Erroneous diagnosis of pancreatic cancer after radiotherapy of testicular cancer.

BACKGROUND: After radiotherapy with or without chemotherapy radiation-induced normal tissue alteration may mimic cancer and may cause major morbidity. RESULTS: Two patients irradiated for seminoma, in one case combined with cisplatin-based chemotherapy, developed clinical symptoms and radiological signs comparable to pancreatic cancer (stenosis of the ductus choledochus). The non-malignant diagnosis was finally established by revision of the histological specimen (case 1) and per-operatively (case 2). In both patients by-pass operations for biliary tract stenosis resulted in excellent palliation. CONCLUSION: Radiation-induced fibrosis within the upper retroperitoneal space is an important differential diagnosis versus pancreatic cancer in patients with prior radiotherapy for seminoma. Diagnosis based only on clinical and radiological findings may lead to incorrect patient information and registration errors in Cancer Registries.

Testicular carcinoma in situ in patients with extragonadal germ-cell tumours: the clinical role of pretreatment biopsy.

BACKGROUND: The aim of this study was to determine the prevalence of testicular carcinoma in situ (CIS) in patients with a malignant extragonadal germ-cell tumour (EGGCT) and the incidence of metachronous invasive testicular cancer (TC) in relation to the pretreatment demonstration of CIS. PATIENTS AND METHODS: Sixty-eight patients with EGGCT (53 retroperitoneal, 15 mediastinal) had pre-chemotherapy histological assessment of one (13) or both (55) testicle(s). A total of 123 testicles were examined for the presence of CIS. RESULTS: Testicular CIS was found in 21 patients (31%) (18 retroperitoneal EGGCT, three mediastinal EGGCT). Two patients had bilateral CIS. Five patients, four of them with proven pretreatment CIS, developed a metachronous TC. The 10-year invasive-free TC survival rate for all 68 patients was 88%, but only 65% for those with proven pretreatment CIS. The overall 10-year survival rate for all patients was 82%. CIS was demonstrated in seven of 48 trans-scrotal core biopsies, in 10 of 56 trans-scrotal surgical biopsies and in five of 11 orchiectomy specimens. CONCLUSIONS: Approximately one-third of patients with EGGCT present with testicular CIS, predominantly those with a retroperitoneal tumour. These patients have a considerable risk of metachronous TC development in spite of chemotherapy. The pretreatment demonstration of testicular CIS in patients with EGGCT gives the possibility of individualised counselling and safe follow-up, and is therefore highly recommended. The data are in agreement with a multi-site development of malignant germ-cell tumours, but do not exclude the possibility that the retroperitoneal EGGCTs in particular represent metastases from a burned-out TC.

Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders.

From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume < 190 ml, 24-h serum methotrexate > 4.5 microM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in > 70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome.

Frequent promoter hypermethylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) gene in testicular cancer.

Testicular germ cell tumours are classified into two major histological subgroups, seminomas and nonseminomas. All tumours display several recurrent chromosomal aberrations, but few target genes have been identified. Previous studies have shown that genome-wide hypermethylation of CpG islands is significantly more prevalent in nonseminomas than in seminomas. We have studied two potential target genes in testicular cancer. A series of 70 tumours were analysed for methylation of CpG sites in the O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter, and in exon 1alpha of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A). In addition, eight microsatellite markers within and flanking these genes at chromosome arms 10q and 9p, respectively, were analysed for allelic imbalances. Allele alterations were frequently seen at 9p loci (47 out of 70, 67%), but none of the tumours (none out of 55) showed methylation of CDKN2A. On the other hand, a high frequency of MGMT promoter methylation (32 out of 69, 46%) was found, as well as allelic imbalances at 10q markers (50 out of 70, 71%). A significantly higher methylation frequency was found in nonseminomas (24 out of 35, 69%) compared to seminomas (eight out of 33, 24%) (P=0.0003, Fisher's exact test). Immunohistochemical analysis of the MGMT protein in a subgroup (n=20) of the testicular tumours supported the hypothesis of gene silencing being the functional consequence of the promoter methylation. In summary, our data suggest that inactivation of MGMT contributes to development of nonseminomatous testicular cancer.

Familial/bilateral and sporadic testicular germ cell tumors show frequent genetic changes at loci with suggestive linkage evidence.

