Survival of patients with basal cell carcinoma, squamous cell carcinoma, and squamous cell carcinoma in situ: A whole population study.

BACKGROUND: Keratinocyte carcinoma (KC) is the commonest type of malignancy in humans; however, the impact of KC on survival is poorly understood. OBJECTIVES: This study characterizes the impact of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and squamous cell carcinoma in situ (SCCis) on the survival of Icelanders. METHODS: This whole population study evaluated relative survival of KC in Iceland by using a cancer registry containing records of all BCC, SCCis, and SCC cases recorded in Iceland between 1981 and 2015. RESULTS: Between 1981 and 2015, 8767 Icelanders were diagnosed with their first localized KC. A total of 6473 individuals with BCC, 1194 with SCCis, and 1100 with invasive SCC, respectively. BCC was not associated with decreased survival except for men diagnosed with BCC between 1981 and 1995 for whom decreased 10-year relative survival was observed (85.3, 95% CI [77.9-92.7]). SCC and SCCis were both associated with a decrease in relative survival for certain population subgroups such as individuals <50 years of age at time of diagnosis. CONCLUSION: Our whole population cohort survival study examining the Icelandic Cancer Registry supports prior studies demonstrating that BCC is not associated with a reduction in relative survival and that SCC and SCCis are associated with comparatively poor relative survival in certain population subgroups.

[Liver surgeries in Iceland 2013-2017 - Comparison with Sweden in terms of quality registration].

INTRODUCTION: Cancers in the liver, bile duct system, gallbladder as well as metastases of the liver, have poor prognosis. Their treatment is comparable, with surgery being the most widespread, available curative treatment. Surgical treatment is anatomical or non-anatomical resection of the liver where the tumor and the adjacent liver tissue are removed. MATERIALS/METHODS: A list of patients diagnosed with cancer in the liver, bile duct system, gallbladder or metastases of the liver, during the time period 2013-2017, was obtained from the Icelandic Cancer Registry. Additional information was retrieved from medical records and entered into the electronic quality registration forms of Landspítalinn. A comparison was made between Sweden and Iceland. RESULTS: In total 108 patients were diagnosed with primary cancer of the liver, of which 24 (22%) underwent liver surgery. Of 264 diagnosed with liver metastases 38 (14%) underwent surgical treatment. A total of 63% of all reported cases were discussed at a multidisciplinary team meeting in Iceland but 93% in Sweden (p<0.0001). A sum of 29 patients (43%) developed complications within 30 days of surgery. Number of partial liver resections per 100.000 inhabitants were 2-8 in Iceland versus 4-13 in Sweden. The difference was even more apparent in patients with liver metastases. CONCLUSION: Liver surgeries performed in Iceland seem to be comparable to Sweden in terms of complications and post operative mortality. In Iceland, considerably fewer operations are performed per capita, especially on liver metastases which could be explained by the fact that fewer patients are discussed at multidisciplinary team meetings.

Automated Cancer Diagnostics via Analysis of Optical and Chemical Images by Deep and Shallow Learning.

Optical microscopy has long been the gold standard to analyse tissue samples for the diagnostics of various diseases, such as cancer. The current diagnostic workflow is time-consuming and labour-intensive, and manual annotation by a qualified pathologist is needed. With the ever-increasing number of tissue blocks and the complexity of molecular diagnostics, new approaches have been developed as complimentary or alternative solutions for the current workflow, such as digital pathology and mass spectrometry imaging (MSI). This study compares the performance of a digital pathology workflow using deep learning for tissue recognition and an MSI approach utilising shallow learning to annotate formalin-fixed and paraffin-embedded (FFPE) breast cancer tissue microarrays (TMAs). Results show that both deep learning algorithms based on conventional optical images and MSI-based shallow learning can provide automated diagnostics with F1-scores higher than 90%, with the latter intrinsically built on biochemical information that can be used for further analysis.

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.

Statins are associated with increased risk of squamous cell carcinoma of the skin: a whole-population study from Iceland.

