Chromosomal aneusomy in bronchial high-grade lesions is associated with invasive lung cancer.

RATIONALE: The development of lung cancer (LC) is accompanied by field changes in the airway mucosa that may have prognostic importance. OBJECTIVES: To compare patients with prevalent LC to control subjects regarding their histologic dysplasia scores and chromosomal aneusomy as measured by fluorescence in situ hybridization (FISH). METHODS: The most advanced bronchial histology lesion was assessed from each of 44 LC cases and 90 cancer-free control subjects using a four-color FISH probe set encompassing the chromosome 6 centromere, 5p15.2, 7p12 (epidermal growth factor receptor), and 8q24 v-myc myelocytomatosis viral oncogene homolog (MYC) sequences. Histology grades were coded as dysplasia (moderate or severe) or carcinoma in situ (CIS). MEASUREMENTS AND MAIN RESULTS: CIS was the highest histologic grade for 32 subjects, and dysplasia was the highest grade for 102 subjects (54 moderate, 48 severe). Chromosomal aneusomy was seen in 64% of the LC cases, but in only 31% of the control subjects (odds ratio [OR], 4.68; 95% confidence interval [CI]. 1.97-11.04). Among those with any level of dysplasia, the OR for positive FISH and LC was 2.28 (95% CI, 0.75-6.86). Among those with CIS, the OR for positive FISH and LC was 5.84 (95% CI, 1.31-26.01). CONCLUSIONS: Chromosomal aneusomy is associated with LC. Prospective examination of aneusomy as a precursor lesion that predicts LC is needed.

Medicolegal liability in pathology: an international perspective.

An inevitable outcome of modern Medicine in any country is that some patients will experience adverse events, some of which would have been preventable. Different nations have developed various approaches to such cases; their legal efficacies are probably dissimilar and dependent on a number of disparate variables. An international "snapshot" of the results of the interacting forces can be obtained by asking physicians in several countries how they view selected subjective facets of their tort systems. In the U.S., many physicians view the structure of malpractice torts as unfair, and that belief is shared by at least some pathologists. The American Medical Association has declared that a multiregional malpractice "crisis" exists which raises medical costs and threatens access to care. Furthermore, malpractice tort decisions are often flawed scientifically because lay jurors and judges cannot properly evaluate the quality of "expert" testimony given by adversarial witnesses. Despite these factors, there has been little effort to investigate the views of pathologists on malpractice actions outside the U.S. In this paper, the authors have collected the responses of an international group of pathologists to a questionnaire on that topic. The respondents practice in academic centers in 15 countries outside the U.S. As expected, a range of views was represented, with some pathologists reporting that malpractice litigation was uncommon and others noting a worrisome trend toward its growth. Interestingly, so-called "defensive medicine" was found to be relatively common in pathology in many countries.

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.

Primary adenocarcinoma of the lung--histological subtypes and outcome after surgery, using the IASLC/ATS/ERS classification of lung adenocarcinoma.

Adenocarcinoma is the most common histological type of lung carcinoma. Recently the histologic classification of adenocarcinomas in the lung was modified to better reflect biologic properties and prognosis. We reviewed the histology of all primary lung adenocarcinomas operated on in Iceland during a 20-year period and assessed the impact of histology on survival. This nationwide study included 285 patients (mean age 67 years, 57% female), who underwent resection in Iceland from 1991 to 2010. Tumors were reclassified according to the current IASLC/ATS/ERS classification system. Overall survival was estimated by the Kaplan-Meier method and Cox regression analysis used to evaluate prognostic factors of overall mortality. Acinar predominant adenocarcinoma was the most common histological subtype (46%) followed by solid-predominant (SPA) with mucin production comprised (23%). Non-invasive carcinomas were rare. A difference in survival between the histological adenocarcinoma subtypes was not seen (p = 0.32) and multivariate analysis showed that advanced stage and age predicted worse outcome, but histologic subtyping of adenocarcinoma did not. In this nation-wide study there was not a statistical difference in survival according to adenocarcinoma subtypes and the histological subtype did not predict mortality. Preinvasive and minimally invasive adenocarcinomas were rare.

Establishment of three human breast epithelial cell lines derived from carriers of the 999del5 BRCA2 Icelandic founder mutation.

