An epidemiological and clinicopathological study of type 1 vs. type 2 morphological subtypes of papillary renal cell carcinoma- results from a nation-wide study covering 50 years in Iceland.

INTRODUCTION: Papillary renal cell carcinoma (pRCC) is the second most common histology of renal cell carcinoma (RCC), accounting for 10-15% of cases. Traditionally, pRCC is divided into type 1 and type 2, although this division is currently debated as a prognostic factor of survival. Our aim was to investigate the epidemiology and survival of the pRCC subtypes in a whole nation cohort of patients during a 50-year period. MATERIALS AND METHODS: A Population based retrospective study including consecutive cases of RCC in Iceland from 1971-2020. Comparisons were made between histological classifications of RCC, with emphasis on pRCC subtypes (type 1 vs. 2) for outcome estimation. Changes in RCC incidence were analyzed in 5-year intervals after age standardization. The Kaplan-Meier method and Cox regression were used for outcome analysis. RESULTS: A total of 1.725 cases were identified, with 74.4%, 2.1% and 9.2% having clear cell (ccRCC), chromophobe (chRCC), and pRCC, respectively. The age standardized incidence (ASI) of pRCC was 1.97/100.000 for males and 0.5/100.000 for females, and the proportion of pRCC increased from 3.7% to 11.5% between the first and last intervals of the study (p < 0.001). Age standardized cancer specific mortality (ASCSM) of pRCC was 0.6/100.000 and 0.19/100.000 for males and females, respectively. The annual average increase in ASI was 3.6% for type 1 pRCC, but the ASI for type 2 pRCC and ASCSM for both subtypes did not change significantly. Male to female ratio was 4.4 for type 1 pRCC and 2.3 for type 2. The average tumor size for type 1 and 2 was 58.8 and 73.7 mm, respectively. Metastasis at diagnosis was found in 8.7% in the type 1 pRCC, compared to 30.0% of patients with type 2 pRCC (p < 0.001). Estimated 5-year cancer-specific survival (CSS) were 94.4%, 80.7%, and 69.3% for chRCC, pRCC and ccRCC, respectively (p < 0.001). For the pRCC subtypes, type 1 was associated with better 5-year CSS than type 2 (86.3% vs. 66.0%, p < 0.001), although this difference was not significant after adjusting for cancer stage and grading. CONCLUSIONS: pRCC histology was slightly less common in Iceland than in other countries. Males are more than three times more likely to be diagnosed with pRCC, compared to other RCC histologies. The subtype of pRCC was not found to be an independent risk factor for worse survival, and as suggested by the most recent WHO Classification of Urinary Tumors, grade and TNM-stage seem to be the most important factors for estimation of survival for pRCC patients.

COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA.

BACKGROUND: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance. CASE PRESENTATION: Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein. CONCLUSIONS: This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome.

Analysis of Varicella-Zoster Virus in Temporal Arteries Biopsy Positive and Negative for Giant Cell Arteritis.

IMPORTANCE: Giant cell arteritis (GCA) is the most common systemic vasculitis in elderly individuals. Diagnosis is confirmed by temporal artery (TA) biopsy, although biopsy results are often negative. Despite the use of corticosteroids, disease may progress. Identification of causal agents will improve outcomes. Biopsy-positive GCA is associated with TA infection by varicella-zoster virus (VZV). OBJECTIVE: To analyze VZV infection in TAs of patients with clinically suspected GCA whose TAs were histopathologically negative and in normal TAs removed post mortem from age-matched individuals. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study for VZV antigen was performed from January 2013 to March 2015 using archived, deidentified, formalin-fixed, paraffin-embedded GCA-negative, GCA-positive, and normal TAs (50 sections/TA) collected during the past 30 years. Regions adjacent to those containing VZV were examined by hematoxylin-eosin staining. Immunohistochemistry identified inflammatory cells and cell types around nerve bundles containing VZV. A combination of 17 tertiary referral centers and private practices worldwide contributed archived TAs from individuals older than 50 years. MAIN OUTCOMES AND MEASURES: Presence and distribution of VZV antigen in TAs and histopathological changes in sections adjacent to those containing VZV were confirmed by 2 independent readers. RESULTS: Varicella-zoster virus antigen was found in 45 of 70 GCA-negative TAs (64%), compared with 11 of 49 normal TAs (22%) (relative risk [RR] = 2.86; 95% CI, 1.75-5.31; P < .001). Extension of our earlier study revealed VZV antigen in 68 of 93 GCA-positive TAs (73%), compared with 11 of 49 normal TAs (22%) (RR = 3.26; 95% CI, 2.03-5.98; P < .001). Compared with normal TAs, VZV antigen was more likely to be present in the adventitia of both GCA-negative TAs (RR = 2.43; 95% CI, 1.82-3.41; P < .001) and GCA-positive TAs (RR = 2.03; 95% CI, 1.52-2.86; P < .001). Varicella-zoster virus antigen was frequently found in perineurial cells expressing claudin-1 around nerve bundles. Of 45 GCA-negative participants whose TAs contained VZV antigen, 1 had histopathological features characteristic of GCA, and 16 (36%) showed adventitial inflammation adjacent to viral antigen; no inflammation was seen in normal TAs. CONCLUSIONS AND RELEVANCE: In patients with clinically suspected GCA, prevalence of VZV in their TAs is similar independent of whether biopsy results are negative or positive pathologically. Antiviral treatment may confer additional benefit to patients with biopsy-negative GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.

Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis.

OBJECTIVE: Varicella-zoster virus (VZV) infection may trigger the inflammatory cascade that characterizes giant cell arteritis (GCA). METHODS: Formalin-fixed, paraffin-embedded GCA-positive temporal artery (TA) biopsies (50 sections/TA) including adjacent skeletal muscle and normal TAs obtained postmortem from subjects >50 years of age were examined by immunohistochemistry for presence and distribution of VZV antigen and by ultrastructural examination for virions. Adjacent regions were examined by hematoxylin & eosin staining. VZV antigen-positive slides were analyzed by PCR for VZV DNA. RESULTS: VZV antigen was found in 61/82 (74%) GCA-positive TAs compared with 1/13 (8%) normal TAs (p < 0.0001, relative risk 9.67, 95% confidence interval 1.46, 63.69). Most GCA-positive TAs contained viral antigen in skip areas. VZV antigen was present mostly in adventitia, followed by media and intima. VZV antigen was found in 12/32 (38%) skeletal muscles adjacent to VZV antigen-positive TAs. Despite formalin fixation, VZV DNA was detected in 18/45 (40%) GCA-positive VZV antigen-positive TAs, in 6/10 (60%) VZV antigen-positive skeletal muscles, and in one VZV antigen-positive normal TA. Varicella-zoster virions were found in a GCA-positive TA. In sections adjacent to those containing VZV, GCA pathology was seen in 89% of GCA-positive TAs but in none of 18 adjacent sections from normal TAs. CONCLUSIONS: Most GCA-positive TAs contained VZV in skip areas that correlated with adjacent GCA pathology, supporting the hypothesis that VZV triggers GCA immunopathology. Antiviral treatment may confer additional benefit to patients with GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.

Pancreatic mass leading to left-sided portal hypertension, causing bleeding from isolated gastric varices.

Mucinous cystic neoplasms (MCN) are an uncommon form of exocrine neoplasms of the pancreas. Symptoms are most often vague and this makes the diagnosis more difficult. The current case is one of three cases yet reported where the MCN caused left-sided portal hypertension leading to the formation of isolated gastric varices and subsequent bleeding from the varices. In the previously reported cases the main symptom was hematemesis. However in the current case the patient experienced no hematemesis, only isolated incidents of dark coloured diarrhea, but the main symptoms were those of iron-deficiency anemia. We present the case report of a 34-year-old woman who presented with dizziness and lethargy and was found to have 12 cm MCN in the pancreas.

The impact of tumour size on the probability of synchronous metastasis and survival in renal cell carcinoma patients: a population-based study.

