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Background Radiation-associated angiosarcoma of the breast (RAASB) is a serious late consequence caused by breast cancer treatment. Initial symptoms are often inconspicuous, thus contributing to diagnostic delay. Most previous studies of the diagnostic aspects of RAASB are case reports. Purpose To perform a complete review of the imaging findings and biopsy methods in a nationwide RAASB cohort. Material and Methods RAASB patients were identified from a national cancer registry and additional patients were included from our hospital. All available information from imaging (mammogram [MGR], ultrasound [US], magnetic resonance imaging [MRI], and computed tomography [CT]) and biopsies was reviewed. The sensitivity of imaging and biopsy methods for detection of RAASB was calculated. Results Fifty-eight patients with RAASB were found. Fourteen MGR, 30 US, 24 MRI, and 25 CT studies were available for evaluation. The sensitivity of MGR, US, MRI, and CT for detection of RAASB was 43%, 50%, 92%, and 84%, respectively. Superior sensitivity was demonstrated for punch biopsy (84%) and incisional biopsy (93%) compared to fine-needle aspiration cytology (0%) and core needle biopsy (18%). Conclusion MRI and CT have comparable sensitivity for detection of RAASB, while MGR and US are unreliable. However, negative findings in MRI or CT must be interpreted with caution. Punch biopsy and incisional biopsy are the preferred biopsy methods.

BackgroundRadiation-associated angiosarcoma of the breast (RAASB) is an aggressive malignancy that is increasing in incidence. Only a few previous population-based studies have reported the results of RAASB treatment.MethodsA search for RAASB patients was carried out in the Finnish Cancer Registry, and treatment data were collected to identify prognostic factors for survival.ResultsOverall, 50 RAASB patients were identified. The median follow-up time was 5.4 years (range 0.4–15.6), and the 5-year overall survival rate was 69%. Forty-seven (94%) patients were operated on with curative intent. Among these patients, the 5-year local recurrence-free survival, distant recurrence-free survival, and overall survival rates were 62%, 75%, and 74%, respectively. A larger planned surgical margin was associated with improved survival.ConclusionsWe found that the majority of RAASB patients were eligible for radical surgical management in this population-based analysis. With radical surgery, the prognosis is relatively good.

Malignant eccrine porocarcinoma is a rare skin adnexal cancer arising from the sweat glands. Little is known about the epidemiology and incidence of eccrine porocarcinoma. This registry-based study examined the epidemiology and incidence data for eccrine porocarcinoma from the Finnish Cancer Registry. The study included all persons diagnosed with eccrine porocarcinoma in 2007 to 2017. There were 69 cases in the study period; 34 (49%) male and 35 (51%) female patients. Mean age at diagnosis was 75.5 years. Incidence for men was 0.06 per 100,000 person-years and for women 0.04 per 100,000 person-years adjusted for age according to the World Standard Population. Incidence increased with age. There was one eccrine porocarcinoma-specific death among the 69 patients. The incidence of eccrine porocarcinoma in Finland is therefore low. The mean age at time of diagnosis and the location of eccrine porocarcinoma are consistent with previous reports. The survival of patients with eccrine porocarcinoma is high. publishedVersion

Background: Genetic alterations occurring in lung cancer are the basis for defining molecular subtypes and essential for targeted therapies. Exhaled breath condensate (EBC) is a form of non-invasive sample that, amongst components, contains DNA from pulmonary tissue. Nextgeneration sequencing (NGS) was herein used to analyze mutations in EBC from patients with lung cancer. Materials and Methods: EBC was collected from 26 patients with cancer and 20 healthy controls. Amplicon-based sequencing using Ion Ampliseq Colon and Lung Cancer gene panel v2 was applied. Results: The sequencing was successful in 17 patients and 20 controls. EBC from patients revealed 39 hotspot mutations occurring in: adenomatous polyposis coli (APC), v-raf murine sarcoma viral oncogene homolog B (BRAE), discoidin domain receptor tyrosine kinase 2 (DDR2), epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 4 (ERBB4), F-box and WD repeat domain containing 7 (FBXW7), fibroblast growth factor receptor 1 (FGER1), FGFR3 (fibroblast growth factor receptor 3), Kirsten rat sarcoma viral oncogene homolog (KRAS), mitogen-activated protein kinase kinase 1 (MAP2K1), met proto-oncogene (MET), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), ret proto-oncogene (RET), SMAD family member 4 (SMAD4), serine/threonine kinase 11 (STK11), and tumorprotein p53 (TP53) genes. EBC from controls revealed 35 hotspot mutations. The average mutant allele fraction was higher in patients than controls. Conclusion: NGS can identify mutations in EBCs from patients with lung cancer. This could provide a promising non-invasive method for the assessment of gene mutations in lung cancer.

Radiation-associated sarcoma (RAS) is a rare complication of radiation therapy (RT) to breast cancer (BC). This study explored RAS after RT to BC in a nationwide population-based material. The Finnish Cancer Registry was queried for patients with BC treated during 1953-2014 who were later diagnosed with a secondary sarcoma in 1953-2014. Registry data, patient files, and sarcoma specimens were analyzed to confirm diagnosis and location of RAS at or close to the RT target volume. A total of 132 512 patients were diagnosed with invasive BC during the study period. A subsequent sarcoma was diagnosed in 355 patients. After exclusion, 96 RAS were identified. Angiosarcoma (AS) was the most prevalent histology in 50 (52%) of 96 patients. However, the first radiation-associated AS was diagnosed in a patient treated for BC with breast-conserving surgery in 1984, and thereafter, the proportion of AS continuously increased. The 5-year sarcoma-specific survival was 75.1% for RAS treated with a curative intent. The distribution of histologic subtypes of RAS has changed during the 60 years of this registry study. The first radiation-associated AS was diagnosed in 1989, and presently, AS is the most common histologic subtype of RAS. It is possible that changes in BC treatment strategies are influencing the characteristics of RAS.