Statins have been associated with an increased risk of keratinocyte carcinoma but data are limited and conflicting. Statins are hypothesized to contribute to KC through immunomodulation. A whole-population case-control study of the Icelandic population was conducted using the Icelandic Cancer Registry and Icelandic Prescription Medicine Register. These are high-quality registers which include all cancer diagnoses, as well as every prescription in the country. Cases included all first-time histologically confirmed diagnoses of (BCC), in situ squamous cell carcinoma (SCCis) and invasive SCC between 2003 and 2017. Each case was paired with 10 age- and sex-matched controls. Multivariate conditional logistic regression analysis was performed. Four thousand seven hundred patients with BCC, 1167 patients with SCCis and 1013 patients with invasive SCC were identified and paired with 47,292, 11,961 and 10,367 controls, respectively. Overall statin use was associated with an increased risk of invasive SCC and SCCis but not BCC (adjusted OR [95% CI]: 1.29 [1.11-1.50]; 1.43 [1.24-1.64]; 1.03 [0.95-1.12], respectively). Subgroup analysis demonstrated that statins were significantly associated with invasive SCC and SCCis in patients over 60, but not in those under 60. Atorvastatin was only associated with an increased risk of SCCis; whereas, simvastatin was associated with an increased risk of both invasive SCC and SCCis. This whole-population study of Iceland demonstrates that statin exposure is associated with increased risk of SCC, but not BCC, in a low UV environment. The reasons are unclear, but our results may suggest that individuals receiving atorvastatin and simvastatin have differing levels of baseline keratinocyte cancer risk or that properties of a statin other than 'statin intensity' affect association with SCC.

Sarcoidosis in Iceland: a nationwide study of epidemiology, clinical picture and environmental exposure.

BACKGROUND: This nationwide study aimed to elucidate the incidence and clinical characteristics of tissue-verified sarcoidosis in Iceland. A secondary aim was to analyse sex differences and identify possible environmental factors contributing to the pathological process. MATERIALS AND METHODS: This is a descriptive study covering 36 years (January 1, 1981 through December 31, 2016). Histopathological reports and electronic hospital discharge registries were reviewed in context for granulomas and/or sarcoidosis. National data were used for comparison regarding smoking habits and occupation, adjusted for age, sex and year of diagnosis. The data were stored in FileMaker and calculations were made by extracting data from this database to the statistical software package R. RESULTS: A total of 418 patients (54% females) were diagnosed with tissue-verified sarcoidosis. The incidence rate was 4.15/100 000/year, similar among females and males. The mean age at diagnosis was higher among females (53.0±14.2 years) than males (48.2±13.8 years). Fatigue was the most frequent single symptom (49.7%), but when all respiratory symptoms were grouped, they were the most frequent symptoms (60%). No significant difference was found between smoking status and sarcoidosis. Possible hazardous exposure in the workplace was reported by 19.4% of the cases. CONCLUSION: The incidence of sarcoidosis in Iceland was higher than in an Asian population where the same inclusion criteria were applied. The clinical picture diverges partly from that in the Asian population but resembles that among other Caucasians. Fatigue and respiratory symptoms were predominant. The biphasic pattern of age at disease debut seen elsewhere among females was not evident in Iceland.

The effect of sample age on the metabolic information extracted from formalin-fixed and paraffin embedded tissue samples using desorption electrospray ionization mass spectrometry imaging.

Background: Metabolites, especially lipids, have been shown to be promising therapeutic targets. In conjugation with genes and proteins they can be used to identify phenotypes of disease and support the development of targeted treatments. The majority of clinically collected tissue samples are stored in formalin-fixed and paraffin embedded (FFPE) blocks due to their tissue conservation ability and indefinite storage capacity. For metabolic analysis, however, fresh frozen (FF) samples are currently preferred over FFPE samples due to concerns of metabolic information being lost when preparing the samples. With little or no sample preparation, desorption electrospray ionisation mass spectrometry imaging (DESI-MSI) allows for the study of spatial as well as spectral information. Methods: DESI-MSI analysis was performed on FFPE breast cancer tissue microarray samples from 213 patients collected between the years 1935-2013. Logistic regression (LR) models were built to classify samples based on age and FF samples were used for feature validation. Results: LR models developed on the FFPE samples achieved an average classification accuracy of 96% when predicting their age with a 10-year grouping. Closer examination of the metabolic change over time revealed that the mean signal intensities for the lower mass range (100 - 500 m/z) linearly decrease over time, while the mean intensities for the higher mass range (500 - 900 m/z), remained relatively constant. Conclusions: In our samples, which span over 70 years, sample age has a weak yet quantifiable impact on metabolite content in FFPE samples, while the higher mass range is seemingly unaffected. FFPE samples thus provide an alternative avenue for metabolic analysis of lipids.

Metformin is associated with decreased risk of basal cell carcinoma: A whole-population case-control study from Iceland.