BACKGROUND: The observed low metastatic potential and favorable survival of small incidentally detected renal cell carcinomas (RCCs) have been a part of the rationale for recommending partial nephrectomy as a first treatment option and active surveillance in selected patients. We examined the relationship between tumor size and the odds of synchronous metastases (SMs) (primary outcome) and disease specific survival (secondary outcome) in a nationwide RCC registry. METHODS: Retrospective study of the 794 RCC patients diagnosed in Iceland between 1971 and 2005. Histological material and TNM staging were reviewed centrally. The presence of SM and survival were recorded. Cubic spline analysis was used to assess relationship between tumor size and probability of SM. Univariate and multivariate statistics were used to estimate prognostic factors for SM and survival. RESULTS: The probability of SM increased in a non-linear fashion with increasing tumor size (11, 25, 35, and 50%) for patients with tumors of ≤4, 4.1-7.0, 7.1-10.0, and >10 cm, respectively. On multivariate analysis, tumor size was an independent prognostic factor for disease-specific survival (HR = 1.05, 95% CI 1.02-1.09, p < 0.001), but not for SM. CONCLUSION: Tumor size affected the probability of disease-specific mortality but not SM, after correcting for TNM staging in multivariate analysis. This confirms the prognostic ability of the 2010 TNM staging system for renal cell cancer in the Icelandic population.

Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer.

Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 × 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.

A common variant at 8q24.21 is associated with renal cell cancer.

Renal cell carcinoma (RCC) represents between 80 and 90% of kidney cancers. Previous genome-wide association studies of RCC have identified five variants conferring risk of the disease. Here we report the results from a discovery RCC genome-wide association study and replication analysis, including a total of 2,411 patients and 71,497 controls. One variant, rs35252396[CG] located at 8q24.21, is significantly associated with RCC after combining discovery and replication results (OR=1.27, P(combined)=5.4 × 10(-11)) and has an average risk allele frequency in controls of 46%. rs35252396[CG] does not have any strongly correlated variants in the genome and is located within a region predicted to have regulatory functions in several cell lines, including six originating from the kidney. This is the first RCC variant reported at 8q24.21 and it is largely independent (r(2)≤0.02) of the numerous previously reported cancer risk variants at this locus.

[Small renal cell carcinomas and synchronous metastases]. / Litil nyrnafrumukrabbamein og fjarmeinvorp.

OBJECTIVE: The incidence of renal cell carcinoma (RCC) is rising in part due to small tumors (≤4cm) detected incidentally with abdominal imaging. Survival for small RCCs has been regarded as favorable and guidelines recommend partial rather than total nephrecteomy. We studied the frequency of synchronous metastasis in patients with small RCCs in Iceland. MATERIALS AND METHODS: A retrospective study on 257 patients with RCC ≤4cm out of 1102 RCC patients diagnosed in Iceland 1971-2010. Patients with metastasis were compared to those with localized disease. Hospital charts were reviewed and histology, TNM-stage and disease-specific survival compared between groups. RESULTS: The proportion of small tumors increased from 9% in 1971-1980 to 33% in 2001-2010 (p<0,001) and incidental detection increased from 14% to 39% during the same period. Out of the 257 patients with small RCCs, 25 (10%) had synchronous metastases, most frequently in lungs or bones. Patients with metastases were on average 1.9 years older, their tumors were 0.2 cm larger and more often located in the right kidney, their hemoglobin was lower and nuclear grade and T-stage higher. Histology was similar in both groups. Five-year survival of patients with and without metastases was 7 vs. 94%, respectively (p<0.001). CONCLUSIONS: One out of ten patients with small RCC has synchronous metastases at diagnosis. This is higher than in most previous reports that usually include surgical patients only. Patients with metastases are significantly older, more often symptomatic, their tumor are larger and their prognosis worse. Our results indicate that small RCC is a potentially systemic disease at diagnosis that has to be taken seriously.

Incidental detection of renal cell carcinoma is an independent prognostic marker: results of a long-term, whole population study.

PURPOSE: The true effect of incidental detection on the survival of patients with renal cell carcinoma has been debated. We used centralized databases in Iceland to study prognostic factors of survival, focusing on the effect of incidental detection. MATERIALS AND METHODS: This retrospective study included all living patients diagnosed with renal cell carcinoma in Iceland from 1971 to 2005. Hospital charts and histology were reviewed. Incidentally diagnosed renal cell carcinomas were compared to symptomatic tumors and prognostic factors were evaluated using Cox multivariate analysis. RESULTS: Of the 910 patients 254 (27.9%) were diagnosed incidentally, most often by abdominal ultrasound (29.5%) or computerized tomography (28.3%). The incidental detection rate increased from 11.1% in 1971 through 1975 to 39.2% in 2001 through 2005 (p <0.001). During the same period the incidence increased significantly in males but in females only during the last 5 study years. Mortality remained unchanged for each gender. Incidentally detected tumors were an average of 2.6 cm smaller and diagnosed at lower stage and lower grade than symptomatic tumors. Age and histology were similar in each group. TNM stage was by far the strongest independent prognostic factor of survival but age, calendar year of diagnosis and ESR were also significant. After correcting for confounders patients with symptomatic renal cell carcinoma had worse survival than those diagnosed incidentally. CONCLUSIONS: With increased incidence and unchanged mortality the survival of patients with renal cell carcinoma has improved. This is mainly related to a steep increase in incidental detection. Incidental detection affects survival favorably and to a greater extent than can be explained by lower stage compared to the survival of patients diagnosed with symptoms.