Background Microbial ecosystems that inhabit the human gut form central component of our physiology and metabolism, regulating and modulating both health and disease. Changes or disturbances in the composition and activity of this gut microbiota can result in altered immunity, inflammation, and even cancer. Aim To compare the composition and diversity of gut microbiota in stool samples from patient groups based on the site of neoplasm in the gastrointestinal tract (GIT) and to assess the possible contribution of the bacterial composition to tumorigenesis. Methods We studied gut microbiota by16S RNA gene sequencing from stool DNA of 83 patients, who were diagnosed with different GIT neoplasms, and 13 healthy individuals. Results As compared to healthy individuals, stools of patients with stomach neoplasms had elevated levels of Enterobacteriaceae, and those with rectal neoplasms had lower levels of Bifidobacteriaceae. Lower abundance of Lactobacillaceae was seen in patients with colon neoplasms. Abundance of Lactobacillaceae was higher in stools of GIT patients sampled after cancer treatment compared to samples collected before start of any treatment. In addition to site-specific differences, higher abundances of Ruminococcus, Subdoligranulum and lower abundances of Lachnoclostridium and Oscillibacter were observed in overall GIT neoplasms as compared to healthy controls Conclusion Our study demonstrates that the alterations in gut microbiota vary according to the site of GIT neoplasm. The observed lower abundance of two common families, Lactobacillaceae and Bifidobacteriaceae, and the increased abundance of Enterobacteriaceae could provide indicators of compromised gut health and potentially facilitate GIT disease monitoring. Electronic supplementary material The online version of this article (10.1007/s10620-018-5190-5) contains supplementary material, which is available to authorized users.

AIM To study cancer hotspot mutations by next-generation sequencing (NGS) in stool DNA from patients with different gastrointestinal tract (GIT) neoplasms. METHODS Stool samples were collected from 87 Finnish patients diagnosed with various gastric and colorectal neoplasms, including benign tumors, and from 14 healthy controls. DNA was isolated from stools by using the PSP (R) Spin Stool DNA Plus Kit. For each sample, 20 ng of DNA was used to construct sequencing libraries using the Ion AmpliSeq Cancer Hotspot Panel v2 or Ion AmpliSeq Colon and Lung Cancer panel v2. Sequencing was performed on Ion PGM. Torrent Suite Software v.5.2.2 was used for variant calling and data analysis. RESULTS NGS was successful in assaying 72 GIT samples and 13 healthy controls, with success rates of the assay being 78% for stomach neoplasia and 87% for colorectal tumors. In stool specimens from patients with gastric neoplasia, five hotspot mutations were found in APC, CDKN2A and EGFR genes, in addition to seven novel mutations. From colorectal patients, 20 mutations were detected in AKT1, APC, ERBB2, FBXW7, KIT, KRAS, NRAS, SMARCB1, SMO, STK11 and TP53. Healthy controls did not exhibit any hotspot mutations, except for two novel ones. APC and TP53 were the most frequently mutated genes in colorectal neoplasms, with five mutations, followed by KRAS with two mutations. APC was the most commonly mutated gene in stools of patients with premalignant/benign GIT lesions. CONCLUSION Our results show that in addition to colorectal neoplasms, mutations can also be assayed from stool specimens of patients with gastric neoplasms.

Background Deletion of the CDKN2A locus is centrally involved in the development of several malignancies. In malignant pleural mesothelioma (MPM), it is one of the most frequently reported genomic alteration. MPM is strongly associated with a patients’ asbestos exposure. However, the status of CDKN2A and the expression of the corresponding protein, p16, in relation to MPM patient’s asbestos exposure is poorly known. Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear. Methods We studied DNA copy numbers for CDKN2A using fluorescence in situ hybridization (FISH) and p16 expression by immunohistochemistry (IHC) in 92 MPM patients, 75 of which with known asbestos exposure status. We also studied, in MPM, copy number alterations in 2p16, 9q33.1 and 19p13 by FISH. Results We were unable to detect an association between p16 expression and pulmonary asbestos fiber count in MPM tumor cells. However, significantly more MPM patients with high pulmonary asbestos fiber count (> 1 million fibers per gram [f/g]) had stromal p16 immunoreactivity than MPM of patients with low exposure (≤ 0.5 million f/g) (51.4% vs 16.7%; p = 0.035, Chi-Square). We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count (p = 0.044, Fisher’s Exact test, two-tailed). In contrast to our earlier findings in asbestos associated lung cancer, DNA copy number changes in 2p16, 9q33 and 19p13 were not frequent in MPM although single cases with variable copy numbers on those regions were seen. Conclusions We found two instances where the gene locus CDKN2A or its corresponding protein expression, is associated with high asbestos exposure levels. This suggests that there may be biological differences between the mesotheliomas with high pulmonary asbestos fiber count and those with low fiber count. Electronic supplementary material The online version of this article (10.1186/s12885-019-5652-y) contains supplementary material, which is available to authorized users.

