Multiple colon tumors. Diagnosis and follow-up of 450 patients with colorectal carcinoma

OBJECTIVE: Failure to diagnose synchronous tumors leads to errors in patient treatment and prognosis. The existence of metachronous tumors requires strict patient follow-up to ensure early identification of the second tumor. The present study evaluates the results obtained in the application of a structured procedure for the diagnosis and follow-up of multiple colorectal carcinoma. MATERIALS AND METHODS: A structured procedure was used to follow for 5 years a group of 12 patients with multiple colorectal tumors (7 synchronous and 5 metachronous) of a series of 450 colorectal neoplasms. RESULTS: Six synchronous tumors were diagnosed preoperatively and one intraoperative. Of the 5 metachronous neoplasms, 4 strictly adhered to the follow-up protocol, as a result of which the second tumor was detected at an early stage. The remaining case involved no follow-up, and the second tumor was diagnosed in an advanced stage as a result of bowel occlusion. The left colon was predominantly involved; polyps were detected in 9 cases, while two patients had 3 malignancies detected by histopathological study. COMMENTS: We emphasize the need for a full evaluation of the colon in all patients with colorectal carcinoma. In the case of incomplete preoperative evaluation, intraoperative colonoscopy is to be considered; if this is not feasible it should be performed one month after surgery. A structured follow-up procedure permits the early detection of these tumors, there by improving patient prognosis.     

Establishment of a hereditary nonpolyposis colorectal cancer registry

INTRODUCTION: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition characterized by early age of onset colorectal cancer, right-sided predominance, excess of synchronous and metachronous colonic neoplasms, and extracolonic cancers. The purpose of this study is to report clinical characteristics of HNPCC families in our registry. METHODS: This is a retrospective review of medical records of patients with a significant history of colorectal cancer and interviews with their families. RESULTS: Three hundred one people with cancer in 40 HNPCC families were identified. In 284 of 301 (94 percent) people, 363 cancers were identified. Colorectal cancer only was identified in 182 people (64 percent) and, in conjunction with extracolonic tumors, in another 31 people (11 percent). Extracolonic cancer alone was noted in 71 people (25 percent). Median age at diagnosis of colorectal cancer was 48 (range, 17-92) years. In patients with documented pathology, right-sided tumors predominated (55 percent), synchronous and metachronous tumors were noted in 53 percent, and synchronous of metachronous adenomas were documented in 51 percent of people. Generational anticipation was also noted. CONCLUSION: This study demonstrates and confirms characteristics that have been described in HNPCC. Namely, early age of onset of colorectal cancer, right-sided predominance, multiple synchronous and metachronous neoplasms, increased extracolonic cancers, and generational anticipation.     

Cytogenetic and immunohistochemical analysis of an adult anaplastic neuroblastoma

Neuroblastomas in children are common tumors and are characterized by a number of recurrent cytogenetic and molecular changes. Adult neuroblastomas are rare, and their relationship to pediatric neuroblastomas is not clear. We report an anaplastic neuroblastoma presenting in a 28-year-old man. Histopathologic identification of the tumor as a neuroblastoma was problematic, and the initial diagnosis was poorly differentiated sarcoma. Tumor cells expressed immunoreactivity for tyrosine hydroxylase in addition to generic neuroendocrine markers, consistent with catecholamine-synthesizing ability. They also extended long, branching neurites in vitro. The tumor was positive for immunoreactive trkA. The karyotype after 6 days in culture was found to be 42,XY with multiple chromosomal abnormalities. The only abnormality shared with pediatric neuroblastomas was a rearrangement of chromosome 17q. Double minute chromosomes or homogeneously staining regions associated with N-myc amplification were not present. To our knowledge, this is the first reported karyotype of an adult neuroblastoma. The cytogenetic findings, together with expression of trkA, suggest that the tumor was more closely related to the favorable prognosis neuroblastomas of infancy than to the poor prognosis tumors that occur in older children, despite its unfavorable histology.     