Germ line mutations in BRCA1 and BRCA2 account for a large proportion of inherited breast and ovarian cancer. Both genes are involved in DNA repair by homologous recombination and are thought to play a vital role in maintaining genomic stability. A major drawback for long-term functional studies of BRCA in general and BRCA2 in particular has been a lack of representative human breast epithelial cell lines. In the present study, we have established three cell lines from two patients harboring the 999del5 germ line founder mutation in the BRCA2 gene. Primary cultures were established from cellular outgrowth of explanted tissue and subsequently transfected with a retroviral construct containing the HPV-16 E6 and E7 oncogenes. Paired cancer-derived and normal-derived cell lines were established from one patient referred to as BRCA2-999del5-2T and BRCA2-999del5-2N, respectively. In addition, one cell line was derived from cancer-associated normal tissue from another patient referred to as BRCA2-999del5-1N. All three cell lines showed characteristics of breast epithelial cells as evidenced by expression of breast epithelial specific cytokeratins. Cytogenetic analysis showed marked chromosomal instability with tetraploidy and frequent telomeric associations. In conclusion, we have established three breast epithelial cell lines from two patients carrying the BRCA2 Icelandic 999del5 founder mutation. These cell lines form the basis for further studies on carcinogenesis and malignant progression of breast cancer on a defined genetic background.

Cancer as a complex phenotype: pattern of cancer distribution within and beyond the nuclear family.

BACKGROUND: The contribution of low-penetrant susceptibility variants to cancer is not clear. With the aim of searching for genetic factors that contribute to cancer at one or more sites in the body, we have analyzed familial aggregation of cancer in extended families based on all cancer cases diagnosed in Iceland over almost half a century. METHODS AND FINDINGS: We have estimated risk ratios (RRs) of cancer for first- and up to fifth-degree relatives both within and between all types of cancers diagnosed in Iceland from 1955 to 2002 by linking patient information from the Icelandic Cancer Registry to an extensive genealogical database, containing all living Icelanders and most of their ancestors since the settlement of Iceland. We evaluated the significance of the familial clustering for each relationship separately, all relationships combined (first- to fifth-degree relatives) and for close (first- and second-degree) and distant (third- to fifth-degree) relatives. Most cancer sites demonstrate a significantly increased RR for the same cancer, beyond the nuclear family. Significantly increased familial clustering between different cancer sites is also documented in both close and distant relatives. Some of these associations have been suggested previously but others not. CONCLUSION: We conclude that genetic factors are involved in the etiology of many cancers and that these factors are in some cases shared by different cancer sites. However, a significantly increased RR conferred upon mates of patients with cancer at some sites indicates that shared environment or nonrandom mating for certain risk factors also play a role in the familial clustering of cancer. Our results indicate that cancer is a complex, often non-site-specific disease for which increased risk extends beyond the nuclear family.

Risk of cancer among relatives of patients with glioma.

We report a population-based, retrospective study of 396 Icelandic people diagnosed with glioma in the years 1940-1995. The purpose of this study was to test whether astrocytomas, other glial tumors, other central nervous system tumors, or other cancers aggregate in families identified through glioma probands who were of Icelandic origin. Pedigrees of the 396 cases were traced by the Genetical Committee of the University of Iceland and linked to the Icelandic Cancer Registry. A total of 25,546 relatives, including 2,080 individuals with cancer were identified within these pedigrees. There was no statistically significant increase of glioma in relatives of glioma patients, nor was there any statistically significant increase in risk for other central nervous system tumors. There was no overall increase in incidence of all cancer combined, nor of specific common cancers (lung, prostate, breast, stomach, and colorectal) and uncommon cancers (melanoma and pancreas) in the relatives of glioma patients. Our results do not support the hypothesis of a familial aggregation of glioma indicative of a glioma susceptibility gene.

Cancer of unknown primary: clinicopathologic correlations.