A single-institution series using a (neo)adjuvant chemotherapy and interdigitated hyperfractionated split-course radiation therapy (CRT) treatment protocol for soft tissue sarcoma was reviewed. Our specific aims were to study recurrence rates and long-term toxicity. Between 1998 and 2016, 89 patients with non-metastatic soft tissue sarcoma were treated with surgery combined with six courses of doxorubicin and ifosfamide and hyperfractionated radiation therapy (42–60 Gy/1.5 Gy twice daily). Patients were considered being at high risk if tumour malignancy grade was high and the tumour fulfilled at least two of the following criteria: size >8 cm, presence of necrosis or vascular invasion. The mean age of the patients was 50.7 years. With a median follow-up of 5.4 years for survivors, the local control rate was 81.4%. Six (7%) patients progressed during neoadjuvant CRT. Seven (8%) patients discontinued the treatment due to toxicity. Eighty-six patients were operated and three (3%) of these developed a long-term complication. The estimated metastasis-free survival was 47.6% and overall survival 53.0% at five years. The limb-salvage rate was 93%. The limb-salvage rate, local control and complication rates were good in these patients with high risk soft tissue sarcoma. Metastases-free survival and overall survival rates were less satisfactory, reflecting the aggressive nature of these tumours.

Aims Merkel cell carcinoma, a rare cutaneous neuroendocrine tumour of the skin, can be categorised into two groups according to Merkel cell polyomavirus (MCV) presence. MCV-negative tumours are more aggressive and frequently associated with gene mutations. Some of the genes are potential therapeutic targets. We have previously reported EGFR mutations in six of 27 MCC tumours and overexpression of ALK and EZH2 at mRNA level in MCC tumours. In this study, we sought to determine expression of ALK, EGFR and EZH2 in MCC samples and assess their correlation to MCV status and clinical parameters. Methods and results Tissue microarrays were utilised and stained with primary antibodies. Staining data were statistically compared to patient sex, tumour location and development of metastasis and MCC-specific death; 112 tumours and their corresponding patient data were included. We found strong expression of ALK in 51% and strong expression of EZH2 in 76% of the tumours. There was evident correlation of ALK expression with MCV-positivity. Expression of EGFR was infrequent, presenting only in seven MCV-negative tumours. None of the proteins associated with development of metastasis or MCC specific death. Conclusions ALK and EZH2 expression are frequent in MCC and ALK expression correlates to MCV positivity. EGFR positive tumours might respond to EGFR inhibiting treatment.

Background: Merkel cell carcinoma (MCC) tumor samples frequently express B-lymphoid lineage markers. However, the reasons for expression of specific B-lymphoid lineage markers are still unclear. We studied the expression of TdT and PAX5 (two B-cell lymphoid lineage markers) in a large pool of MCC tissue microarray samples. Methods: Immunoexpression and staining intensities of TdT and Pax-5 were statistically correlated with patient, tumor, Merkel cell polyomavirus (MCV), and disease-specific parameters. Results: In a cohort of 117 MCC patients and their corresponding tumor samples, TdT was expressed in 37 (31.6%) samples and PAX5 in 26 (22.2%). Simultaneous immunostaining for TdT and PAX5 was observed in 13 (11.1%) samples. A statistically significant relationship was observed between MCV virus copy number and positive TdT expression (P = 0.0056). Similarly, a significant relationship was also observed between positive TdT and tumor MCV virus positivity (P = 0.000495). Conclusion: We observed frequent TdT and PAX5 immunoexpression in MCC tumor samples. However, simultaneous immunoexpression of these markers was scarce. TdT expression was statistically significantly associated with MCV positivity. The absence of a statistically significant association between tumor parameters and disease progression markers undermines the systemic use of these markers in clinical practice.

Background: Osteosarcomas (OS) in the craniomaxillofacial (CMF) region are typically diagnosed at later age than long-bone OS, but they are reported to have better 5-year survival. Curative treatment warrants wide surgical resection, which is often not possible in the CMF region. The purpose of this article is to present a nationwide series of CMF in Finland to discuss the role of surgery. Patients and methods: All 21 CMF OS patients managed in Finland from 1992 to 2009 were included. The mean age was 40 years (range 15e72). Data on patient and tumor characteristics, treatment modalities, and survival were recorded. All patients had a minimum follow-up of 5 years or until death. Results: OS was evenly represented in the mandible and maxillary bones, which together constituted 76% of all sites. Surgery with curative intent was carried out in 20 patients. Clear margins were achieved in only five cases. Eight (40%) of these 20 patients died due to OS, and their average survival time was 1.3 years. Seven (35%) out of the 20 patients received radiotherapy due to close/intralesional surgical margins, and four of them did not develop recurrences during the follow-up. Conclusions: The results suggest that postoperative radiotherapy may alter the prognosis in CMF OS, particularly in cases with close or intralesional margins. This may increase the survival rates achieved by prompt action in performing radical surgery. (C) 2019 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue cancer in need for novel therapies. Here we show that the PROX1 transcription factor, which is essential for normal myoblast differentiation, is highly expressed in RMS tumors. We demonstrate that PROX1 is needed for RMS cell stemness and growth in vitro, and for RMS tumor formation in mouse xenograft models. In addition, we unveil that PROX1 is an essential for myogenic properties in RMS. PROX1 depletion reprogrammed the RMS transcriptome to resemble benign mesenchymal stem cells and repressed many of the previously identified RMS effector transcripts and myogenic genes. By using proximity labeling and mass spectrometry, we found that PROX1 interacts with the NuRD and CoREST complexes containing class I HDACs. Our studies reveal a major role of PROX1-HDAC interaction in RMS and give insights that inhibiting this interaction could be a promising therapeutic approach.