BACKGROUND: Metformin has anticarcinogenic properties and is also known to inhibit the sonic hedgehog pathway, but population-based studies analyzing the potential protective effect for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are needed. OBJECTIVES: To delineate the association between metformin use and invasive SCC, SCC in situ (SCCis), and BCC. METHODS: A population-based case-control study design was employed using all 6880 patients diagnosed in Iceland between 2003-2017 with first-time BCC, SCCis, or invasive SCC, and 69,620 population controls. Multivariate odds ratios (ORs) were calculated using conditional logistic regression. RESULTS: Metformin was associated with a lower risk of developing BCC (OR, 0.71; 95% confidence interval [CI], 0.61-0.83), even at low doses. No increased risk of developing SCC was observed. SCCis risk was mildly elevated in the 501-1500 daily dose unit category (OR, 1.40; 95% CI, 1.00-1.96). LIMITATIONS: This study was retrospective in nature with the inability to adjust for ultraviolet exposure, Fitzpatrick skin type, and comorbidities. CONCLUSION: Metformin is associated with decreased risk of BCC development, even at low doses. Metformin might have potential as a chemoprotective agent for patients at high risk of BCC, although this will need confirmation in future studies.

Salivary gland tumours in Iceland 1986-2015: a nationwide epidemiological analysis over a 30-year time period.

Salivary gland tumours (SGT) are a vast and heterogenous group of neoplasms. There is a relative lack of comprehensive nationwide epidemiological studies on the subject. The aim of this nationwide analysis was to gain insight into epidemiological traits, such as site, incidence and histological subtypes of SGT in general. Patients diagnosed with a primary SGT between 1986 and 2015 were identified from The Icelandic Cancer Registry and registries from all pathology departments in Iceland. Information on age, sex, tumour location and histology was retrieved from pathology reports. A total of 687 patients were diagnosed with a SGT, 609 (89%) were benign and 78 (11%) malignant. 9% of parotid gland tumours, 22% of submandibular gland tumours and 26% of minor SGT were malignant. The most common malignant tumours were mucoepidermoid carcinoma, acinic cell carcinoma and adenoid cystic carcinoma. The incidence of benign SGT was 4.9 per 100 000 among men and 7.0 per 100 000 among women. The incidence of malignant tumours was 0.59 per 100 000 for men and 0.79 per 100 000 for women. The proportion of malignant SGT is lower than most often reported. Only 10% of parotid gland tumours, 20% of submandibular gland tumours and 25% of minor salivary gland tumours are malignant.

Association between hydrochlorothiazide and the risk of in situ and invasive squamous cell skin carcinoma and basal cell carcinoma: A population-based case-control study.

BACKGROUND: Population-based studies analyzing hydrochlorothiazide's (HCTZ's) effect on keratinocyte carcinoma, and particularly invasive squamous cell carcinoma (SCC), are lacking. OBJECTIVES: To characterize the association between HCTZ use and invasive SCC, SCC in situ (SCCis), and basal cell carcinoma (BCC). METHODS: This population-based case-control study included all 6880 patients diagnosed with first-time BCC, SCCis, and invasive SCC between 2003 and 2017 in Iceland and 69,620 population controls. Conditional logistic regression analyses were used to calculate multivariate odds ratios (ORs) for keratinocyte carcinoma associated with HCTZ use. RESULTS: A cumulative HCTZ dose above 37,500 mg was associated with increased risk of invasive SCC (OR, 1.69; 95% confidence interval [CI], 1.04-2.74). Users of HCTZ also had an increased risk of SCCis (OR, 1.24; 95% CI, 1.01-1.52) and BCC (OR, 1.14; 95% CI, 1.02-1.29). LIMITATIONS: Limitations include this study's retrospective nature with the resulting inability to adjust for ultraviolet exposure, Fitzpatrick skin type, and comorbidities. CONCLUSIONS: High cumulative exposure to HCTZ is associated with the development of keratinocyte carcinoma and, most importantly, invasive SCC. Sun protective behaviors alone may not eliminate the carcinogenic potential of HCTZ.

ECM1 secreted by HER2-overexpressing breast cancer cells promotes formation of a vascular niche accelerating cancer cell migration and invasion.