Cancer of unknown primary origin (CUP) accounts for 5-10% of all malignant tumors at presentation and remains the death certificate diagnosis in 0.5-5% of patients. We investigated CUP patients whose primary site remained unknown throughout the entire clinical course. We reviewed 9,436 consecutive autopsies performed between 1984 and 1999 at the Mayo Clinic, matched with 177,167 cancer patients treated in the same time period. Sixty-four patients who died of CUP underwent postmortem examination. Antemortem pathologic diagnoses were obtained in 57 patients, agreed with postmortem diagnoses in 98%, and included adenocarcinoma (n=44), undifferentiated carcinoma (n=7), squamous cell carcinoma (n=3), and others (n=3). Autopsy located the primary site in 35 patients (55%). Common primary sites were lung (n=8), the pancreaticobiliary (n=13) and GI tracts (n=9). Of 43 patients evaluated for tumor-specific therapy, only six received no further oncologic treatment and untreated patients survived a median of 57 (range 10-280) days, compared with 225 (range 19-1,129) days for patients treated with chemotherapy and/or radiotherapy (n=37). Our findings show that (1) autopsy studies provide a valuable tool for quality control in the setting of CUP, and (2) treated patients have a small but significant survival benefit.

Epithelioid angiomyolipoma of the liver: case report and review of the literature.

Hepatic angiomyolipoma is a rare tumor. Here we describe a case and review the literature.

Cardiac amyloidosis presenting with elevations of cardiac troponin I and angina pectoris.

We present the case of a 43-year-old male who was initially evaluated for angina pectoris and dyspnea. His CK, CK-MB, and cTnI were all elevated following a blood transfusion and he underwent coronary arteriography, which demonstrated no luminal obstructions. After several months, he was transferred to Mayo Clinic where diagnoses of fulminant cardiac amyloidosis and systemic multiple myeloma were established. The cTnI remained elevated despite normalization of the CK and CK-MB. Despite aggressive treatment, the patient died. Postmortem analysis demonstrated amyloid cardiac deposition including involvement of the coronary microvasculature. Electron microscopy revealed myocyte compression injury from amyloid infiltration. We believe this is the first report of elevated troponin I in a patient with cardiac amyloidosis. The electron microscopy in our case confirms cardiac damage as the mechanism for cTnI elevation. This observation strengthens our knowledge about the specificity of cTnI for the detection of cardiac injury.

Tetraploidy in BRCA2 breast tumours.

Tetraploidy and aneuploidy can be caused by cell division errors and are frequently observed in many human carcinomas. We have recently reported delayed cytokinesis in primary human fibroblasts from BRCA2 mutation carriers, implying a function for the BRCA2 tumour suppressor in completion of cell division. Here, we address ploidy aberrations in breast tumours derived from BRCA2 germline mutation carriers. Ploidy aberrations were evaluated from flow cytometry histograms on selected breast tumour samples (n=236), previously screened for local BRCA mutations. The ploidy between BRCA2-mutated (n=71) and matched sporadic (n=165) cancers was compared. Differences in ploidy distribution were examined with respect to molecular tumour subtypes, previously defined by immunohistochemistry on tissue microarray sections. Tetraploidy was significantly 3 times more common in BRCA2 breast cancers than sporadic. However, no differences were found in the overall ploidy distribution between BRCA2-mutation carriers and non-carriers. In BRCA2 cancers, tetraploidy was associated with luminal characteristics. The increased frequency of tetraploidy in BRCA2 associated cancers may be linked to cell division errors, particularly cytokinesis. Additionally, tetraploidy emerges predominantly in BRCA2 breast cancers displaying luminal rather than triple-negative phenotypes.

The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.

There are three prolyl hydroxylases (PHD1, 2 and 3) that regulate the hypoxia-inducible factors (HIFs), the master transcriptional regulators that respond to changes in intracellular O(2) tension. In high O(2) tension (normoxia) the PHDs hydroxylate two conserved proline residues on HIF-1α, which leads to binding of the von Hippel-Lindau (VHL) tumour suppressor, the recognition component of a ubiquitin-ligase complex, initiating HIF-1α ubiquitylation and degradation. However, it is not known whether PHDs and VHL act separately to exert their enzymatic activities on HIF-1α or as a multiprotein complex. Here we show that the tumour suppressor protein LIMD1 (LIM domain-containing protein) acts as a molecular scaffold, simultaneously binding the PHDs and VHL, thereby assembling a PHD-LIMD1-VHL protein complex and creating an enzymatic niche that enables efficient degradation of HIF-1α. Depletion of endogenous LIMD1 increases HIF-1α levels and transcriptional activity in both normoxia and hypoxia. Conversely, LIMD1 expression downregulates HIF-1 transcriptional activity in a manner depending on PHD and 26S proteasome activities. LIMD1 family member proteins Ajuba and WTIP also bind to VHL and PHDs 1 and 3, indicating that these LIM domain-containing proteins represent a previously unrecognized group of hypoxic regulators.