Background and objectives Desmoid tumors are soft-tissue tumors originating from myofibroblasts with a tendency to recur after surgery. High expression of proliferation markers is associated with shortened progression-free and/or overall survival in many neoplasms, including soft-tissue sarcomas. We investigated the prognostic role of cyclin A and Ki67 in desmoid tumors by immunohistochemistry. Methods The study included 76 patients with desmoid tumor operated at Helsinki University Hospital between 1987 and 2011. A tissue micro array (TMA) was constructed and the TMA sections were immunostained with cyclin A and Ki67 antibodies. A computer-assisted image analysis was performed. Results Cyclin A expression was evaluable in 74 and Ki67 in 70 patients. Cyclin A immunopositivity varied from 0% to 9.9%, with a mean of 1.9%. Cyclin A expression correlated significantly with Ki67. Cyclin A expression was associated with recurrence-free survival (HR 1.9, 95% CI = 1.1-3.2, P = .02), as were positive margin (HR 6.0, 95% CI = 1.6-22.5, P = .008) and extremity location (HR 5.3, 95% CI = 1.7-16.8, P = 0.005). Ki67 immunopositivity varied from 0.33% to 13.8%, with a mean of 4.6%, but had no significant prognostic impact (HR 1.1, P = .2). Conclusions Our study indicates that cyclin A may be a new prognostic biomarker in surgically treated desmoid tumors.

Background and purpose - Soft-tissue sarcoma (STS) is rare, with challenging individualized treatment, so diagnostics and treatment should be centralized. Historical controls are sometimes used for investigation of whether new diagnostic or therapeutic tools affect patient outcome. However, as yet unknown factors may affect the outcome. We investigated prognostic factors and prognosis in 2 nationwide cohorts of patients diagnosed with a local STS during the periods 1998-2001 and 2005-2010, with special interest in finding factors lying behind possible improvement of prognosis. Patients and methods - 2 cohorts of patients with STS of the extremities or trunk diagnosed during the periods 1998-2001 and 2005-2010 were retrieved from the nationwide Finnish Cancer Registry. Detailed information was gathered from patient files. Results - Compared to first cohort, a larger proportion of patients with inadequate surgery in the second cohort received radiation therapy, and both the local control rate and the sarcoma-specific survival rate improved in the second cohort. For sarcoma-specific survival, cohort (HR =0.6, 95% CI: 0.5-0.9), age, depth, grade, and margin were significant factors in multivariate analysis. For local control, cohort (HR =0.6, 95% CI: 0.5-0.9), age, and margin were significant in multivariate analysis. Interpretation - Known prognostic factors including type of treatment did not entirely explain the secular trend of continuous improvement in prognosis in STS. This illustrates the danger of using historical controls for investigation of whether new diagnostic or therapeutic tools have an effect on patient outcome.

// Omar Youssef 1 , Aija Knuuttila 2 , Paivi Piirila 3 , Tom Bohling 4 , Virinder Sarhadi 1, * , Sakari Knuutila 1, * 1 Faculty of Medicine, Department of Pathology, University of Helsinki, Helsinki, Finland 2 Department of Pulmonary Medicine, University of Helsinki and Helsinki University Hospital, Heart and Lung Center, Helsinki, Finland 3 Unit of Clinical Physiology, HUS-Medical Imaging Center, Helsinki University Hospital and Helsinki University, Helsinki, Finland 4 Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland * These authors have contributed equally to this work Correspondence to: Sakari Knuutila, email: sakari.knuutila@helsinki.fi Keywords: exhaled breath condensate, mutations, healthy individuals, next generation sequencing Received: December 10, 2016 Accepted: January 16, 2017 Published: February 09, 2017 ABSTRACT Exhaled breath condensate (EBC) is a non-invasive source that can be used for studying different genetic alterations occurring in lung tissue. However, the low yield of DNA available from EBC has hampered the more detailed mutation analysis by conventional methods. We applied the more sensitive amplicon-based next generation sequencing (NGS) to identify cancer related mutations in DNA isolated from EBC. In order to apply any method for the purpose of mutation screening in cancer patients, it is important to clarify the incidence of these mutations in healthy individuals. Therefore, we studied mutations in hotspot regions of 22 cancer genes of 20 healthy, mainly non-smoker individuals, using AmpliSeq colon and lung cancer panel and sequenced on Ion PGM. In 15 individuals, we detected 35 missense mutations in TP53, KRAS, NRAS, SMAD4, MET, CTNNB1, PTEN, BRAF, DDR2, EGFR, PIK3CA, NOTCH1, FBXW7, FGFR3, and ERBB2: these have been earlier reported in different tumor tissues. Additionally, 106 novel mutations not reported previously were also detected. One healthy non-smoker subject had a KRAS G12D mutation in EBC DNA. Our results demonstrate that DNA from EBC of healthy subjects can reveal mutations that could represent very early neoplastic changes or alternatively a normal process of apoptosis eliminating damaged cells with mutations or altered genetic material. Further assessment is needed to determine if NGS analysis of EBC could be a screening method for high risk individuals such as smokers, where it could be applied in the early diagnosis of lung cancer and monitoring treatment efficacy.

