DNA adducts in human pancreatic tissues and their potential role in carcinogenesis.

Pancreas cancer is the fourth and fifth leading cause of cancer death for men and women, respectively, in the United States. Although the etiology of this cancer is poorly understood, smoking and dietary fat have been implicated by epidemiological studies. To test the hypothesis that DNA damage derived from carcinogen exposure and diet is involved in pancreatic carcinogenesis, aromatic and lipid peroxidation-related DNA adducts in 13 normal tissues adjacent to tumor and 20 tumors from pancreatic cancer patients were analyzed by 32P-postlabeling. Normal pancreatic tissues from 5 nonpancreatic cancer patients and 19 healthy organ donors served as controls. To correlate the DNA adduct level with patients' characteristics, information on age, sex, body mass index, and smoking status of pancreatic cancer patients were collected from medical records. A significantly higher level of total DNA adducts was detected in pancreatic cancer patients as compared with controls. The mean level of adducts/10(8) nucleotides in adjacent normal pancreatic tissues from pancreatic cancer patients (A tissues) was 102 +/- 21 compared with 39 +/- 6 and 13 +/- 1 in pancreatic tumor tissues (T tissues) and normal pancreatic tissues from controls (C tissues), respectively. Among the adducts observed, one single aromatic adduct (spot 1) was present in 100, 90, and 0% of the A, T, and C tissues, respectively. Two novel clusters of adducts (spots 2 and 3) were observed in 11 of 13, 12 of 20, and 2 of 24 of A, T, and C tissues, respectively, and the presence of these adducts was positively correlated with smoking status. In addition, the previously defined smoking-related diagonal radioactive zone was detected in three A samples only, although 50% (10 of 20) of the patients with pancreatic cancers in this study were ever smokers. Putative lipid peroxidation-related adducts were detected in all samples examined and were significantly higher in A than in T and C samples. Multiple regression analyses showed that body mass index was positively correlated to the levels of spot 1 and the lipid peroxidation-related adducts in A tissues and the total aromatic adducts in tumors. Smoking was also positively correlated to the level of total adducts. These observations are consistent with previous epidemiological findings and support the hypothesis that DNA damage related to carcinogen exposure and lipid peroxidation is involved in human pancreatic carcinogenesis.

Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin.

PURPOSE: Diagnostic strategies designed to identify the underlying primary malignancies in patients with unknown primary tumors (UPTs) have relied on retrospective analyses. We analyzed 879 consecutive patients referred with suspected UPTs to determine the yield and cost of a limited diagnostic evaluation, assess the contribution of specific studies to diagnosis, and analyze the survival patterns of patients in whom the primary tumor was diagnosed. PATIENTS AND METHODS: Data from patients with a suspected UPT were entered into a computerized data base, and the patients underwent a predefined limited diagnostic evaluation. Primary malignancies were diagnosed by pathologic review alone or by pathologic criteria plus a physical or radiographic finding. Survival was measured from diagnosis, estimated using the Kaplan-Meier method, and compared using the Cox-Mantel log-rank test. RESULTS: A primary tumor was found in 179 of 879 patients (20%). The survival duration of patients in whom the primary tumor was diagnosed was superior to that of patients in whom the primary tumor remained unknown. Specific patient subsets contributed most to the improved survival duration of the group in which the primary tumor was found, including lymphoma patients diagnosed solely by pathologic criteria and female patients with primary breast or ovarian cancer. The cost of diagnosis was mostly due to the extensive use of computed tomography. Except for ovarian cancer, computed tomography rarely identified treatable primary tumors. CONCLUSION: The limited diagnostic evaluation used in this study identified patients with treatable malignancies and increased the survival duration of a population of suspected UPT patients. Primary malignancies with the best survival can be diagnosed through careful pathologic review and focused evaluations for breast and ovarian cancer in women.

Poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown origin: favorable subsets of patients with unknown-primary carcinoma?

PURPOSE: The objectives of this study were to assess clinical outcomes and prognostic factors in unselected, consecutive patients with poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA). PATIENTS AND METHODS: The 1,400 patients analyzed were referred to our unknown-primary tumor (UPT) clinic from January 1, 1987 through July 31, 1994. Clinical data from these patients were entered into a computerized data base for storage, retrieval, and analysis. Survival was measured from the time of diagnosis; survival distribution was estimated using the product-limit method. Multivariate survival analyses were performed using proportional hazards regression and by recursive partitioning. RESULTS: Nine hundred seventy-seven patients were diagnosed with unknown-primary carcinoma (UPC) and 337 of these patients had PDC or PDA. No clinical differences were identified among patients with PDC, PDA, or UPC patients with other carcinoma or adenocarcinoma subtypes. PDC patients enjoyed better survival than PDA patients. Poor cellular differentiation was not an important prognostic variable. Variables predictive of survival included lymph node metastases, sex, number of metastatic sites, histology (PDC v PDA), and age. Although chemotherapy did not appear to influence survival for the entire group of PDC or PDA patients, a subset of patients with good prognostic features experienced median survival durations of up to 40 months. CONCLUSION: The long median survival and chemotherapy responsiveness of UPC patients with PDC and PDA could not be confirmed. However, subpopulations with prolonged median survival durations could be defined, and the value of chemotherapy in this group remains to be determined. Identification and exclusion of treatable or slow-growing malignancies may account for the poor survival of the PDC and PDA patients reported in this study.

Unknown primary tumors metastatic to liver.