Cardiac myxoma in Iceland: a case series with an estimation of population incidence.

Cardiac myxoma (CM) is the most common primary benign tumor of the heart, but the true age-standardized incidence rate (ASR) has remained unknown. We therefore used nationwide registries in Iceland to study CM and establish its incidence rate. This was a retrospective study involving all patients diagnosed with CM in Iceland between 1986 and 2010. Cases were identified through three different registries, and hospital charts and histology results reviewed. An ASR was estimated based on a world standard population (w). Nine cases of CM (six women) were identified with a mean age of 62.8 years (range: 37-85), giving an ASR of 0.11 (95% CI: 0.05-0.22) per 100,000. The mean tumor size was 4.4 cm (range: 1.5-8.0) with all the tumors located in the left atrium. Dyspnea (n = 6) and ischemic stroke (n = 2) were the most common symptoms. All patients underwent complete resection of the tumor and there were no postoperative deaths or CM-related deaths at follow-up (mean 85 months). The ASR of CM in Iceland was 0.11 per 100,000. To our knowledge, this is the first study to determine the incidence of CM in an entire population. In Iceland, the presenting symptoms and mode of detection of CM are similar to those in other series.

European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.

Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.

Chromophobe renal cell carcinoma in Iceland: an epidemiological and clinicopathological study.

OBJECTIVE: Numerous studies have suggested that the rare chromophobe renal cell carcinoma (CRCC) has a more favourable prognosis than the other more common subtypes of RCC, clear cell RCC (CCRCC) and papillary RCC (PRCC). These studies have, however, usually involved selected patient cohorts and not whole populations. This study compared CRCC patients with patients with the other two major histological subtypes and established a population-based age-standardized incidence rate (ASR). MATERIAL AND METHODS: Of 828 histopathologically confirmed RCCs diagnosed between 1971 and 2005 in Iceland, 15 CRCC cases were identified. Histological material was reviewed, the TNM system was used for staging and cancer-specific survival was estimated. Univariate and multivariate analysis was used to compare CRCC to both CCRCC (n = 740) and PRCC (n = 66). Mean follow-up was 6.7 years. RESULTS: CRCC accounted for 1.8% of RCCs, the ASR being 0.17/100,000 per year. Compared to other subtypes, CRCC was detected incidentally less often (7% vs 29%, p = 0.02), but was more often diagnosed at lower stages (73% vs 45% at stage I + II, p < 0.001). One patient had synchronous metastasis and another developed recurrent CRCC; both died of CRCC. Five-year survival for CRCC, CCRCC and PRCC was 86%, 59% and 50%, respectively (p = 0.004). After correcting for TNM stage (odds ratio 1.98), multivariate analysis did not indicate that CRCC subtype was an independent predictive factor for survival. CONCLUSION: CRCC is a rare neoplasm with an ASR of 0.17/100,000 per year. These tumours often present with symptoms despite being at lower stages than the other RCC subtypes. The more favourable survival of the CRCC subtype appears to be explained by these tumours being diagnosed at low stages. These findings may suggest that CRCC has a different biological behaviour.

Sequence variant on 8q24 confers susceptibility to urinary bladder cancer.

We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7)).

[Renal cell carcinoma diagnosed at autopsy in Iceland 1971-2005]. / Nýrnafrumukrabbamein greind vid krufningu á Islandi 1971-2005: Samanburdur vid aexli greind í sjúklingum á lífi.