Testicular germ cell tumor (TGCT) is the most common tumor type among adolescent and young adult males. Familial clustering and bilateral disease are suggestive of a genetic predisposition among a subgroup of these patients, but susceptibility genes for testicular cancer have not yet been identified. However, suggestive linkage between disease and genetic markers has been reported at loci on chromosome arms 3q, 5q, 12q, 18q, and Xq. We have analyzed primary familial/bilateral (n=20) and sporadic (n=27) TGCTs, including 28 seminomas and 19 nonseminomas, for allelic imbalance (AI) within the autosomal regions. DNA from all tumors were analyzed by fluorescent polymerase chain reaction of 22 polymorphic loci at 3q27-ter, 5q13-35.1, 12q21-ter, and 18q12--ter. All tumor genotypes were evaluated against their corresponding constitutional genotypes. The percentages of TGCTs with genetic changes at 3q, 5q, 12q, and 18q, were 79%, 36%, 53% and 43%, respectively. The frequencies at 3q and 12q in nonseminomas were significantly higher than in seminomas (P=.003 and P=.004). In order to evaluate changes at hemizygous Xq loci, five loci were analyzed by co-amplification with an autosomal reference marker known to reveal retained heterozygosity in the tumor DNA. Gain of Xq sequences was seen in more than 50% of the tumors. The degree of amplification varied among the loci in each of five tumors, and based on these breakpoints, a common region of overlapping gains was found at Xq28. No significant differences were found between the frequencies of genetic changes in familial/bilateral versus sporadic tumors, an observation speaking in disfavor of the existence of a single susceptibility gene for TGCT in any of the analyzed regions. Our data suggest that gain of genetic material at distal Xq and losses at 5q and 18q contribute to establishment of seminomas, whereas imbalances at 3q as well as gain at distal part of 12q are associated with further progression into nonseminomas.

Biallelic inactivation of TP53 rarely contributes to the development of malignant peripheral nerve sheath tumors.

About 10% of the patients with neurofibromatosis type 1 (NF1) develop malignant peripheral nerve sheath tumors (MPNSTs), accounting for half of all MPNST cases. Several nonrandom chromosomal aberrations have been found, but the target genes remain mostly unrecognized. Mutations in the NF1 and TP53 genes have been found in some MPNSTs, and recent data from mouse models support a synergistic effect of these two genes in the development of MPNST. In the present study, we have analyzed 16 MPNSTs, including 11 from patients with NF1 and 5 sporadic cases, for mutations in the coding sequence of the TP53 gene (exons 2-11). We applied denaturing gradient gel electrophoresis and modifications of this technique for analyses of 12 genomic fragments, followed by direct sequencing for identification of the mutated base(s). None of the MPNSTs revealed mutations. The detection of control mutants for each fragment analyzed, the high sensitivity of the technique, the detection of polymorphisms in some samples, and the high content of tumor tissue in the biopsies imply that false negatives are highly unlikely. Although we cannot exclude that deletions including large parts of the gene remain undetected by the mutation analyses, previous comparative genomic hybridization (CGH), cytogenetic banding analysis, and/or loss of heterozygosity studies on 14 of the cases included here had revealed 17p deletions in only three. We thus conclude that TP53 biallelic inactivation is rare in MPNST, and that the potential impact of an altered TP53 pathway on the malignant transformation of a neurofibroma into an MPNST may more frequently occur by changes in other components of that pathway.

High frequency of clonal chromosome abnormalities in prostatic neoplasms sampled by prostatectomy or ultrasound-guided needle biopsy.

Cancer of the prostate remains poorly characterized cytogenetically. This is due in part to methodological problems and in part to the paucity of radical prostatectomies, until now the main source of material for cytogenetic analyses. We have improved existing techniques for the culturing of prostatic neoplasms removed by radical prostatectomy or sampled by ultrasound-guided needle biopsy. Successful short-term cultures were obtained from all 10 prostatectomy samples and from all 10 ultrasound-guided needle biopsies, always with a pure epithelial morphology. Of the 19 cases yielding a sufficient number of high-quality metaphases for chromosome banding analysis, the single atypical epithelial hyperplasia had a normal karyotype, whereas both prostatic intraepithelial neoplasias and 12 of 16 (75%) invasive carcinomas were shown to have clonal abnormalities. Ten of the 12 (83%) karyotypically abnormal invasive carcinomas presented structural chromosomal rearrangements. A recurrent deletion, del(10)(p13), was seen in three tumors; in one of them the terminal nature of the deletion was confirmed by two-color FISH. A del(17)(p11) was seen in one PIN lesion, but since the analysis of exons 4-8 of the TP53 tumor suppressor gene revealed no mutations, there probably was no inactivation of the second TP53 allele. Our study thus leads to the following main conclusions. First, better culturing methods allow the detection of abnormal karyotypes in a much higher percentage of prostatic neoplasms than has hitherto been possible. Second, ultrasound-guided needle biopsies of prostatic neoplasms are a sufficient source of material for cytogenetic analysis. Third, a terminal deletion of the short arm of chromosome 10, del(10)(p13), seems to identify a subgroup of prostatic cancer.

