Universal tumor screening in a population with MSH6- and PMS2-associated Lynch syndrome.

PURPOSE: Universal screening for Lynch syndrome (LS) on resected colorectal carcinomas (CRCs) and endometrial carcinomas (ECs) was implemented in Iceland in 2017 using immunohistochemistry (IHC) for mismatch repair (MMR) proteins. We examined the efficacy of the universal screening algorithm to detect LS and the diagnostic accuracy of MMR IHC by comparing results with a population-based genotype database. METHODS: All patients diagnosed with CRC or EC per the Icelandic Cancer Registry from 2017 to 2019 who had tumor MMR IHC performed were included. Pathology reports and patient charts were reviewed. MMR IHC stains were crossmatched with genotyping results obtained from the deCODE database. RESULTS: IHC staining was done on 404 patients with CRC and 74 patients with EC. A total of 61 (15.1%) patients with CRC and 15 (20.3%) patients with EC were MMR-deficient. MMR IHC had 88.9% sensitivity in identifying patients with LS and a positive predictive value of 10.7%. Only 50% of individuals were appropriately referred for genetic testing, leading to underdiagnosis of LS. CONCLUSION: Universal screening for LS using MMR protein IHC in CRC and EC accurately identified patients appropriate for genetic testing in a population with MSH6 and PMS2 LS predominance. Because of lack of referral to genetic counseling, only 50% of patients with LS were identified through the screening algorithm.

Proteomic analysis of follicular fluid during human ovulation.

INTRODUCTION: Human ovulation is a biologically complex process that involves several biochemical factors, promoting follicular rupture and release of a fertilizable oocyte. Proteins which are present in follicular fluid at high concentrations during ovulation are likely to be active participants in the biochemical pathways of ovulation. The aim of the study was to identify, by use of a modern proteomic technique, proteins of human follicular fluid which are differentially regulated during ovulation of the natural menstrual cycle. MATERIAL AND METHODS: This prospective experimental study over 3 years included women planned for laparoscopic sterilization. During surgery, retrieval of the dominant follicle was performed either at the preovulatory stage or during ovulation. Four women of preovulatory phase and four women of ovulatory phase met the predetermined criteria of hormone levels for respective phases, and samples of these were finally included out of the 15 women operated. Follicular fluid was aspirated from the excised follicle and subjected to mass spectrometry with the isobaric tags for relative and absolute quantification (iTRAQ) technology for isobaric tagging of peptides. This enables simultaneous identification and quantification of proteins. The protein profiles of the follicular fluid of the preovulatory phase and the ovulatory phase were analyzed, and proteins that were present were identified. RESULTS: A total of 502 proteins were identified, several of which previously have not been identified in human follicular fluid. Of the 115 proteins that were found in all samples, 20 proteins were at higher levels during ovulation. These were inflammatory-related proteins, coagulation factors, proteins in lipid metabolism, complement factors and antioxidants. Five proteins were present in lower levels during ovulation, with three being enzymes and the other two proteins of lipid metabolism and iron transport. CONCLUSIONS: Twenty-five follicular fluid proteins, with differential regulation during ovulation, were identified in human follicular fluid of the natural menstrual cycle. These proteins may have essential roles in the ovulatory cascade.

Cervical cancer staging, pretreatment planning, and surgical treatment in the Nordic countries-Survey from the Surgical Subcommittee of the Nordic Society of Gynecological Oncology.

INTRODUCTION: Women with cervical cancer in the Nordic countries are increasingly undergoing pretreatment imaging by ultrasound, magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT) or computed tomography, or sentinel lymph node procedure. The present survey reports the influence of pretreatment imaging findings on the recorded clinical International Federation of Gynecology and Obstetrics (FIGO) stage in Nordic countries and its impact on treatment planning and preferred surgical approach in cervical cancer. MATERIAL AND METHODS: The Nordic Society of Gynecological Oncology Surgical Subcommittee developed a questionnaire-based survey that was conducted from 1 January to 31 March 2017. All the 22 Nordic Gynecological Oncology Centers (Denmark 5, Finland 5, Iceland 1, Norway 4, and Sweden 7) were invited to participate. RESULTS: The questionnaires were returned by 19 of 22 (86.3%) centers. The median number (range) of women with cervical cancer treated at each center annually was 32 (15-120). In 58% (11/19) of the centers, imaging findings were reported to influence the clinical staging. MRI in combination with PET-CT was the preferred imaging method and the results influenced treatment planning. Robotic-assisted radical hysterectomy was the preferred surgical method in 72% (13/18) of the centers. Sentinel lymph node procedure was not routinely implemented in the majority of the Nordic centers. CONCLUSION: More than half of the Nordic Gynecological Oncology Centers already report a clinical FIGO stage influenced by pretreatment imaging findings. The trend in preferred treatment is robotic-assisted radical hysterectomy and the sentinel lymph node procedure is gradually being introduced.

Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits.

Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established risk loci for hormone-related traits (endometriosis and breast cancer) at 1q36.12 (CDC42/WNT4), 2p25.1 (GREB1), 20p12.3 (MCM8), and 6q26.2 (SYNE1/ESR1). Polygenic score for leiomyoma, computed using UKB data, is significantly correlated with risk of cancer in the Icelandic population. Functional annotation suggests that the non-coding risk variants affect multiple genes, including ESR1. Our results provide insights into the genetic background of leiomyoma that are shared by other benign and malignant tumors and highlight the role of hormones in leiomyoma growth.

Testicular germ cell tumours in Iceland: a nationwide clinicopathological study.

The purpose of this study was to examine the pathology of all germ cell tumours of the testis diagnosed in Iceland 1955-2002. A total of 214 patients were included in the study. The current age-standardized incidence was found to be 6.1 per 100,000 and had increased almost fourfold during the study period. Seminoma was diagnosed in 55% of cases. Non-seminomas were diagnosed in 45%, and these were further classified as mixed germ cell tumours (33%), embryonal carcinoma (8%), teratoma (3%), and yolk sac tumour (n=1). The mean age at diagnosis was significantly higher for the seminomas than the non-seminomas (38 years versus 29 years) (p<0.001) and the non-seminomas were diagnosed at a significantly higher stage than the seminomas (p<0.001). Thus, in seminoma patients the tumour was localized to the testis (stage I) in 81% of cases, in 17% of patients the tumour had spread to the lymph nodes (stage II or III), and only 2% had extranodal metastasis at diagnosis (stage IV). In contrast, in the non-seminoma patients, the tumours were found to be stage I in 56%, stage II or III in 24%, and stage IV in 20% of cases. No significant difference in staging was found between non-seminoma subtypes. Identification of necrosis or vascular invasion was significantly associated with metastatic disease at diagnosis (p=0.002). During the study period a significant increase in stage I tumours was found as well as a decrease in the size of the tumours.

A genome-wide study of allelic imbalance in human testicular germ cell tumors using microsatellite markers.

Testicular germ cell tumors (TGCT) arise by multistep carcinogenesis pathways involving selective losses and gains of chromosome material. To locate cancer genes underlying this selection, we performed a genome-wide study of allelic imbalance (AI) in 32 tumors, using 710 microsatellite markers. The highest prevalence of AI was found at 12p, in line with previous studies finding consistent gain of the region in TGCTs. High frequency of AI was also observed at chromosome arms 4p, 9q, 10p, 11q, 11p, 13q, 16q, 18p, and 22q. Within 39 candidate regions identified by mapping of smallest regions of overlap (SROs), the highest frequency of AI was at 12p11.21 approximately p11.22 (62%), 12p12.1 approximately p13.1 (53%), 12p13.1 approximately p13.2 (53%), 11q14.1 approximately q14.2 (53%), 11p13 approximately p14.3 (47%), 9q21.13 approximately q21.32 (47%), and 4p15.1 approximately p15.2 (44%). Two genes known to be involved in cancer reside in these regions, ETV6 at 12p13.2 (TEL oncogene) and WT1 at 11p13. We also found a significant association (P = 0.02) between AI at 10q21.1 approximately q22.2 and higher clinical stage. This study contributes to the ongoing search for genes involved in transformation of germ cells and provides a useful reference point to previous studies using cytogenetic techniques to map chromosome changes in TGCTs.

The water permeability channels aquaporins 1-4 are differentially expressed in granulosa and theca cells of the preovulatory follicle during precise stages of human ovulation.

