Sverrir Hardarson

A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas.

The etiology of RCC is incompletely understood and the inherited genetic contribution uncertain. Although there are rare mendelian forms of RCC stemming from inherited mutations, most cases are thought to be sporadic. We sought to determine the extent of familial aggregation among Icelandic RCC patients in general. Medical and pathologic records for all patients diagnosed with RCC in Iceland between 1955 and 1999 were reviewed. This included a total of 1,078 RCC cases, 660 males and 418 females. With the use of an extensive computerized database containing genealogic information on 630,000 people in Iceland during the past 11 centuries, several analyses were conducted to determine whether the patients were more related to each other than members drawn at random from the population. Patients with RCC were significantly more related to each other than were subjects in matched groups of controls. This relatedness extended beyond the nuclear family. RRs were significantly greater than 1.0 for siblings, parents and cousins of probands. RRs were 2–3 for first‐degree relatives and 1.6 for third‐degree relatives. The risk of RCC is significantly higher for members of the extended family of an affected individual, as well as the nuclear family. Our results indicate that germline mutations are significantly involved in what has been defined as sporadic RCC.

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.

Renal oncocytoma: a clinicopathological analysis of 45 consecutive cases.

To evaluate the clinical behaviour and pathology of renal oncocytoma in a well‐defined population over a 30‐year period.

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.

Risk of second cancers in classical Kaposi's sarcoma

An association between Kaposis sarcoma (KS) and malignant lymphoma has been suspected for many years. Both cancers belong to the group of malignancies associated with immune suppression and have been known to occur in the same individual. Accordingly, a common etiology has been suspected. Through linkage within the Nordic cancer registries, we studied the occurrence of cancers in a population‐based cohort of 741 patients with classical KS. The relative risk of subsequent malignancies was expressed as the ratio of the observed numbers of cancer to the numbers expected based on age‐, sex‐, period‐ and country‐specific incidence rates, i.e., the standardized incidence ratio (SIR). A total of 104 cancers was observed during 5,802 person‐years of follow‐up, which was close to the expected 98.8 cases (SIR, 1.05). During the first year of follow‐up, 3 lymphomas were observed, which is in significant excess of the 0.2 lymphomas expected (SIR, 13.0). In contrast, no lymphomas occurred in the period beyond the first year of follow‐up vs. 2.3 expected. Cancers of the buccal cavity and pharynx (SIR, 10.6; n = 4) and of the colon (SIR, 2.7; n = 7) occurred in excess among women but not among men. Accordingly, our results indicate that patients with classical KS are not at increased risk of cancer in general. In particular, the overall risk of lymphomas was not significantly increased. The high relative risk of malignant lymphoma immediately after KS was based on a limited number of cases, and this observation is unlikely to indicate a common etiology. Int. J. Cancer 73:840–843, 1997.

Resolution of proteinuria in a patient with X-linked Alport syndrome treated with cyclosporine

We report a 9-year-old Icelandic male with Alport syndrome and nephrotic-range proteinuria who responded well to cyclosporine therapy. He presented at the age of 2 years with gross hematuria and proteinuria during an episode of upper respiratory tract infection. Three years later he had developed persistent proteinuria; kidney function was normal. A renal biopsy revealed marked irregularities in the glomerular basement membrane consistent with Alport syndrome. Mutation analysis revealed a single base insertion in COL4A5 which was predicted to cause a major structural defect in the collagen IV α5 chain. Despite angiotensin-converting enzyme inhibitor therapy his proteinuria progressed to the nephrotic range associated with edema. At the age of 7 years, cyclosporine therapy was instituted, which promptly resulted in almost complete resolution of proteinuria. Three years later his urinary protein excretion was close to the normal range and serum creatinine remained within normal limits. We conclude that closely monitored cyclosporine therapy may be a safe and effective treatment in patients with severe proteinuria and Alport syndrome.

Renal cell carcinoma in young compared to older patients: Comparison of clinicopathological risk factors and survival

Objective. Renal cell carcinoma (RCC) is primarily a disease of the elderly, most patients being diagnosed in their mid-60s. However, a significant number of patients are diagnosed at a younger age. The true effect of age at diagnosis on survival has been debated, tumor stage and grade being the strongest prognostic factors of survival. The aim of this nationwide study was to study the significance of young age at diagnosis as a prognostic factor in RCC. Material and methods. This retrospective study included all living patients with histologically verified RCC in Iceland diagnosed between 1971 and 2000 (n=629). Different clinicopathological factors of patients diagnosed aged <50 years (n=99) were compared to those of patients diagnosed aged ≥50 years (n=530). Disease-specific survival was compared and multivariate analysis was used to evaluate prognostic variables. Results. Clinical presentation, TNM stage, grade, tumor size and histological subtypes were comparable between the two groups. Prognostic factors were the same in both groups, most of them having a stronger prognostic value in younger patients. Both 5- and 10-year disease-specific survival was significantly higher in the younger group (66.4% vs 54.5% at 5 years). Conclusions. The clinicopathological profiles are comparable in RCC patients aged < and ≥ 50 years. The reason for the more favorable survival of younger patients is not known. Further studies are needed, including studies on possible differences in age-specific host–tumor response.

Chromophobe renal cell carcinoma in Iceland: An epidemiological and clinicopathological study

Abstract 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.