False-negative biopsy for testicular intraepithelial neoplasia and high-risk features for testicular cancer.

The purpose of this report is to emphasize the possibility of false-negative biopsies for testicular intraepithelial neoplasia (TIN) in men with high-risk features of testicular cancer and to review the relevant literature. At the Norwegian Radium Hospital patients in this category are offered the chance to undergo a testicular biopsy. A patient is described who had a normal testicular biopsy a decade before presenting with an invasive testicular cancer. Furthermore, this patient is the first case reported with a false-negative biopsy for TIN and a family history of testicular cancer. The evaluation of the biopsies included immunohistochemical staining for c-kit and PIAP (placental-like alkaline phosphatase) in order to diagnose early TIN. Though multifocal or diffuse extension seems to be the most frequent pattern of distribution of TIN, the presented case and another 14 cases from the literature review indicate that the focality of TIN may be a reason for a TIN-negative biopsy.

Ejaculation in testicular cancer patients after post-chemotherapy retroperitoneal lymph node dissection.

The purpose of this study was to evaluate fertility after different types of post-chemotherapy retroperitoneal lymph node dissection (RPLND). During 1980-1994, 192 patients with metastatic testicular cancer underwent post-chemotherapy RPLND with a gradual shift from modified bilateral template RPLND to nerve-sparing RPLND. Modified bilateral template RPLND was done in 92% of the patients operated during 1980-1984 as compared to 16% during 1989-1994. Pre- and post-treatment fertility was assessed by microscopic sperm analysis, determination of serum FSH and information on ejaculation and paternity. There was no significant difference of the survival rates between the three treatment periods. Antegrade ejaculation was preserved in 11% of the patients after modified bilateral template RPLND as compared to 89% after the nerve-sparing operation technique. The median ejaculatory volume decreased post-operatively, serum FSH increased and sperm density remained unchanged. Fifty-six patients attempted fatherhood after their treatment, and 27 fathered at least one child after an observation-time of 55 months, nine of them by assisted fertilization. Patients with initially advanced testicular cancer but limited residual retroperitoneal masses after induction chemotherapy can safely undergo limited post-chemotherapy RPLND as a part of multimodality treatment. After nerve-sparing RPLND antegrade ejaculation is preserved in 89% of the patients though the ejaculatory volume decreases after RPLND. Post-treatment fatherhood can be achieved in at least 50% of the patients attempting paternity.

Malignant pleural mesothelioma: US-guided histologic core-needle biopsy.

PURPOSE: To assess the clinical use of ultrasonographically (US) guided core-needle biopsy, performed with a one-hand automatic sampling technique, in the diagnosis of malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: The authors reviewed the findings in 70 patients with a tentative diagnosis of MPM who underwent US-guided core-needle biopsy at our institution during the past 10 years. RESULTS: Fifty-two of the 70 patients who underwent automatic high-speed core-needle biopsy at our institution had MPM; 18 had other disorders. The correct diagnosis was made in 56 patients. Twelve of 14 inadequate biopsy specimens were false-negative for MPM. There were no false-positive biopsy results. In the detection of MPM, US-guided core-needle biopsy had a sensitivity of 77%, specificity of 88%, accuracy of 80%, positive predictive value of 100%, and negative predictive value of 57%. There were no serious complications. CONCLUSION: US-guided core-needle biopsy is highly effective in the diagnosis of MPM. Owing to its simplicity, low cost, and few side effects, it could be the biopsy method of choice for detection of this condition.

Postchemotherapy residual masses in germ cell tumor patients: content, clinical features, and prognosis. Medical Research Council Testicular Tumour Working Party.