The tumor microenvironment is increasingly recognized as key player in cancer progression. Investigating heterotypic interactions between cancer cells and their microenvironment is important for understanding how specific cell types support cancer. Forming the vasculature, endothelial cells (ECs) are a prominent cell type in the microenvironment of both normal and neoplastic breast gland. Here, we sought out to analyze epithelial-endothelial cross talk in the breast using isogenic non-tumorigenic vs. tumorigenic breast epithelial cell lines and primary ECs. The cellular model used here consists of D492, a breast epithelial cell line with stem cell properties, and two isogenic D492-derived EMT cell lines, D492M and D492HER2. D492M was generated by endothelial-induced EMT and is non-tumorigenic while D492HER2 is tumorigenic, expressing the ErbB2/HER2 oncogene. To investigate cellular cross talk, we used both conditioned medium (CM) and 2D/3D co-culture systems. Secretome analysis of D492 cell lines was performed using mass spectrometry and candidate knockdown (KD), and overexpression (OE) was done using siRNA and CRISPRi/CRISPRa technology. D492HER2 directly enhances endothelial network formation and activates a molecular axis in ECs promoting D492HER2 migration and invasion, suggesting an endothelial feedback response. Secretome analysis identified extracellular matrix protein 1 (ECM1) as potential angiogenic inducer in D492HER2. Confirming its involvement, KD of ECM1 reduced the ability of D492HER2-CM to increase endothelial network formation and induce the endothelial feedback, while recombinant ECM1 (rECM1) increased both. Interestingly, NOTCH1 and NOTCH3 expression was upregulated in ECs upon treatment with D492HER2-CM or rECM1 but not by CM from D492HER2 with ECM1 KD. Blocking endothelial NOTCH signaling inhibited the increase in network formation and the ability of ECs to promote D492HER2 migration and invasion. In summary, our data demonstrate that cancer-secreted ECM1 induces a NOTCH-mediated endothelial feedback promoting cancer progression by enhancing migration and invasion. Targeting this interaction may provide a novel possibility to improve cancer treatment.

[Primary sclerosing cholangitis in Iceland 1992-2012].

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease affecting the intra- and/or extrahepatic biliary tree with inflammation and progressive stricture formation that can lead to cirrhosis, end stage liver failure and liver transplantation. Known risk factors include inflammatory bowel diseases (IBD), mainly ulcerative colitis (UC). Highest reported incidence in an adult population is 1.2-1.3/100.000 in Norway and Sweden, where 60-76% have IBD. The aim of this study was to investigate epidemiology of PSC in Iceland in the years 1992 to 2012 and the patients outcomes. METHODS: A search for the diagnosis "cholangitis" (ICD-10, K83.0) was performed in the database for hospital records in Landspítali (The National University Hospital of Iceland, LSH) and Akureyri Hospital from 1992 to 2012. We also looked through all ERCP and MRCP imaging done in LSH in the same period along with a text search in both the hospital records and the pathology database for liver biopsies. Data on these patients was collected until the end of 2016. RESULTS: A total of 42 patient got the diagnosis PSC within the period. Median age at diagnosis was 34 years, 67% were male and 90% adults (≥18 years old). Mean incidence per year was 0.69/100.000. Overall 88% of patients had IBD, thereof 89% UC. Seven patients have been diagnosed with cancer, four with cancer in the bile ducts and one in the gallbladder. Within the study period a total of five patients died (12%), 51 months (median) from diagnosis and three from cholangiocarcinoma, 51 months (median) from diagnosis. Three patients (7%) underwent liver transplantation, one required a transplant two times. CONCLUSIONS: The incidence of PSC in Iceland turned out to be lower than in our neighbouring countries in Scandinavia. It is unclear if this is due to underdiagnosis or, more likely, that PSC is simply more uncommon in Iceland. Overall 7% underwent liver transplantation and 12% died within the study period, main cause of mortality being cholangiocarcinoma.

Gastroenteropancreatic neuroendocrine tumors in Iceland: a population-based study.