INTRODUCTION: The incidence of renal cell carcinoma (RCC) is rising in Iceland. This has been attributed to increased diagnostic activity, such as abdominal imaging of unrelated diseases, rather than changes in the behavior of the disease. The aim of this study was to compare RCCs diagnosed in living patients and at autopsy, but also to investigate the relationship between the incidence of RCC and autopsy findings. MATERIAL AND METHODS: RCC found incidentally in individuals at autopsy was compared to patients diagnosed alive over three decades in Iceland (1971-2005). Stage at diagnosis and tumor histology was reviewed. RESULTS: 110 tumors were diagnosed at autopsy with a rate of 7.1/1000 autopsies. When compared to patients diagnosed alive (n = 913) the mean age at diagnosis was higher in the autopsy group (74.4 vs. 65 yrs.) while male to female ratio and laterality was similar. Tumors found at autopsy were smaller (3.7 vs. 7.3 cm), at lower stage (88% at stage I+II vs. 42%) and at lower tumor grade (85% at grade I+II vs. 56%). A difference, although smaller, is present when the autopsy detected cases are compared to only incidentally detected RCCs in living patients. Furthermore the autopsy detected tumors were more frequently of papillary cell type (21% vs. 8%). After correcting for declining autospy rate (>50%), a slight trend for a reduced rate of autopsy dectected RCC cases was seen during the last 10 years of the period but the difference was not significant. CONCLUSION: RCCs diagnosed at autopsy are at a lower stage and tumor grade than in patients diagnosed alive. The autopsy-rate is declining in Iceland with fewer RCCs found per autopsy. After correcting for the decline in autopsy rate, the rate of RCC detected at autopsy is relatively unchanged. The increase in incidence of RCC is therefore not explained by findings at autopsy.

Effect of incidental detection for survival of patients with renal cell carcinoma: results of population-based study of 701 patients.

OBJECTIVES: To conduct a population-based study to evaluate the effect of incidental detection of renal cell carcinoma (RCC) on survival. Incidental detection of RCC has increased significantly in recent years because of widespread use of abdominal imaging. The patients with incidentally diagnosed RCC have better survival; however, because of possible "lead time" bias and stage migration, the real implications of incidental detection on survival have been a matter of debate. METHODS: All living patients diagnosed with RCC in Iceland between 1971 and 2000 were included (n = 701). The histologic findings were verified, the stage (extent) of the disease was determined, and the incidence, mortality, and survival were evaluated. RESULTS: The strongest predictors of mortality were stage and nuclear grade. After correcting for these factors in the multivariate analysis, incidental diagnosis, histologic subtype, and gender lost their significance as independent prognostic factors of death. However, the incidentally diagnosed tumors were 2.3 cm smaller on average and at a lower stage and grade than symptomatic tumors, with significantly better patient survival than those with symptomatic tumors on univariate analysis (76% versus 44% 5-year disease-specific survival). An increased incidence of RCC was only seen in men, but incidental detection increased threefold during the study period in both sexes, with significant improvement in survival for the whole group as a result. CONCLUSIONS: The increased frequency of incidental detection has improved the survival of patients with RCC in Iceland. Incidental detection was not an independent prognostic factor of death, indicating that these tumors are of a similar biologic nature as symptomatic RCCs, only diagnosed earlier.

Quantitative DNA perturbations of p53 in endometriosis: analysis of American and Icelandic cases.

OBJECTIVE: To investigate quantitative aberrations involving p53 copy numbers in eutopic endometrial and endometriotic tissue from two populations. DESIGN: Comparative analysis of normal and diseased tissue. SETTING: Tissue specimens collected in Iceland and USA. PATIENT(S): Subjects with moderate/severe endometriosis (Iceland, n = 26; USA, n = 45). Paraffin-embedded tissue from 19 matched Icelandic cases and seven unaffected controls. American cases were fresh surgical tissue from 17 matched cases and 28 unaffected controls. DNA isolation and real-time polymerase chain reaction (PCR) with TaqMan assay were performed. MAIN OUTCOME MEASURE(S): The frequency of p53 loss and/or gain based on quantitative differences for copy numbers of p53 located on chromosome (17p) and GAPDH on a control locus (chromosome 12p). RESULT(S): Among American cases, significant p53 gain (n = 13) or loss (n = 4) was observed in 17 of 21 cases. In Icelandic cases this was not seen to the same degree. Mean normalized p53 values were 3.46 and 1.16 copies per reaction, respectively. Significant differences were observed between normalized p53 in the control blood and affected tissue for the American and Icelandic cases compared to standard GAPDH control but not in normal Icelandic and American endometrium. CONCLUSION(S): The results continue to support a role for nonrandom somatic p53 locus alterations in the pathogenesis of late or severe-stage endometriosis. Differences between Icelandic and American subjects have implications for generalization of genome-wide approaches.