Discrete synchronous multifocal osteoid osteoma of the humerus

A 24-year-old patient is described who had a 4-year history of pain in the right upper arm, with distinct night pain, that responded to salicylates. From the findings on conventional radiography, bone scintigraphy and MRI a multifocal osteoid osteoma was suspected, with one focus in the cancellous region of the greater tuberosity and a second cortical focus at the proximal humeral diaphysis. The resection "en bloc" of both tumors and histological examination confirmed the diagnosis. The patient was painfree after the curative resection of the two osteoid osteomas. Osteoid osteoma is a frequently found benign bone tumor, accounting for approximately 11% of cases. In rare cases a multicentric occurrence has been described. A possible occurrence of more than one osteoid osteoma in a single bone, not verified histologically, has been reported only three times in the literature. In patients with scintigraphic and radiographic findings of two foci, discrete synchronous multifocal osteoid osteomas should be suspected.     

CASES--clinical audit; scenarios for evaluation and study

The incidence of bilateral involvement it is generally estimated to be 5% to 10%. It shows association with certain congenital anomalies and it has an increased occurrence of familial cases. The records of 9 children (5 boys, 4 girls) diagnosed at Vall d'Hebron Hospital with bilateral Wilms tumor between 1976-1995 were analyzed. Six patients had synchronous tumors and 3 had metachronous lesions. Genitourinary malformations were present in 4 children and another had hemihypertrophy. Two children were brothers. Eight patients underwent pre-operative radiation therapy and/or chemotherapy. Five patients had nephrectomy on one side (3 of them had metachronous presentation) and partial nephrectomy on the other side. The other children had bilateral partial nephrectomy or tumorectomy. Seven out of the nine patients are alive (78%). The two children who died presented with stage IV tumors and high grade malignant. One boy suffers cardiomyopathy. All survivors have normal renal function. With the proven efficacy of chemotherapy, bilateral renal salvage procedures were demonstrated to be effective in controlling disease without compromising renal function or survival. The innovative approaches developed for the treatment of bilateral Wilms tumor may influence the treatment of unilateral Wilms.     

Synchronous and metachronous primary malignancies in organs other than the stomach in patients with early gastric cancer

BACKGROUND/AIMS: We investigated the outcomes of patients with early gastric cancer, with special reference to the prognosis of patients with synchronous or metachronous primary malignancies in organs other than the stomach. PATIENTS AND METHODS: Among 890 patients with early gastric cancer, 97 (10.9%) had synchronous or metachronous primary malignancies in organs other than the stomach. Ten-year survival rates were compared between patients who had additional malignancies and patients who had early gastric cancer but no other malignant disease (control group). RESULTS: Synchronous primary malignancies were detected in 32 patients and metachronous primary malignancies were detected in 65 patients (17 had developed before gastrectomy and 48 developed after gastrectomy). Hepatic cell carcinoma, lung cancer and colorectal cancer were frequently detected between 2 and 24 years after gastrectomy. The 10-year survival rate was 80.8% for 769 patients in the control group but it was only 49.7% for the 92 patients with additional malignancies. Moreover, metachronous malignant disease was found more over 10 years after gastrectomy in 30 of the 48 cases (62.5%). CONCLUSIONS: These results suggest the importance of long-term follow-up for detection of metachronous carcinomas at sites other than the stomach for patients with early gastric cancer.     