CONTEXT: Changes in vascular permeability and expansion of the fluid-filled antrum are major events in the LH-induced ovulatory process. OBJECTIVES: Our objective was to investigate the presence and expression levels of aquaporins (AQPs) in the granulosa and theca cell compartments of the follicle during defined phases of human ovulation. DESIGN AND SETTING: We conducted a prospective experimental study at the Department of Obstetrics and Gynaecology at a university hospital. PARTICIPANTS: Twenty-eight women underwent laparoscopic sterilization and at the same time follicle retrieval at four periovulatory phases. MAIN OUTCOME MEASURES: mRNA levels of AQP1-4 were measured in separated granulosa and theca cells from preovulatory phase, early ovulatory (EO) phase, late ovulatory phase, and postovulatory phase. Immunohistochemistry was done for AQP1-4 in intact human follicles. RESULTS: All four AQPs were expressed in both the theca and granulosa cells during ovulation. In granulosa cells, AQP1 levels increased in the late ovulatory and postovulatory phases. Expression of AQP2-3 followed a similar pattern with a marked increase in the EO phase, whereas AQP4 levels decreased from preovulatory to the EO phase. The presence of AQP1-4 in the human follicle was verified by immunohistochemistry. CONCLUSIONS: The results show for the first time the presence of AQP1-4 in human follicles during ovulation. The marked early rise in expression of AQP2 and AQP3 suggests a role during the process leading to follicular rupture, and the late rise of AQP1 suggests a role in corpus luteum formation.

[Renal cell carcinoma in Iceland]. / Nýrnafrumukrabbamein á Islandi--yfirlitsgrein.

Renal Cell Carcinoma (RCC) is by far the most common malignant tumor of the kidney. It is a disease with many faces, known for its clinical diversity and often unpredictable behavior. Less is known about its etiology and risk factors than for most other human cancers. Mortality-to-incidence ratio is higher compared to other urologic malignancies, and the malignancy confers adverse prognosis for the majority of patients. At the same time as incidence of RCC has been rising globally, progress has been made in the understanding of the disease, especially within the field of genetics and biological research. Immunotherapies together with tyrosine kinase inhibitors and growth factor/angiogenesis modulators are being developed for patients with advanced disease and improvements have been made in the surgical approach. This, together with increased incidental detection secondary to the widespread use of modern imaging procedures, suggests improved prognosis of these patients in the future. For unknown reasons the incidence of RCC is higher in Iceland than in most other countries, about 30 new cases being diagnosed every year, with 14 deaths due to RCC occurring. This evidence-based article reviews major studies on different aspects of RCC with special emphasis on the epidemiology and clinicopathological presentation of the disease in Iceland.

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.

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.

Spontaneous regression of pleural metastases after nephrectomy for renal cell carcinoma--a histologically verified case with nine-year follow-up.

Spontaneous regression of metastatic renal cell carcinoma is a rare but well documented event, most often involving pulmonary metastases. A case of spontaneous regression of histologically verified pleural metastases after nephrectomy is reported.

Operative mortality after nephrectomy for renal cell carcinoma.

OBJECTIVE: To study the rate and causes of operative and treatment-related mortality after nephrectomy for renal cell carcinoma (RCC) in Iceland. MATERIAL AND METHODS: This retrospective population-based study included all patients who underwent nephrectomy for RCC in Iceland between 1971 and 2000. Patients who died <30 days after the operation were analyzed and compared to those who survived surgery. Disease stage, tumor size, patient age and preoperative American Society of Anesthesiologists classification were compared between the two groups. Autopsy records were examined to determine the causes of death. RESULTS: During the study period 880 patients were diagnosed with RCC and 575 (65%) of them underwent a nephrectomy, 116 (20%) with palliative intent. Operative mortality (OM) was 2.8% and did not change during the 30-year period. Patients with OM were significantly older than those without (73 vs 64 years, respectively) but disease stage, tumor size, ASA classification and gender were comparable between the groups. OM was comparable for patients operated on with palliative (3.4%) vs. curative (2.6%) intent (ns). Median time of death was 10 days postoperatively but no patient died intraoperatively. Causes of death were peri- and postoperative bleeding in five patients, infection/sepsis in four, arrhythmia in three, acute renal failure in two, pulmonary embolism in one and multiorgan failure in one. CONCLUSIONS: OM after nephrectomy for RCC has remained low during the past three decades in Iceland. It is most often caused by perioperative bleeding and infections. We find that the low OM in patients with metastases gives support to the use of palliative nephrectomy as a treatment option when other forms of treatment have failed.