Background: We aimed to assess the connection between chronic inflammatory disorders (CIDs) and Merkel cell carcinoma (MCC). Methods: Merkel cell carcinoma cases diagnosed in 1978–2009 were extracted from the Finnish Cancer Registry and controls from the Population Registry. Information on reimbursed CIDs was linked to clinicopathological data including Merkel cell polyomavirus (MCV) status by qPCR and immunohistochemistry for the large T antigen of MCV (LTA), Ki-67 and tumour-infiltrating lymphocytes. Results: Chronic inflammatory disorders increased the risk of MCC significantly (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.03–1.88), specifically connective tissue/systemic diseases (OR 1.75, 95% CI 1.09–1.80) and diabetic conditions (OR 1.51, 95% CI 1.03–2.22). Chronic inflammatory disorders associated with larger tumour diameter (P=0.02) and higher Ki-67 expression (P=0.005). The expression of LTA was seen significantly more often in the absence of CIDs (P=0.05). Conclusions: Patients with CID are at significantly higher risk for aggressive MCC. Merkel cell polyomavirus positivity is more common in MCC patients unafflicted by CID.

Background The primary neuroendocrine skin cancer, Merkel cell carcinoma (MCC), has a well-known predilection to metastasize systemically. However, the experience of systemic metastases in MCC is mainly disseminated through case reports due to the rarity of MCC. Purpose To elucidate the frequency and locations of systemic metastasis in MCC by reviewing the imaging of patients with metastatic MCC in a national cohort. Material and Methods Patients with diagnosed metastatic MCC by imaging studies in Finland during 1999–2012 were included in this study. We reviewed their imaging studies to evaluate the most frequent sites for systemic metastasis and determined the latency between the primary tumor diagnosis and systemic metastasis. The material includes 30 MCC patients with complete imaging series and 187 examinations, of which 102 (54%) were CT images. Results The mean latency from the primary tumor diagnosis to systemic metastasis was 2.1 years and the mean latency between the radiologic diagnosis of the metastases and death was 299 days. Metastases were recorded in several organ systems in most of the cases, and at least two separate metastatic sites in 63% of the cases. Metastatic spread was noted in 60% of the cases in distant lymph nodes. Liver and lungs were the most affected solid organs. Conclusion Systemic metastasis in MCC has no predilection site, basically every organ system can be involved. Most of the systemic metastases were recorded during the first two years after the MCC diagnosis.

Clear cell papillary renal cell carcinoma (CCPRCC) is a recently recognised neoplasm with a broad spectrum of morphological characteristics, thus representing a challenging differential diagnosis, especially with the low malignant potential multicystic renal cell neoplasms and clear cell renal cell carcinoma. We selected 14 cases of CCPRCC with a wide spectrum of morphological features diagnosed on morphology and CK7 immunoreactivity and analysed them using a panel of immunohistochemical markers, focusing on 34 beta E12 and related CKs 1,5,10 and 14 and several molecular analyses such as fluorescence in situ hybridisation (FISH), array comparative genomic hybridisation (aCGH), VHL methylation, VHL and TCEB1 sequencing and multiplex ligation-dependent probe amplification (MLPA). Twelve of 13 (92%) CCPRCC tumours were positive for 34 beta E12. One tumour without 3p alteration by FISH revealed VHL mutation and 3p deletion at aCGH; thus, it was re-classified as clear cell RCC. We concluded that: (1) immunohistochemical expression of CK7 is necessary for diagnostic purposes, but may not be sufficient to identify CCPRCC, while 34 beta E12, in part due to the presence of CK14 antigen expression, can be extremely useful for the recognition of this tumour; and (2) further molecular analysis of chromosome 3p should be considered to support of CCPRCC diagnosis, when FISH analysis does not evidence the common loss of chromosome 3p.

Malignant tumours are the foremost complications of immunosuppressive treatment. They are a major challenge for organ transplant recipients and their treating physicians. This paper reviews the aetiology and current treatment of an unusual neuroendocrine skin cancer, Merkel cell carcinoma (MCC), caused by a Merkel cell polyomavirus infection. MCC occurs more frequently than expected in immunosuppressed subjects, especially in organ transplant recipients. The current literature comprises reports of 79 organ transplant recipients with MCC. The risk of MCC in organ transplant recipients is increased up to 66-182-fold compared with the general population. In addition to the increased risk of developing MCC, immunosuppressed individuals have poorer MCC-specific survival. The aim of this review article is to familiarize organ transplant doctors with this unique and clinically challenging skin cancer, and to provide recent data on the diagnosis and current treatment recommendations for an immunosuppressed population.

Merkel cell polyomavirus (MCV) infection underlies most Merkel cell carcinoma (MCC), a primary neuroendocrine carcinoma of the skin. While previous research has focused on MCV-positive MCC tumors, less is known about the oncogenesis in MCV-negative tumors. In this study, we analyzed mutational status of 27 MCC tumors with known MCV status for hotspot regions of 50 cancer-related genes by targeted next-generation sequencing using the Ion AmpliSeq Cancer Hotspot Panel. In addition to previously reported TP53 , KIT , and PIK3CA gene mutations, we found somatic mutations in the tyrosine kinase domain of the EGFR gene in a small proportion of the cells in six tumor tissues. RB1 mutations were seen only in virus negative tumors. Hotspot mutations were more frequent in MCV-negative tumors, although the difference was not statistically significant. No clear hotspot mutation profile was observed. Novel RB1 mutations were detected only in MCV-negative tumors.

cited By 0 Myxoinflammatory fibroblastic sarcoma is a soft-tissue neoplasm most frequently found in the distal extremities of middle-aged adults. Most myxoinflammatory fibroblastic sarcoma are low-grade tumors with propensity for local recurrence after incomplete removal. We report a myxoinflammatory fibroblastic sarcoma which developed in the foot of a 41-year-old male and showed an exceptionally aggressive course with metastatic spread and fatal outcome within 16 months. We managed to establish a spontaneously transformed continuous cell line, called JU-PI, from a metastatic lesion. The JU-PI cells have a sub-tetraploid karyotype including the 1;10 chromosomal translocation and amplification of the proximal end of 3p; these features are considered genetic signatures of myxoinflammatory fibroblastic sarcoma. Both the primary tumor and the JU-PI cells showed nuclear expression of the TFE3 transcription factor but TFE3-activating chromosomal rearrangements were not found. To our knowledge, JU-PI is the first established myxoinflammatory fibroblastic sarcoma cell line. JU-PI cells offer a tool for investigating the molecular oncology of myxoinflammatory fibroblastic sarcoma. © 2018, © The Author(s) 2018.