Mass screening for neuroblastoma at 6 months of age: difficult to justify

BACKGROUND/PURPOSE: A statistical analysis of the mass screening for neuroblastoma in Japan based on a population study rarely has been reported. This study aims to evaluate retrospectively the effectiveness of mass screening at 6 months of age using the available population data. METHODS: The data on the neuroblastoma cases registered by the Committee for Pediatric Solid Malignant Tumors in the Kyushu area were analyzed based on both screened and unscreened populations in the Kyushu area. RESULTS: From 1988 to 1992, the cumulative incidence of neuroblastoma in children less than 5 years of age was 82 in 484,599 for screened children, and 11 in 92,966 for unscreened children, respectively. Fourteen of the 82 screened patients had negative findings at 6 months of age (MS-negative cases). No significant difference was observed in the cumulative mortality rates from neuroblastoma in children younger than 5 years of age between the screened children and the unscreened children. Six of seven patients who died among the screened children were MS-negative cases with stage III or IV disease. In addition, no significant difference was found in the cumulative mortality rates from the neuroblastoma cases in patients less than 5 years of age between the children screened from 1988 to 1992 (7 of 484,599) and all children from 1980 to 1984 (14 of 668,084). CONCLUSIONS:These findings suggests that the majority of the patients detected by mass screening had a favorable prognosis, and, mass screening in Japan for children less than 6 months of age was not observed to reduce the incidence and mortality from neuroblastoma. Therefore, mass screening at 6 months of age was not found to improve substantially the prognosis of patients with unfavorable neuroblastoma identified over 1 year of age, which is the primary purpose of such mass screening for neuroblastoma.     

Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract

Recent molecular genetic studies have suggested that multifocal urothelial cancers are derived from an identical progenitor cell. However, the clonal origin of multifocal urothelial cancers of a low-grade superficial type has not been fully defined. Using microsatellite markers, we examined genetic alterations at 20 loci on eight chromosomal arms (2q, 4p, 4q, 8p, 9p, 9q, 11p, and 17p) in 87 metachronous and/or synchronous multifocal urothelial cancers, which included 84 low-grade superficial papillary tumors from 29 patients. Judging from the patterns of loss of heterozygosity, microsatellite shifts, and the subchromosomal partial deletion, multifocal tumors in at least 20 (80%) of the 25 evaluable patients were considered to be derived from a single progenitor cell, although the possibility remained that multifocal tumors in a small subset of patients might develop from distinct progenitor cells due to field cancerization. In 13 of the 20 patients, a chronological genetic analysis was available: genetic heterogeneity was detected in 3 (23%) patients, and an apparent accumulated pattern of genetic alterations was detected in only 1 (8%) patient. In the 20 patients with multifocal tumors of an identical clonal origin, discordant microsatellite alterations were observed, with significantly lower frequencies on chromosome 9 compared to those on the other chromosomes tested. The results indicate that most multifocal low-grade superficial urothelial cancers are genetically stable despite their incidence of frequent recurrence, and genetic divergence occurs in a subset of patients. This heterotopic spread and genetic divergence may occur long before the clinical manifestation of multiplicity from a single transformed cell. These data support the previous view that heterotopic spread of transformed progenitor cells and genetic divergence occur after chromosome 9 alterations in most of low-grade superficial urothelial cancers.     

Differential activation of pp60(c-src) and pp62(c-yes) in human colorectal carcinoma liver metastases

pp60(c-src) and pp62(c-yes) are protein tyrosine kinases whose specific activities are increased in primary colorectal carcinomas. Activity of pp60(c-src) is further increased in colorectal liver metastases. This study was undertaken to compare pp60(c-src) and pp62(c-yes) expression and activity in human colorectal carcinoma liver metastases and to determine the potential prognostic significance of differences in activation of these two kinases. The pp60(c-src) and pp62(c-yes) tyrosine kinase activities and protein levels relative to those in normal colonic mucosa were determined using an immune complex kinase assay and immunoblot analysis in tissue specimens from 22 patients with primary colorectal carcinoma and synchronous metastatic liver disease and from 9 patients with metachronous colorectal carcinoma liver metastases. Of the primary colon tumors, 64% of the tumors contained elevated activities of both pp60(c-src) and pp62(c-yes). For liver metastases, however, only 10% had activation of both tyrosine kinases, 61% had elevated pp60(c-src) activity only, and 23% had elevated pp62(c-yes) activity only. Analysis of synchronous metastases from primary tumors with elevated activities in both kinases demonstrated that in 71% of these patients, the activity of either pp60(c-src) or pp62(c-yes) decreases relative to the primary tumor. Protein levels of pp60(c-src) and pp62(c-yes) in primary carcinomas and metastases remained unchanged from levels in normal colonic mucosa. These results demonstrate that differential regulation of the activities of pp60(c-src) and pp62(c-yes) occurs during tumor progression. Patients with either synchronous or metachronous liver metastases and elevated pp62(c-yes) kinase activity have biologically more aggressive disease and a worse prognosis than patients without elevated pp62(c-yes) activity in their liver metastases (median survival, 13 months versus 30 months, P < 0.005, Wilcoxon signed rank test). Analysis of patients with synchronous liver metastases also demonstrated a worse prognosis for those with elevated pp62(c-yes) kinase activity (P < 0.05, Wilcoxon signed rank test).     