[Two cases of spontaneous regression of metastasis secondary to renal cell carcinoma.].

Spontaneous regression of metastatic renal cell carcinoma is a rare but well documented event, most often involving pulmonary metastasis. Two cases involving brain and pleural metastasis are presented. In both cases nephrectomy was the only treatment.

A population-based analysis of increased incidence and improved survival of testicular cancer patients in Iceland.

OBJECTIVE: For unknown reasons the incidence of testicular cancer has risen dramatically in many industrialized countries. At the same time, the prognosis for these patients has improved even more significantly. This has mostly been explained by the introduction of an effective cisplatin-based multidrug chemotherapy regimen for patients with metastatic or recurrent disease, but better diagnostic tools and surveillance may also play a role. In this population-based study the clinical behaviour of testicular cancer cases (n = 198) in Iceland between 1955 and 1999 was investigated, with a special emphasis on changes in incidence, staging and survival. MATERIAL AND METHODS: The tumours were staged and pathologically classified and the crude probability of survival evaluated. The incidence was calculated for the whole period and further clinical evaluation was done for all the patients diagnosed after 1970 (n = 172). RESULTS: Of 198 patients, 111 (58%) were diagnosed with seminomas and 82 with non-seminomas (42%). Age-adjusted incidence increased from 2.2 per 100,000 men between 1955 and 1959 to 5.3 per 100,000 men between 1995 and 1999 (p < 0.01). More patients were diagnosed with localized disease (stage I) in the second compared to the first time period of the study: 71% vs 52% respectively (p < 0.01). After the introduction of cisplatin-based multidrug chemotherapy in Iceland in 1978, 5-year survival has increased from 67% in the period 1955-77 to 96% in the period 1978-99. CONCLUSIONS: During the study period the incidence of testicular cancer in Iceland increased almost threefold. After multidrug chemotherapy was introduced in 1978 only two patients have died from the disease. Since 1987, patients with stage I disease have been followed with surveillance after orchiectomy, without any deaths. Our population-based findings of increased incidence, lower staging and improved survival of patients with testicular cancer in Iceland are important for planning future treatment strategies. The availability of effective treatment, even for patients with advanced disease, stresses the importance of reducing treatment-related morbidity (infertility and secondary malignancies).

[Acute pancreatitis. Prospective study of incidence, aetiology, severity, and mortality in Iceland.].

OBJECTIVE: To evaluate the aetiology, severity and mortality of patients with acute pancreatitis at Landspítali - University Hospital (LSH) and to estimate the incidence in Iceland. MATERIAL AND METHODS: A prospective study of all patients diagnosed with acute pancreatitis LSH during the one-year period October 1998 - September 1999 inclusive. The main outcome measures were APACHE II, Ranson, and Imrie scores, and C-reactive protein (CRP) concentrations. The Balthazar - Ranson criteria were used for scoring of computed tomograms (CT). RESULTS: Twenty seven of the 50 patients were male. The median age of the whole series was 60 years (range 19-85). The estimated incidence was 32/100000 for the first attack of acute pancreatitis. The causes were; gallstones 42%, alcohol 32%, miscellaneous 24%, and idiopathic 2%. Thirty three percentage of the patients had APACHE II scores 9, 38% had Ranson scores of 3, 50% had Imrie scores of 3, and 34% had CRP concentrations >210 mg/L during the first 4 days or >120 mg/L during the first week. Seven patients had severe pancreatitis. Two patients in the whole group died, and both had clinically severe pancreatitis. CONCLUSIONS: Incidence and aetiology of acute pancreatitis in Iceland is in concordance to that described in other studies. Prospective assessment makes it possible to evaluate the aetiological factors more accurately. Measurement of the CRP concentration is an attractive and simple alternative to the severity scoring systems currently in use.

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.