Background Mediator is a multiprotein interface between eukaryotic gene-specific transcription factors and RNA polymerase II. Mutations in exon 2 of the gene encoding MED12, a key subunit of the regulatory kinase module in Mediator, are extremely frequent in uterine leiomyomas, breast fibroadenomas, and phyllodes tumors. These mutations disrupt kinase module interactions and lead to diminished Mediator-associated kinase activity. MED12 mutations in exon 26, resulting in a substitution of leucine 1224 to phenylalanine (L1224F), have been recurrently observed in prostate cancer. Methods To elucidate the molecular mechanisms leading to tumorigenesis in prostate cancer, we analyzed global interaction profiles of wild-type and L1224F mutant MED12 with quantitative affinity purification-mass spectrometry (AP-MS). Immunoprecipitation and kinase activity assay were used to further assess the interactions between Mediator complex subunits and kinase activity. The presence of L1224F mutation was analyzed in altogether 877 samples representing prostate hyperplasia, prostate cancer, and various tumor types in which somatic MED12 mutations have previously been observed. Results In contrast to N-terminal MED12 mutations observed in uterine leiomyomas, the L1224F mutation compromises neither the interaction of MED12 with kinase module subunits Cyclin C and CDK8/19 nor Mediator-associated CDK activity. Instead, the L1224F mutation was shown to affect interactions between MED12 and other Mediator components (MED1, MED13, MED13L, MED14, MED15, MED17, and MED24). Mutation screening revealed one mutation in a Finnish (Caucasian) prostate cancer patient, whereas no mutations in any other tumor type were observed. Conclusions Specific somatic MED12 mutations in prostate cancer and uterine leiomyomas accumulate in two separate regions of the gene and promote tumorigenesis through clearly distinct mechanisms. Prostate © 2015 Wiley Periodicals, Inc.

Merkel cell polyomavirus (MCV) is frequently detectable in Merkel cell carcinoma (MCC) tumors, but the significance of MCV infection is not yet totally understood. Thus far, no key regulatory miRNA has been identified for MCC tumorigenesis. However, distinct miRNA expression profiles have been suggested for MCV-positive and MCV-negative tumors. We used microarray hybridization to identify miRNA expression differences in MCC tumor samples according to MCV status and further validated these results by quantitative reverse transcription polymerase chain reaction (qRT-PCR). When compared with MCV-negative tumors, we detected overexpression of miR-34a, miR-30a, miR-142-3p, and miR-1539 in those MCV positives. In addition, slight underexpression was detectable in MCV-positive tumors of miR-181d. We confirmed the distinct expression of miRNAs in MCV-positive and MCV-negative tumors and confirmed statistically significant underexpression of miR-34a in MCV-negative tumors by both array analysis and qRT-PCR. Neither tumor location nor development of metastases affected miRNA expression.

Desmoid tumours are uncommon non-malignant tumours that show a locally aggressive growth pattern and a high local recurrence rate after surgery. Approximately 10% of the desmoid tumours are associated with familial adenomatous polyposis (FAP). Variable natural history of the disease challenges treatment decision-making in the absence of prospective, randomised data. Association of this rare tumour to GIST is speculated and the tumorigenesis may share common steps. This study reviews given treatment and reports prognostic factors for local control and concurrent neoplasms in patients evaluated by a single soft tissue tumour group. Patients referred to the soft tissue tumour group at Helsinki University Central Hospital (HUCH) for a desmoid tumour (primary or recurred) during 1987-2007 and receiving surgical treatment with or without adjuvant treatment were included in this retrospective review. All locations and also patients with a FAP-associated tumour were included. Extra-abdominal location showed lower local control despite the fact that 27% of patients also received radiation therapy. One amputation was performed. Female sex and location in the rectus abdominis muscle predicted improved local control in multivariate analysis. In this review, the occurrence (14%) of concurrent neoplasms was higher than expected with unusual tumour types noted including two GISTs. In those patients in whom surgical treatment is chosen, adjuvant radiation therapy should also be considered in order to decrease morbidity from aggressive surgery aiming at R0 resection. Further studies are suggested to illuminate the biological association between the desmoid tumour and other neoplasms.