Four multiple primary malignant neoplasms of the aerodigestive tract

Multiple primary cancers of the head, neck, and upper aerodigestive tract have been documented in patients previously treated for oropharyngeal cancer. There generally is no causal relationship established between the different tumors. Two synchronous or metachronous cancers are common, three are unusual, and four are very unusual. We describe the treatment of a patient with tonsillar and synchronous esophageal and pulmonary cancers followed by a tongue cancer over a 6-year period.     

111In octreotide scintigraphy in the evaluation of head and neck lesions

PURPOSE: To evaluate indium 111 octreotide scintigraphy for the detection of suspected neuroendocrine lesions of the head and neck. METHODS: After receiving 6 mCi of 111In octreotide, 22 patients with suspected lesions of the head and neck were examined with both planar and single-photon emission CT (SPECT). Static images, obtained at 4 hours, included the head/neck, chest, abdomen, and pelvis. Additional SPECT images were obtained at 4 or 24 hours. Studies were compared with available conventional radiologic examinations (12 CT, 11 MR, and three angiographic studies) as well as with clinical and pathologic findings. RESULTS: Eighteen of the 22 patients had abnormal findings at scintigraphy. Eleven paragangliomas were seen in 10 patients, metastatic medullary thyroid carcinoma in three patients, thyroid adenoma in two patients, and Merkel cell tumor, carcinoid, and plasmacytoma in one patient each. Surgical confirmation was available in 13 patients. The smallest lesion detected was 1.5 cm. There was one false-positive and one false-negative examination. CONCLUSION: 111In octreotide scintigraphy is a useful imaging tool for the detection of primary and metastatic neuroendocrine tumors of the head and neck that are larger than 1.5 cm. This technique enables distinction of glomus tumors from other masses (such as neuromas) and can be used in the postoperative setting to distinguish scar from recurrent paraganglioma. Since it is an examination of the entire body, it has great utility for detecting multicentric paraganglioma and for screening patients with familial paraganglioma.     

Outcome after multiple colorectal tumours

BACKGROUND: Patients with primary colorectal cancers have a higher risk of development of second tumours synchronously or metachronously. This special group of patients raise a particular interest in their characteristics and outcome. METHODS: The records of 1009 patients with colorectal cancer were scrutinized. A group with multiple cancers was identified. Perioperative investigations, patterns of follow-up, pathological variables and outcome were noted. RESULTS: There were 22 patients with metachronous tumours and 39 with synchronous tumours following 'curative' operations in 20 and 28 respectively. There was no difference in Dukes classification between the two groups: Polyps were associated with metachronous lesions in ten of 22 patients and synchronous lesions in 17 of 39 patients. Five-year survival was 75 per cent for patients with metachronous tumours and only 18 per cent for those with synchronous tumours. CONCLUSION: In this study patients with metachronous tumours seemed to do very well while those with synchronous lesions did very badly. There were no identifiable demographic or clinical characteristics to account for this. There is a need to study this group of patients and identify factors like tumour biology or host resistance which prevent spread of tumour.     