Mutations in BRIP1 confer high risk of ovarian cancer.

Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer.

Thymic epithelial tumours in Iceland: incidence and histopathology, a population-based study.

The objective of this study was to re-examine histologically and restage thymic epithelial tumours during a 25-year period and to correlate clinical and follow-up data. We utilized centralized registries in Iceland to establish a true nationwide incidence rate, previously unreported. A retrospective whole population study was carried out by including all patients diagnosed with a thymic epithelial tumour in Iceland between 1 January 1984 and 30 April 2010. Medical records were reviewed and presenting symptoms, diagnostic procedures and surgical outcome tabulated. The histology of all cases was reclassified according to the 2004 World Health Organization classification (A-TC). The Masaoka system was used for tumour staging. Median follow-up was 67 months. A total of 19 patients were identified, 11 men (58%) and 8 women, with mean age at presentation of 63 years (31-87 years). The age-standardized incidence rate (ASR) was 0.3 and 0.2/100 000/year for men and women, respectively. Types B2 (n = 5) and A (n = 5) were the most common histological subtypes. Half of the patients had local symptoms, and eight were diagnosed incidentally. Of 19 patients, 11 underwent resection of the tumour through median sternotomy. Five-year overall survival was 53%. All four patients with thymic carcinoma (TC) died of disease within 2 years of diagnosis. For the other 15 patients, no recurrences were reported. Thymic tumours are rare in Iceland with an ASR (w) of 0.28 per 100 000 a year. To our knowledge, these are the first nationwide ASR (w) figures reported. The prognosis for most thymic epithelial cell tumours is excellent. However, TCs have a dismal long-term survival.

[Mediastinoscopy in Iceland: indications and surgical outcome]. / Miomaetisspeglanir á Islandi: árangur og ábendingar.

INTRODUCTION: Mediastinoscopy is an important tool for staging lung cancer and evaluating mediastinal pathology. The objective of this retrospective study was to investigate the indications and safety of mediastinoscopy in a well defined cohort of patients. MATERIAL AND METHODS: All patients that underwent mediastinoscopy in Iceland between 1983-2007 were included. Clinical information was obtained from patient charts and pathology reports rewied. The study-period was divided into 5-year periods for comparison. RESULTS: Altogether 278 operations were performed but in 17 cases data was missing, leaving 261 patients for analysis (mean age 59 yrs, range 11-89, 159 males). A steady increase was seen in the number of operations, or from 16 to 85 during the first and last periods, respectively (p<0.01). Staging of lung cancer (61,3%), evaluation of mediastinal tumors (24,5%), and suspected sarcoidosis (8,8%) were the most common indications. Mean operating time was 30 minutes (range 10-320) and median hospital stay 1 day (range 0,5-26). The most common histological diagnosis were nonspecific changes (33,6%), lung cancer (23,8%) and sarcoidosis (12,7%). Seven patients (2.7%) had complications; including 4 (1.5%) with hoarsness due to left recurrent nerve injury, one (0,3%) with pneumothorax and two with >500 ml hemorrhage (1.1%). There were two operative deaths (<30 days), one due to major intraoperative bleeding. CONCLUSIONS: The number of mediastinoscopies is increasing in Iceland, especially as a part of lung cancer staging. Mediastinoscopy is a safe procedure with low mortality and morbidity, where a specific diagnosis is obtained in most cases.

Primary Rosai-Dorfman disease of bone: a clinicopathologic study of 15 cases.