Background: Prokineticin-1 (PROK1) and prokineticin-2 (PROK2) are chemokine-like proteins that may influence cancer growth by regulating host defence and angiogenesis. Their significance in viral infection-associated cancer is incompletely understood. We studied prokineticins in Merkel cell carcinoma (MCC), a skin cancer linked with Merkel cell polyomavirus (MCPyV) infection. Methods: Carcinoma cell expression of PROK1 and PROK2 and their receptors (PROKR1 and PROKR2) was investigated with immunohistochemistry, and tumour PROK1 and PROK2 mRNA content with quantitative PCR from 98 MCCs. Subsets of tumour infiltrating leukocytes were identified using immunohistochemistry. Results: Merkel cell polyomavirus-positive MCCs had higher than the median PROK2 mRNA content, whereas MCPyV-negative MCCs contained frequently PROK1 mRNA. Cancers with high tumour PROK2 mRNA content had high counts of tumour infiltrating macrophages (CD68+ and CD163+ cells). Patients with higher than the median PROK2 mRNA content had 44.9% 5-year survival compared with 23.5% among those with a smaller content (hazard ratio (HR): 0.53; 95% confidence interval (CI): 0.34–0.84; P=0.005), whereas the presence of PROK1 mRNA in tumour was associated with unfavourable survival (P=0.052). Conclusions: The results suggest that prokineticins are associated with MCPyV infection and participate in regulation of the immune response in MCC, and may influence outcome of MCC patients.

Statins (HMG-CoA-reductase inhibitors) are suggested to act as a predisposing factor for autoimmune diseases, have immunomodulatory effects, and possibly prevent some cancer types - the sum of these effects is unknown in cancers of viral aetiology, such as Merkel cell carcinoma (MCC). Aim of our study was to find out whether statin users in Finland have an increased incidence of MCC.A cohort of 224715 male and 230220 female statin users during 1994-2007 was identified from the Prescription Register of the National Social Insurance Institution. This cohort was followed up through the Finnish Cancer Registry for MCC up to 2009.There were altogether 50 cases of MCCs, while the expected number of cases, calculated on the basis of the MCC incidence in comparable Finnish population, was 39.9 (SIR 1.25, 95% CI 0.93-1.65). The standardized incidence ratio (SIR) for MCC in ages60 years was 3.16 (95% CI 0.65-9.23), in ages 60-74 years 1.94 (95% CI 1.23-2.90) and in ages ≥75 years 0.89 (95% CI 0.57-1.31). The relative risk of MCC decreased significantly, 0.79 fold (95% CI 0.67-0.92), at each 5 year step when moving towards older age groups. There was no significant variation in SIR related to years since starting the statin use, or between the genders.MCC is the first neuroendocrine cancer linked to statin use. The association is statistically significant and biologically plausible through immunomodulatory effects of statins. The excess of MCCs was observed in atypically young patients, a similar phenomenon as noted earlier in patients with immunocompromising states.

Merkel cell carcinoma (MCC) is an aggressive dermal tumour of neuroendocrine origin. The recently found Merkel cell polyomavirus (MCV) integrates clonally in the tumour genome, which suggests an important role in the pathogenesis of the disease. Previous small-scale studies have detected anti-apoptotic protein bcl-2 in 80 % of MCC tumours, but its correlation to the prognosis of MCC remains controversial. Our aim was to clarify the correlation of immunohistochemical expression of bcl-2 to MCV presence and MCC prognosis. We analyzed 116 primary MCC specimens with corresponding clinical data by immunohistochemistry for bcl-2. The presence of MCV DNA had been analyzed by quantitative PCR for 108 tumours. The correlations were analyzed statistically. Of the primary MCC samples, 85 % were bcl-2 positive. No significant differences in MCV DNA occurred between the bcl-2-positive and bcl-2-negative tumours. Local and systemic metastasis was more common in patients with bcl-2 negative tumours (33 %) than in patients with bcl-2-positive tumours (12 %; p = 0.04) at the time of diagnosis. The mean overall survival was higher in patients with bcl-2-positive tumours than of those with negative tumours (mean survival 1,814 days (5.0 years) vs. 769 days (2.1 years), p = 0.01). Bcl-2 positivity indicates better clinical stage at the time of diagnosis and a longer survival in MCC.

Purpose: Merkel cell carcinoma (MCC) is a rare skin cancer that often harbors Merkel cell polyomavirus (MCPyV) DNA. The clinical importance of intratumoral immune cells and their associations with MCPyV infection are poorly understood. Experimental Design: We identified T lymphocytes (CD3-positive cells), T-cell subsets (CD4, CD8, and FoxP3-positive cells), natural killer cells (small CD16-positive cells), and macrophages (CD68 and CD163-positive cells) in tumors of 116 individuals diagnosed with MCC in Finland from 1979 to 2004 using immunohistochemistry and detected MCPyV DNA with quantitative PCR. The associations between immune cell counts, MCPyV DNA, patient and tumor characteristics, and patient outcome were examined. Results: MCPyV DNA-positive cancers contained higher numbers of CD3+, CD8+, CD16+, FoxP3+, and CD68+ cells as compared with MCPyV DNA-negative carcinomas (all P values < 0.05). High intratumoral numbers of CD3+, CD8+, or FoxP3+ cells, and high CD8+/CD4+ or FoxP3+/CD4+ ratios, were significantly associated with favorable overall survival. Individuals with a high tumor CD3+ count had metastases less often and survived longer, irrespective of the tumor MCPyV status. Tumor CD3+ count and MCPyV DNA status had independent influence on survival in a Cox multivariable model that also included presence of locoregional metastases at diagnosis and gender as covariates. Conclusions: High intratumoral T-lymphocyte counts are associated with favorable survival in MCC. Although the numbers of T cells are generally higher in MCPyV-positive than in MCPyV-negative MCC, high intratumoral T-cell counts are also associated with favorable survival in MCPyV-negative MCC. Clin Cancer Res; 18(10); 2872–81. ©2012 AACR.