Membrane type 1-matrix metalloproteinase is involved in the formation of hepatocyte growth factor/scatter factor-induced branching tubules in madin-darby canine kidney epithelial cells

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the cell cycle and a potential tumor suppressor gene. Because we had previously demonstrated that loss of p27 protein is associated with aggressive behavior in colorectal adenocarcinomas, we used immunohistochemistry and in situ hybridization to evaluate the potential role of alterations in p27 expression in primary and metastatic colorectal adenocarcinomas. Parallel immunostaining was performed for Ki-67 and p53. We evaluated 13 cases of metachronous and 23 cases of synchronous primary and metastatic colorectal tumor pairs. In the synchronous subgroup (Stage IV tumors), 57% of the primary tumor and metastases pairs did not express p27 protein and the remainder were low expressors. In the metachronous subgroup, 54% of the primary tumors were low expressors and the remainder high expressors of p27 protein. There was a significant reduction in the expression of p27 in the metachronous metastases (mean positive cells: 14.5%) when compared to the corresponding primary tumors (mean positive cells: 41.8%), P = 0.0023. All the primary and metastatic tumors in the metachronous subgroup showed high levels of p27 mRNA expression. There was no association between loss of p27 and either Ki-67 count or p53 expression. Because p27 is known to be up-regulated when epithelial cells are grown in suspension, the down-regulation of p27 in circulating tumor cells may confer the ability to grow in an environment of altered extracellular matrix or intercellular adhesion properties, two situations which may facilitate metastases.     

Oesophageal cancer associated with other primary cancers: a study of 31 patients

The aim of this study was to investigate the characteristics of oesophageal cancer associated with other primary cancers and the survival rate after surgery for the patients with these cancers. Of 202 patients with oesophageal cancer treated in the Second Department of Surgery, Shinshu University School of Medicine between 1981 and 1995, 31 patients (15.3%) had oesophageal cancer associated with other primary cancers. Twenty-one synchronous and 10 metachronous associated cancers were found and 25 of them were resected. Early-stage oesophageal cancer was much more frequent in the associated cases than in the non-associated cases. The stomach was the most frequently associated organ. The numbers of cases with triple and quadruple cancers were three and one, respectively. Three of these cases had intervals of over 6 years between tumours. Three cases with other primary cancers which had intervals of over 7 years after oesophagectomy were found, and two were carcinomas of the reconstructed gastric tube. In the outcome after surgery for oesophageal cancer, there was no difference between the associated and the non-associated cases, and also no difference between the synchronous and metachronous associated cases. Regarding the five-year and 10-year survival rates after surgery for the first cancers, the synchronous cases had a poorer outcome than did the metachronous cases. In conclusion, oesophageal cancer with other primary cancers is not always rare, and its outcome is not poor compared with that of the non-associated cases. These patients may achieve survival by early detection of both lesions and positive treatment. It is important to consider the risk of other primary cancers after oesophagectomy, and the success of the reconstructed gastric tube should be followed by endoscopy.     

Comparison of p53 gene abnormalities in bilateral and unilateral breast cancer

BACKGROUND: The results of recent studies have suggested that p53 gene abnormalities are associated with carcinogenesis in several neoplasms. It is believed that bilateral breast carcinomas develop as a result of a different carcinogenetic mechanism and genetic environment from those of unilateral lesions. METHODS: p53 Gene abnormalities in bilateral primary breast cancer were detected by polymerase chain reaction-single strand comformation polymorphism (PCR-SSCP) analysis. A total of 76 paraffin embedded tissue specimens from 38 patients with bilateral primary breast cancer were examined, and 62 patients with unilateral breast cancer were analyzed as control subjects. The bilateral tumors were defined as primary, based on clinical parameters and the presence of an intraductal component. There were 13 patients with synchronous bilateral breast cancer and 25 with metachronous bilateral breast cancer. RESULTS: p53 Gene abnormalities were detected in 50% of the bilateral and 25.8% of the unilateral cases, and the difference was significant (P < 0.01, chi-square test). Abnormalities were detected in 56% of the metachronous cases, representing a much higher incidence than that of the unilateral cases (P < 0.001, chi-square test). The incidence of p53 gene abnormalities in the first and second tumors of the metachronous cases was 44% and 68%, respectively. The percentage of patients with a p53 gene abnormality and positive family history was higher for those with bilateral than with unilateral breast cancer (P < 0.01, chi-square test). CONCLUSION: These findings indicate that the genetic changes and mechanism of carcinogenesis in bilateral and unilateral breast cancer are different.     