Renal oncocytoma: a clinicopathological analysis of 45 consecutive cases.

OBJECTIVE: To evaluate the clinical behaviour and pathology of renal oncocytoma in a well-defined population over a 30-year period. PATIENTS AND METHODS: In a retrospective population-based study we assessed relevant clinical and pathological factors in 45 patients (31 men and 14 women) diagnosed with renal oncocytoma in Iceland between 1971 and 2000. Clinical presentation, pathology, survival and causes of death were evaluated. RESULTS: The age-standardized incidence was 0.3 per 100,000 per year for both men and women, the incidence of oncocytomas being 5.5% of renal cell carcinomas (RCCs) diagnosed during the same period in Iceland. Fourteen patients were diagnosed at autopsy for an unrelated disease. Of 31 living patients (mean age 70.5 years), seven were diagnosed incidentally (23%), and the others had presented with haematuria (32%), abdominal pain (29%), and weight loss (10%). All the patients had a radical nephrectomy, except for one with bilateral oncocytoma who had a partial nephrectomy. The mean (range) tumour size was 5.7 (0.9-12) cm. Eighteen patients (58%) were diagnosed at Tumour-Node-Metastasis stage I, 10 at stage II (32%) and three at stage III (10%), all of those at stage III having renal capsular penetration or tumour invasion into perirenal fat tissue (T3aN0M0). No patients were diagnosed with lymph node or distant metastasis. Two cases of coexisting RCC were detected. After a median follow-up of 8.3 years there were no recurrences or deaths from oncocytoma (100% disease-specific survival). The overall 5-year survival was 63%, with most patients dying from cardiovascular diseases or nonrenal cancers. CONCLUSIONS: In most cases renal oncocytoma behaves like a benign tumour; the long-term prognosis is excellent. Thus, in the present patients, radical nephrectomy could be regarded as an over-treatment and nephron-sparing surgery as more appropriate, especially in patients with small tumours. However, both coexisting RCC and perirenal fat invasion, a hallmark of malignant behaviour, might indicate that more radical surgery is warranted in some of these patients.

Histological subtyping and nuclear grading of renal cell carcinoma and their implications for survival: a retrospective nation-wide study of 629 patients.

OBJECTS: The aim of this study was to evaluate the prognostic significance of the current WHO histological subtyping and Fuhrman nuclear grading on the survival of patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: A retrospective population-based study was carried out on all patients with a histopathologically confirmed diagnosis of RCC in Iceland between 1971 and 2000. Fuhrman grade, TNM stage, and survival were evaluated and multivariate analysis applied in order to determine prognostic factors. RESULTS: Out of 629 patients (387 males, 242 females, mean age 64 years), 558 (88.7%) had clear cell, 53 (8.4%) papillary, and 13 (2.1%) chromophobe RCC. Patient demographics were comparable for the two major subtypes, but chromophobe RCCs were larger in size and were diagnosed at a younger age. Clear cell RCCs were more often of higher grades (G3+G4, 48.4%) and at advanced TNM stages (III+IV, 59.3%) than papillary RCCs (22.6% and 34% respectively, p<0.001). Linear regression analysis showed a strong correlation between grade, tumor size, and stage (p<0.001). Chromophobe RCCs had a better survival in univariate analysis than both papillary and clear cell RCCs (84.6% vs. 66.5% and 54.9% 5-year disease specific survival, p<0.001). However, in the multivariate analysis, only the patient's age, calendar year of diagnosis, TNM stage, and nuclear grade were independent prognostic factors of survival. CONCLUSION: In this complete nation-wide series nuclear grading is important in predicting survival of patients with RCC. It is strongly related to both tumor size and stage, with stage being by far the strongest prognostic factor. Different histological subtypes confer different survival. However, in spite of the distinctive cytogenetic and molecular characteristics of the subtypes, the survival difference is to a large extent due to differences in grade and particularly stage.