Sinus histiocytosis with massive lymphadenopathy or Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disorder of unknown etiology. Most patients present with lymph node involvement manifesting as adenopathy; however, RDD may arise primarily in a variety of extranodal sites, including bone. We report herein our experience with 15 cases of primary intraosseous RDD. The patients include 8 females and 7 males, who ranged in age from 3 to 56 (mean 27) years. The lesions arose in a variety of anatomical locations, including the tibia, femur, clavicle, skull, maxilla, calcaneus, phalanx, metacarpal, and sacrum. Radiographically, the lesions were lytic with well defined and usually sclerotic margins. Histologically, the lesions demonstrated the classic features of RDD and consisted of a mixed inflammatory infiltrate with numerous large histiocytes with abundant eosinophilic cytoplasm which exhibited emperipolesis. Some cases also contained numerous neutrophils. Immunohistochemical stains showed that the large histiocytes were S-100 positive. Follow-up information was available for 12 patients. Five patients eventually developed additional extraosseous manifestations, including testicular, lymph node, and subcutaneous lesions. One of these 5 also developed a new bony lesion within the sternum. One patient developed additional lesions within multiple bones of the hand and wrist, without extraosseous disease. One patient had stable bony lesions, whereas 5 remained disease free after treatment.

[Lung cancer--review]. / Lungnakrabbamein--Yfirlitsgrein.

Lung cancer is the second most common cancer in Iceland and the most frequent cause of cancer related deaths. Smoking is by far the most important cause but familial factors also contribute. The symptoms of lung cancer are often subtle and the diagnosis, in about 70% of cases, is made when metastases have occurred. Curative surgical treatment is therefore only possible in about a third of the cases whereas other patients receive chemotherapy and/or radiation therapy. In recent years some important advances have been made in the diagnostic and therapeutic approaches to lung cancer. New imaging techniques have improved diagnosis and staging practices and consequently also treatment. Recent evidence suggests that screening with low dose CT may improve survival. New approaches to chemotherapy have been shown to improve survival and well being of patients with advanced disease. Chemotherapeutic agents are now being used in conjunction with surgery to reduce the risk of tumour spread. Furthermore, advances in surgical techniques have made resections possible in cases deemed inoperable in the past. In this review we present important advances in the diagnosis and treatment of lung cancer as reflected by recent literature that should be of interest to a wide variety of specialists.

[Spontaneous pneumothorax: a review article]. / Sjálfkrafa loftbrjóst--Yfirlitsgrein.

Spontaneous pneumothorax is a relatively common disease primarily affecting young and otherwise healthy individuals. Chest pain and dyspnea are the most common presenting symptoms and in majority of cases only a chest X-ray is needed to confirm the diagnosis. The initial treatment usually consist of a chest tube drainage, however, persistent airleakage and recurrent pneumothorax are frequent, these patients often requiring surgery. Open thoracotomy was the most common surgical approach with wedge resection of the leaking part of the lung. Today, video-assisted thoracoscopic surgery has in most centers replaced open surgery for spontaneous pneumothorax. In this article the presentation, diagnosis and treatment of spontaneous pneumothorax, including different surgical strategies, are reviewed in an evidence-based approach.

[Sarcoidosis in Iceland 1981-2003]. / Sarklíki á Islandi 1981-2003.

OBJECTIVE: To investigate the incidence of sarcoidosis in Iceland, its clinical manifestations and potential environmental influences. MATERIALS AND METHODS: All histopathological diagnoses of non-necrotizing granulomas generated in Iceland during the period 1981-2003 were reviewed with respect to a diagnosis of sarcoidosis. Further, patients were identified by searching hospital discharge diagnoses at the University Hospital in Reykjavik and the Regional Hospital in Northern Iceland. Only histologically verified cases were included. RESULTS: A total of 235 patients were found with histopathologically proven sarcoidosis. Limited to patients verified by tissue diagnosis, the annual incidence of sarcoidosis is 3,84/100.000/year. The incidence was found to be 2,8/100,000/year during the first half of the investigation period and 5,0/100,000/year during the second. This rate is lower than in other Nordic countries. There were 122 women and 113 men. The mean age at diagnosis was 50,8 years for women and 47,5 for men. The mean age at diagnosis was higher in Iceland than elsewhere. Clinically, respiratory symptoms predominated. Ocular symptoms and erythema nodosum are rare, and life-threatening cardiovascular and neurological manifestations are distinctly unusual. CONCLUSION: The low incidence is undoubtedly due to the strict inclusion criteria in the present study, i.e. only those with a tissue diagnosis were included. We have no explanation as to the higher age at diagnosis in Iceland than elsewhere. Registration of possible environmental factors and clinical evaluation may be improved.