Rate of insufficient samples for fine-needle aspiration for nonpalpable breast lesions in a multicenter clinical trial: The Radiologic Diagnostic Oncology Group 5 Study. The RDOG5 investigators

Metaiodobenzylguanidine (MIBG) was developed 18 yr ago for scintigraphic imaging of the adrenomedullary tumors pheochromocytoma and neuroblastoma. Many studies have shown the usefulness of this agent for the management of patients with neuroblastoma or pheochromocytoma, and the 131I-labeled form was recently approved by the Food and Drug Administration for use in the U.S. This article summarizes our current concepts on the diagnostic use of MIBG in children. The radioisotopes available for labeling of MIBG and related compounds, the dosimetry, metabolism and mechanisms of uptake and retention are discussed. Our protocols for imaging both 131I-MIBG and 123I-MIBG, along with the normal distribution of these compounds, are reviewed. The use of MIBG for the management of neuroblastoma, and comparisons with other radiotracers available for imaging neuroblastomas are also addressed.     

Acute myelomonocytic leukemia secondary to synchronous carcinomas of the breast and lung, and to metachronous renal cell carcinoma

We describe a patient in whom synchronous breast cancer and small-cell lung cancer, and metachronous renal cell carcinoma were diagnosed within an 11 months period. All three tumors were treated surgically, followed by administration of tamoxifen, adjuvant chemotherapy with etoposide (2.8 g/m2 total) and vindesine, and administration of interferon alpha and flutamide. The patient developed acute myelomonocytic leukemia 26 months after discontinuation of etoposide-containing chemotherapy. This pattern of multiple neoplasms fits the wider disease spectrum associated with germline mutations of the p53 gene; however, analysis of p53 exons 5-8 did not disclose any sequence abnormalities in this patient. In conclusion, clustering of four (synchronous and metachronous) malignancies may on rare occasions occur in an individual patient and in the absence of a family history of cancer; the sequence during which treatment of primary malignancies may result in treatment-related acute myelocytic leukemia is discussed.     

123I-metaiodobenzylguanidine (MIBG) scintigraphy for the staging of neuroblastoma

Nineteen children with neuroblastoma (aged 2 w.-7 y.o.) were studied to evaluate the optimal scan conditions for Iodine-123-Metaiodobenzylguanidine (MIBG) scintigraphy for accurate staging at the time of diagnosis. Six and 24 hours after an injection of 123I-MIBG, whole body image and truncal spot and SPECT images were obtained. Compared with other studies (CT or MRI and bone scintigraphy), each 123I-MIBG image was evaluated visually to investigate which image can demonstrate the extent of neuroblastoma most exactly. MIBG images demonstrated primary tumors in all patients, and metastatic lymphadenopathy in 8 of 9 patients. Twenty-four hour SPECT images gave us the most detailed information about the extent of abnormal accumulation. As to bone and bone marrow lesions, 6 hour images were superior to 24 hour images in detectability. Moreover, MIBG showed many more lesions and more extended accumulation than the bone scan. 123I-MIBG scintigraphy was very useful in detecting neuroblastomas. In order to get the most valuable information, both delayed SPECT and early whole body planar images should be obtained.