OBJECTIVE: To determine the incidence, distribution, and prognosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) over the last 30 years and analyze changes over time. METHODS: All patients diagnosed with GEP-NETs in Iceland from 1985 to 2014 were identified through the Icelandic Cancer Registry and pathology laboratory records. Relevant clinical information was obtained from medical records. In order to assess trends, the study period was divided into two periods, 1985-1999 and 2000-2014. RESULTS: A total of 364 patients with GEP-NETs were identified. Overall, 18 patients diagnosed at autopsy or with primary tumors of an unknown site were excluded, leaving 346 patients with 351 primary tumors for final analysis. The overall mean annual incidence 1985-2014 was 3.65/100,000, 3.39/100,000 during 1985-1999 and 3.85/100,000 during 2000-2014 (p = NS). The most common primary tumor site was the appendix (32%), followed by the jejunum/ileum (24%) and stomach (17%). In all, 18% of patients presented with distant metastases at the time of diagnosis, most noticeably patients with primary tumors of the colon (47%), pancreas (46%) and jejunum/ileum (39%). The most favorable 5-year survival was observed for tumors of the appendix (94%) and rectum (88%) and the least favorable for tumors of the pancreas (31%), colon (47%) and jejunum/ileum (66%). There were no statistically significant changes in incidence, staging or survival between the two time periods. CONCLUSIONS: In this population-based study, the incidence of GEP-NETs has not changed significantly over the last decades. The incidence of metastatic disease has remained stable and overall prognosis has not improved in recent years.

The risk of developing a mismatch repair deficient colorectal cancer after undergoing cholecystectomy.

OBJECTIVES: Mismatch repair deficient (dMMR) colorectal cancer (CRC) is caused by inactivation of the MMR DNA repair system, most commonly via epigenetic inactivation of the MLH1 gene, and these tumors occur most frequently in the right colon. The objective was to determine whether cholecystectomy (CCY) increases the risk of a dMMR CRC by comparing CCY incidence in patients with dMMR CRC and proficient MMR (pMMR) CRC to unaffected controls. MATERIALS AND METHODS: All patients diagnosed with CRC in Iceland from 2000 to 2009 (n = 1171) were included. They had previously been screened for dMMR by immunohistochemistry (n = 129 were dMMR). Unaffected age- and sex-matched controls (n = 17,460) were obtained from large Icelandic cohort studies. Subjects were cross-referenced with all pathology databases in Iceland to establish who had undergone CCY. Odds ratios were calculated using unconditional logistic regression. RESULTS: Eighteen (13.7%) dMMR CRC cases and 90 (8.7%) pMMR CRC cases had undergone CCY compared to 1532 (8.8%) controls. CCY-related odds ratios (OR) were 1.06 (95% CI 0.90-1.26, p = .577) for all CRC, 1.16 (95% CI 0.66-2.05 p = .602) for dMMR CRCand 1.04 (95% CI 0.83-1.29, p = .744) for pMMR CRC. Furthermore, OR for dMMR CRC was 0.51 (95% CI 0.16-1.67, p = .266), 2.04 (95% CI 0.92-4.50, p = .080) and 1.08 (95% CI 0.40-2.89, p = .875) <10 years, 10-20 years and >20 years after a CCY, respectively. CONCLUSIONS: There was no evidence of increased risk of developing dMMR CRC after CCY although a borderline significantly increased 2-fold risk was observed 10-20 years after CCY. Larger studies are warranted to examine this further.

Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome.

Lynch syndrome (LS) is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele, lead to cancer development. Universal tumor screening for LS is routinely performed on colon cancer, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009); Columbus, Ohio (1999-2005); and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Because histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency.

[Surgical treatment of hepatocellular carcinoma at Landspitali The National University Hospital of Iceland 1993 - 2012].

INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. The incidence in Iceland is very low probably due to a low prevalence of cirrhosis. The only curative treatment is surgery, either transplant or resections, but only about 30% of patients are operable at the time of diagnosis. The aim of this study was to determine the number of patients who undergo liver resection due to HCC and to investigate outcomes after surgery at Landspitali University Hospital in Iceland. MATERIAL AND METHODS: A retrospective study of all HCC patients, 18 years of age or older, who underwent surgical resection at Landspitali University Hospital from January 1st 1993 to December 31st 2012. Data was collected from clinical records. Descriptive statistical analysis was used. RESULTS: During the time period 22 patients were operated with a liver resection and of those patients 12 (55%) had a major hepatectomy. 105 individuals in total were diagnosed with HCC in the time period, six patients had transplantation which results in 28 operations (27%). The average size of the tumors was 8.5 cm (3-22). Four individuals had cirrhosis. The frequency of intra-operative complications was 23% and post-operative complications 32% (Clavien-Dindo grade III and IV). A total of three individuals needed reoperation. The 30 day mortality rate was 0%. Twelve (55%) individuals were diagnosed with recurrence during the research period and eleven died. The one year mortality rate was 23%. CONCLUSION: The proportion of operable individuals with HCC in Iceland is low, few of whom have cirrhosis or other chronic liver disease. The mortality rate is comparable to other researches but the frequency of serious complications is higher probably due to tumor size.