification. Endosonography was superior to computed tomography in the evaluation of the depth of tumor infiltration, especially in the early stages and in nonresectable carcinoma (overall accuracy: endosonography 89%, computed tomography 59%). Endosonography was also more accurate than computed tomography in the assessment of regional lymph node metastases (overall accuracy: endosonography 80%, computed tomography 51%). The incidence of lymph node metastasis increased with the progression of the depth of tumor infiltration. The definitive exclusion factor for endosonography is severe stenosis, which cannot be passed with the instrument (26% of the cases). In these cases computed tomography was superior to endosonography in diagnosing celiac lymph node metastasis (overall accuracy: computed tomography 82%, endosonography 68%).

Long-term follow-up after colectomy and ileorectal anastomosis in familial adenomatous polyposis coli. Is there still a place for the procedure?

Forty-four patients with familial adenomatous polyposis coli treated with colectomy and ileorectal anastomosis were studied. Mean age at operation was 27 years. The mean follow-up period was 10 years (median 8 years). Three patients (7%) developed rectal cancer 1, 4, and 24 years after the initial operation, respectively. Proctectomy with ileostomy was performed in one patient, and 7 patients underwent a conversion to an ileoanal procedure for an increasing number of rectal polyps in the rectum stump. Although frequent bowel actions and episodes of diarrhea were common findings in patients after colectomy and ileorectal anastomosis, almost all patients (96%) were more or less satisfied with their quality of life after the procedure. On the basis of our results and the results reported in the literature, colectomy with ileorectal anastomosis is still the operation of choice in selected patients with familial adenomatous polyposis coli. An initial ileal pouch - anal anastomosis, or a conversion to such a procedure after colectomy and ileorectal anastomosis is indicated, depending on the number and size of rectal polyps.

Primary non-Hodgkin's lymphoma of the stomach: changing aspects and therapeutic choices.

Eighty-five consecutive patients, seen between 1970 and 1987, with primary gastric non-Hodgkin's lymphoma were studied to evaluate diagnostic findings and treatment results. At endoscopy three main patterns were recognized: ulceration (n = 21), diffuse infiltration (n = 16) and a polypoid mass (n = 26). Recently, the new technique of endoscopic ultrasonography was used to measure depth of infiltration and regional lymph nodes. Preoperative diagnosis altered the indication of surgery. Since 1978 surgical staging was performed in only 29% of the patients compared to 90% in the earlier period. In the later period stage II was more systematically treated with a combination of chemotherapy and radiotherapy. Over the whole period patients in stage I (n = 52) had a 5 year disease-free survival of 63%. In stage II 38% had a 5 year disease-free survival. Complications were one perforation and one haemorrhage after radiotherapy and two cases of haemorrhage after radiotherapy combined with chemotherapy. Intraabdominal recurrences were found in two cases. Recognition of endoscopic features may lead to early detection and ultimately improved survival.

Screening for hereditary non-polyposis colorectal cancer: a study of 22 kindreds in The Netherlands.

PURPOSE: Identification of the hereditary non-polyposis colorectal carcinoma syndrome (HNPCC) is a basis for secondary prevention. The objectives of this study are to investigate the natural history of HNPCC and to assess the effect of screening. PATIENTS AND METHODS: Screening for colorectal carcinoma was performed in 22 HNPCC families (colonoscopy or double-contrast barium enema and sigmoidoscopy). The patients were subdivided into two groups. Group A comprised patients with colorectal cancer who were referred because they were symptomatic. Group B included family members of these patients who were found to have a colorectal lesion by screening. We compared these groups with respect to the stage of tumor growth. RESULTS: Histologic examination of the tumors in Group A (87 patients) revealed Dukes A carcinomas in six patients, Dukes B carcinomas in 37, Dukes C carcinomas in 21, and Dukes D carcinomas in 10 patients (classification unknown in 13 patients). In Group B (20 patients), adenoma was found in 14 and carcinoma in six patients (Dukes A in two and Dukes B in four patients). A total of 93 patients, including those whose tumors were detected by screening, had a colorectal carcinoma. The age at diagnosis ranged from 24 to 81 years (mean age: 46 years). The location of the colonic tumors was proximal in 60 percent. Multiple primary tumors were found in 26 percent. CONCLUSION: These results suggest that screening leads to the early detection of colorectal carcinomas and adenomas in asymptomatic members of HNPCC families. Screening should be initiated at the age of 20 and continued during the life of the individual. Careful examination of the right colon is indicated because of the frequent occurrence of tumors in the proximal colon. A subtotal colectomy is indicated at the time of diagnosis of the initial colon cancer because of the risk of multiple primary tumors.

Expression of the nuclear oncogene p53 in colon tumours.

The nuclear tumour antigen p53 is expressed by a gene localized on the p-arm of human chromosome 17, a region frequently deleted in colon carcinomas. Using a monoclonal antibody to p53 antigen, immunohistochemical analysis of carcinomas and dysplastic tubular adenomas of the colon has been performed to study the relation between p53 expression and dysplasia or malignancy. With this methods p53 was detectable in 55 per cent of colon carcinomas (n = 29). In 8 per cent of adenomas (n = 74), focal nuclear p53 expression was found in dysplastic epithelial cells. In general, these p53-positive regions of the polyps were histologically indistinguishable from the neighbouring tubuli. Sometimes the p53-positive nuclei were found in a focus of more highly dysplastic epithelium. The results suggest that expression of the p53 gene may be part of the process of malignant transformation of dysplastic colon polyps.

Treatment results of primary stage I and II non-Hodgkin's lymphoma of the stomach.

Gastric lymphoma in stage I or II was usually treated by partial gastrectomy and total abdominal irradiation in our institute since 1970. Since 1978, a number of patients were also treated without laparotomy, in clinical stage I with radiotherapy only and in clinical stage II with combined modality treatment. Treatment results of 58 patients are reported. A relapse-free survival rate of 85% was reached for 24 patients treated with resection and irradiation either in stage I or II, and for seven patients in stage I who did not undergo surgery. For these patients, survival in stage I was 85%, in stage II, however, survival dropped to 60% due to intercurrent deaths. Seven stage II2 patients received intensive chemotherapy and radiotherapy with 58% relapse-free survival. Twenty patients could not be treated according to the outlined treatment protocol. For the total group, survival in stage I is 65% and in stage II 35%. In the Addendum, an additional group of 17 patients is mentioned with the same result.