BACKGROUND: In a retrospective study that included a detailed histopathologic review, the clinicopathologic features of patients with germ cell tumors (GCT) and resectable residual masses after chemotherapy were assessed. METHODS: Histologic material from 153 patients was available for review. Recorded details included primary histologic diagnosis, location, size and number of metastases, marker levels before and after chemotherapy, and completeness of surgical excision. A median of seven histologic sections per resection were reviewed by two pathologists independently (and together when disagreement occurred). In each case, details were recorded regarding fibrosis, necrosis, hemorrhage, embryonal carcinoma (undifferentiated teratoma), yolk sac tumor, choriocarcinoma (trophoblastic tumor), differentiated teratoma (mature and immature), dysplasia in somatic tissues, and non- germ cell tumor (GCT) malignancies. The percentage of the sample that each of these components comprised was also estimated. RESULTS: The median postchemotherapy follow-up time was 7 years, and 38 of 153 patients (25%) experienced disease progression. In a multivariate analysis, incomplete resection of all residual masses (in 38 patients) and the presence of malignant elements (in 23 patients) were independent risk factors for progression. In the subset of patients in whom all masses were completely resected, the presence of embryonal carcinoma (undifferentiated teratoma) was the single most significant risk factor for progression. Seven percent of patients had this factor, which was associated with a 2-year progression free survival rate of 12.5%, compared with 88.0% where this component was absent. CONCLUSIONS: Progression free survival can be predicted well by the completeness of excision of residual masses and the presence of malignant germ cell elements. The latter confers a relatively poor prognosis even if all of these elements are completely resected.

Immunohistochemical analysis of p53 protein in uterine sarcomas.

This study was undertaken to evaluate the frequency and prognostic significance of p53 protein accumulation in uterine sarcomas. Immunostaining for p53 protein was performed on formalin-fixed, paraffin-embedded sections from 158 patients with verified uterine sarcomas using monoclonal p53 antibody (DO-1). Antigen retrieval was performed with microwave oven technique. Nuclear p53 protein accumulation was demonstrated in 45% of the cases, more often in carcinosarcomas (73%) than in leiomyosarcomas (38%) and endometrial stromal sarcomas (27%). A significant correlation was found between p53 protein accumulation and malignancy grade (P = 0.003), mitotic count (P = 0.007), and DNA ploidy (P = 0.007), but not to FIGO stage (P = 0.6). The 5-year survival was not influenced by level of p53 protein accumulation. In Cox multivariate analysis, free resection margins at primary surgery (P < 0.0001), tumor diameter (P = 0.002), malignancy grade (P = 0.0004), and age at diagnosis (P = 0.0001) were found to be of independent prognostic significance while p53 protein accumulation had no significance (P = 0.022). Our results indicate that p53 alterations may play an important role in the carcinogenesis of uterine sarcomas, but in our study p53 protein accumulation had no impact on prognosis.

Prevalence and prognostic significance of epilepsy in patients with gliomas.

The aim of this study was to evaluate the prevalence and prognostic significance of epilepsy in 1028 patients diagnosed in the computer tomography (CT) era with histological low- or high-grade intracranial gliomas. Survival analysis included Kaplan-Meier plots, log-rank tests, logistic regression and Cox's analysis as implemented in the SPSS statistical package. Epilepsy was a positive univariate (P < 0.0001) and multivariate, (P < 0.03) prognostic factor for survival in the total patient group (n = 1028, relative risk of death 0.83, 95% confidence interval (CI) 0.70-0.98) as well as in the high-grade patient group (n = 649, relative risk of death 0.80, 95% CI 0.66-0.96), but not in the group of low-grade glioma patients (P > 0.2). The prevalence of epilepsy in glioblastoma patients was 251/512 (49%), 95/137 (69%) in anaplastic gliomas, and 322/379 (85%) in patients with low-grade gliomas, with 97 of the 102 T1 low-grade subgroup (95%) having epilepsy, indicating that the presence of epilepsy may select patients for early radiological diagnosis. The frequency of epilepsy at presentation decreased with age in high-grade glioma patients, and increased with age in low-grade glioma patients to a plateau in the fourth decade of life (P < 0.01). The prevalence of epilepsy in patients with histological intracranial gliomas varied with patient age and tumour histology, with low-grade patients having the highest prevalence. Epilepsy was a significant positive prognostic factor except in patients with low-grade gliomas, and may select low-grade patients for early diagnosis.

Somatic mutations in LKB1 are rare in sporadic colorectal and testicular tumors.

Germ-line mutations in a serine/threonine kinase gene, LKB1, were recently shown to underlie Peutz-Jeghers syndrome (PJS), a hereditary disorder that predisposes to benign and malignant tumors of multiple organ systems. Most mutations that have been described thus far dramatically change the predicted protein and are likely to be of an inactivating nature. This observation and a previous observation that the LKB1 locus is often deleted in PJS polyps suggest that the gene may function as a tumor suppressor. We examined whether somatic mutations in this gene are present in sporadic carcinomas of the colon and testis, tumors that are characteristic of PJS. First, 20 randomly selected colorectal and 28 testicular tumors were analyzed by single-strand conformation polymorphism analysis. No mutations in LKB1 were found in colorectal tumors. One testicular tumor displayed a heterozygous missense type variant, in which glycine 163 was changed to aspartic acid. This change was absent in the DNA of normal tissue. To better focus our efforts, we tested 75 additional colon carcinomas for loss of heterozygosity at 19p, where LKB1 is localized. Of 75 samples analyzed, 50 were informative with a closely linked marker, D19S886, and 13 (26%) of these displayed loss of heterozygosity. The 13 tumors were scrutinized for LKB1 mutations by genomic sequencing. This analysis revealed no changes. Together, these findings suggest that somatic mutations of LKB1 are not frequent in colorectal and testicular cancer.