PURPOSE: The objectives of this study were to identify prognostic factors for unknown primary tumor (UPT) patients with hepatic metastases, determine the common primary tumors identified, assess the yield of specific diagnostic studies, and evaluate the impact of therapy on survival. PATIENTS AND METHODS: The 1,522 patients analyzed were referred from January 1, 1987 through June 30, 1995. Clinical data from these patients were entered into a computerized database for storage, retrieval, and analysis. Survival was measured from the time of diagnosis; survival distribution was estimated by the product limit method. Multivariate survival analyses were performed by proportional hazards regression. RESULTS: Five hundred UPT patients had liver metastases. Primary tumors, usually lung, colorectal, or pancreatic neoplasms, were identified in 135 patients (27%). The remaining 365 unknown primary carcinoma (UPC) patients with liver involvement had a higher death rate than those without liver involvement (hazards ratio, 1.63; P < .0001). Neuroendocrine carcinoma patients had a lower death rate than patients without this histology (hazards ratio, 0.29; (P < .0001). Two hundred sixteen of 365 patients with UPC and liver metastases received chemotherapy. Chemotherapy-treated patients had a lower death rate than those who were not treated with chemotherapy (hazards ratio, 0.52; P < .0001). The effect of chemotherapy was most pronounced in patients with adenocarcinoma. CONCLUSION: Hepatic metastases in UPC patients portend a generally poor prognosis. However, subsets of patients with more favorable outcomes can be identified by available clinical and pathologic data. Chemotherapy may be beneficial for the large subset of UPC patients with adenocarcinoma that involves the liver.

Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients.

PURPOSE: To evaluate the natural history, validate previous observations, and identify prognostic factors in patients with unknown primary carcinoma (UPC). PATIENTS AND METHODS: Nine hundred twenty-seven consecutive patients referred to the M.D. Anderson Cancer Center with a preliminary diagnosis of UPC were prospectively identified. A standardized evaluation narrowed the study population to 657 patients with UPC. All data were recorded and computerized for storage, retrieval, and analysis. The primary end point for the study was survival, which was calculated from the first day of patient registration. Survival curves were estimated using the Kaplan-Meier method and compared using the Cox-Mantel log-rank test. To identify important prognostic factors, univariate and multivariate analyses were conducted. RESULTS: The demographics of the UPC patient population mirrored those of the general population of patients referred to our cancer center except for an excess of men among the UPC patients. Most patients had histologic or cytologic evidence of adenocarcinoma and had more than one organ site metastatically involved. Univariate and multivariate analyses identified numerous important prognostic factors with a significant influence on survival, including sex, number of organ sites involved, specific organ sites involved, and pathologic subtypes. CONCLUSION: This study validated previously identified important prognostic factors for survival in UPC. Additional variables that had an impact on survival were identified and the complex interaction of the factors was explored. As patient numbers increase, this database will be able to provide further analyses of patient subsets and potentially relate specific clinical features to the evolving molecular and biochemical understanding of these malignancies.

Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma.

The clinical features and survival times of patients with unknown primary carcinoma (UPC) are heterogeneous. Therefore, the goals of this study were to apply a novel analytical method to UPC patients to: (a) identify novel prognostic factors; (b) explore the interactions between clinical variables and their impact on survival; and (c) illustrate explicitly how the covariates interact. The 1000 patients analyzed were referred to the University of Texas M. D. Anderson Cancer Center from January 1, 1987 through November 30, 1994. Clinical data from these patients were entered into a computerized database for storage, retrieval, and analysis. Multivariate analyses of survival were performed using recursive partitioning referred to as classification and regression tree (CART) analysis. The median survival for all 1000 consecutive UPC patients was 11 months. CART was performed with an initial split on liver involvement, and 10 terminal subgroups were formed. Median survival of the 10 subgroups ranged from 40 months (95% confidence interval, 22-66 months) for UPC patients with one or two metastatic organ sites, with nonadenocarcinoma histology, and without liver, bone, adrenal, or pleural metastases to 5 months (95% confidence interval, 4-7 months) in UPC patients with liver metastases, tumor histologies other than neuroendocrine carcinoma, age >61.5 years, and a small subgroup of patients with adrenal metastases. Two additional trees were also explored. These analyses demonstrated that important prognostic variables were consistently applied by the CART program and effectively segregated patients into groups with similar clinical features and survival. CART also identified previously unappreciated patient subsets and is a useful method for dissecting complex clinical situations and identifying homogeneous patient populations for future clinical trials.

Unknown primary cancer presenting as an adrenal mass: frequency and implications for diagnostic evaluation of adrenal incidentalomas.

BACKGROUND: Fine-needle aspiration biopsy to identify adrenal metastasis from an occult primary malignancy has been recommended as part of the evaluation of the patient who presents with an incidentally discovered adrenal mass. This recommendation was assessed by examining the frequency of adrenal involvement in patients with suspected unknown primary cancer. METHODS: Data from 1715 patients referred for evaluation of suspected unknown primary cancer were retrospectively reviewed. RESULTS: Of 1639 patients found to have cancer, the adrenal gland was identified as a site of involvement at presentation in 95 (5.8%). Involvement was limited to the adrenal gland in 4 patients (0.2%). All 4 patients had large (> or = 6 cm) adrenal tumors, 3 of 4 had bilateral involvement, and all had symptoms that otherwise mandated evaluation for an occult malignancy; none had a true adrenal incidentaloma. CONCLUSIONS: Although cancer of an unknown primary site occasionally involves the adrenal gland, metastatic cancer presenting as a true adrenal incidentaloma is extremely rare. Therefore, in the absence of a history of prior malignancy or symptoms, physical examination findings, radiographic findings, or laboratory findings suggestive of an occult malignancy, we do not recommend fine-needle aspiration biopsy as part of the diagnostic evaluation of the patient who presents with a unilateral adrenal mass.