Treatment and outcome of patients with extragonadal germ cell tumours--the Norwegian Radium Hospital's experience 1979-94.

This report reviews 48 patients who from 1979 to 1994 were treated at the Norwegian Radium Hospital for newly diagnosed noncerebral extragonadal malignant germ cell tumour (EGGCT). Based on histology and/or serum tumour markers, 12 patients had a seminoma and 36 a non-seminoma. At diagnosis, 33 and 15 patients were classified as having abdominal and mediastinal EGGCT respectively. At the time of diagnosis 13 patients, all with non-seminomatous tumours, had metastases to bone, liver or brain. One patient with abdominal seminoma was cured by radiotherapy alone, whereas cisplatin-based chemotherapy (with or without surgery) was planned in the 47 remaining patients. Twenty-seven out of 42 patients receiving four or more chemotherapy cycles were rendered tumour free by induction chemotherapy, including 5 of the 13 patients with extralymphatic non-pulmonal disease. An additional tumour-free patient died of septicaemia after only two cycles of chemotherapy. Late relapses (after > 2 years) were observed in three patients, and a testicular primary was diagnosed during follow-up in three cases. Seven patients died of treatment-related complications, five of these because of neutropenic septicaemia. The median age of these patients was 52 years compared with 35 years in the remaining 41 patients (P < 0.05). The 5-year overall survival for all 48 patients was 60% (95% CI 46-74%) [cancer-specific 5-year survival 71% (95% CI 50-92%)]. EGGCT is a potentially curable disease, even in patients with very advanced disease. Special attention should, however, be devoted to patients above the age of 40 years because of an increased risk of treatment-related side-effects. Late relapses and the subsequent development of testicular tumours indicate the need for long-term follow-up.

Liver hemangioma: US-guided 18-gauge core-needle biopsy.

PURPOSE: To assess the clinical usefulness of ultrasound (US)-guided, 18-gauge core-needle biopsy of liver hemangiomas performed with a one-hand automatic-sampling technique. MATERIALS AND METHODS: In 491 US-guided core-needle biopsies of the liver, hemangioma was suspected at US in 51 cases. Hemangiomas were confirmed histologically in 29 cases, a malignant lesion was revealed in six cases, and no specific diagnosis could be made in 16 cases. Hemangioma was diagnosed in 18 lesions that appeared malignant at US. The hemangiomas were 7-114 mm in diameter (mean, 45 mm). RESULTS: The histologic diagnosis of hemangioma was unequivocal in 47 biopsy specimens. A cuff of normal hepatic parenchyma could be interposed between the capsule and the margin of the hemangioma in all procedures but one, in which two direct punctures were made of a protruding giant hemangioma. An average of 1.4 punctures were performed at each biopsy session. There were no false-positive findings and 15 or perhaps 16 false-negative findings. There were no serious complications. CONCLUSION: US-guided core needle biopsy seems to be a safe procedure when the diagnosis of hemangioma must be ascertained. Conclusive biopsy findings may shorten the diagnostic work-up, benefiting the patient and the hospital.

An evaluation of prognostic factors in uterine carcinosarcoma.

The traditional clinical and histopathological prognostic variables and DNA ploidy were analyzed in 46 patients with histologically verified uterine carcinosarcoma. Twenty-three tumors were of the homologous and 23 of the heterologous type. Evaluable flow cytometric DNA histograms from paraffin-embedded tumor tissue were obtained in 39 patients. The overall 5-year cancer related survival was 31%. All tumors were of high malignancy grade. In univariate analysis of survival, extrauterine spread of tumor (P = 0.007), age (P = 0.008), and tumor diameter (P = 0.04) obtained statistical significance. Tumors with components of serous or clear cell carcinomas had a less favorable prognosis (P = 0.017). There was no difference in survival between patients with homologous and heterologous tumors (P = 0.39). Mitotic count, vessel invasion, and DNA ploidy did not obtain prognostic significance. In Cox multivariate analysis, extrauterine spread of tumor (P = 0.004) and age (P = 0.004) were found to be the most important prognostic factors followed by content of serous or clear cell carcinoma components (P = 0.027).