Background Merkel cell carcinoma (MCC) is a rare malignancy of the skin, and its incidence is reported to be rising. The purpose of this study was to calculate its incidence and survival ratios, and to describe the clinical characteristics of Merkel cell carcinoma patients in Finland. Methods We calculated the incidence of MCC based on data from the Finnish Cancer Registry. In addition, patient files from hospitals and primary health care centres were reviewed for detailed data on the treatment and disease recurrence of 181 patients diagnosed with MCC in Finland during 1983–2004, and relative survival ratios were calculated for them. Results The incidence (per 100,000) of MCC in Finland in 1989–2008 was 0.11 for men and 0.12 for women, adjusted for age to the world standard population. The mean age at diagnosis was 76 years (range 27–100), and 69% of the patients were women. The most common site of the primary tumour was the head and neck (53%). No extra benefit was gained from a wide surgical margin (⩾2 cm) compared to a margin of 0.1–0.19 cm, but an intralesional excision was more often associated with local recurrence. None of the patients with Stage I–II disease who had received postoperative radiotherapy to the tumour bed had a local recurrence. The 5-year relative survival ratio amongst men was 36% (95% confidence interval 20–54%), and amongst women 69% (56 to −82%). Conclusions MCC is a rare disease in Finland, with incidence rates similar to those in the other Nordic countries. Our results support the view that complete excision with clear margins and post operative radiotherapy decrease local recurrences.

BACKGROUND: We developed a web-based, prognostic tool for extremity and trunk wall soft tissue sarcoma to predict 10-year sarcoma-specific survival. External validation was performed. METHODS: Patients referred during 1987-2002 to Helsinki University Central Hospital are included. External validation was obtained from the Lund University Hospital register. Cox proportional hazards models were fitted with the Helsinki data. The previously described model (SIN) includes size, necrosis, and vascular invasion. The extended model (SAM) includes the SIN factors and in addition depth, location, grade, and size on a continuous scale. Models were statistically compared according to accuracy (area under the ROC curve = AUC) of 10-year sarcoma-specific survival prediction. RESULTS: The AUC of the SAM model in 10-year survival prediction in the Helsinki patient series was 0.81 as compared with 0.74 for the SIN model (P = 0.0007). The corresponding AUCs in the external validation series were 0.77 for the SAM model and 0.73 for the SIN model (P = 0.03). A web-based calculator for the SAM model is available at http://www.prognomics.org/sam. CONCLUSION: Addition of grade, depth, and location as well as tumour size on a continuous scale significantly improved the accuracy of the prognostic model when compared with a model that includes only size, necrosis, and vascular invasion. British Journal of Cancer (2012) 106, 1076-1082. doi:10.1038/bjc.2012.48 www.bjcancer.com Published online 21 February 2012 (C) 2012 Cancer Research UK

A prospective diagnostics and treatment protocol for extremity and trunk wall soft tissue sarcoma (STS) was introduced by the Scandinavian Sarcoma Group in 1986 and it was also widely adopted in Finland. We have updated the protocol and made it more detailed at the Helsinki University Central Hospital. We retrospectively compared diagnostics and treatment of STS in a nationwide population-based material to this protocol with special emphasis on local control.Data for 219 patients with an STS of extremity or trunk wall diagnosed during 1998-2001 was retrieved from the nationwide Finnish Cancer Registry. Histologic review was performed. Treatment centres were divided into high-, intermediate- and low-volume centres based on the number of patients with final surgery during the study period.Significantly more patients were operated with a preoperative histological or cytological diagnosis at high-volume centres. No preoperative diagnosis was a strong predictor for the patient to undergo more than one operation (p0.0001). Wide surgical margin was achieved more often at high-volume centres, but in all centre categories a considerable percentage of patients with inadequate surgical margin did not receive adjuvant radiation therapy. Local control at five years was 82% at high-volume centres, 61% at intermediate-volume centres treating highest percentage of deep tumours and 69% at low-volume centres (p = 0.046). Local control improved as the number of patients operated (surgical volume of the centre) increased.The present quality-control study is the first nationwide population-based study to assess diagnostics and treatment of STS. When referred to a specialised sarcoma centre even patients with inadequate surgery can achieve good local control. STS is a rare cancer and its treatment should be centralised in Finland, which has 5.4 million inhabitants and approximately 100 new STSs of extremities and trunk wall annually.

Patients diagnosed with osteosarcoma in Finland during 1991-2005 were retrospectively analyzed in a nationwide, population-based study. We focused on the incidence, treatment and outcome of osteosarcoma patients. We also evaluated the value of known prognostic parameters.Osteosarcomas were retrieved from the files of the national Finnish Cancer Registry. Only patients with histologically confirmed osteosarcoma were included in the analysis. Histological review was performed.The study consists of 144 osteosarcoma patients with a mean follow-up of 9.8 years for survivors. Mean annual incidence of histologically confirmed osteosarcoma was 1.8 new osteosarcomas per million. The 10-year sarcoma-specific survival for the whole population was 63% and 73% for patients with local disease at presentation. Overall limb-salvage rate was 73% and local control was 84% for patients with a peripheral tumor. Development of local recurrence and major deviation from the chemotherapy protocol were significant adverse factors for sarcoma-specific survival in multivariate analysis.The present nationwide and population-based study is our second report of treatment and prognosis of osteosarcoma in Finland. With modern chemotherapy the prognosis of local osteosarcoma has improved in Finland from 47% during 1971-1980 and 65% during 1981-1990 at five years to the present 73% during 1991-2005 at 10 years. The 10-year sarcoma-specific survival of 73% is excellent and comparable to results reported with contemporary treatment protocols in high-volume centers. However, improvement in limb-salvage rate and local control probably requires centralization of treatment of this rare disease.

Introduction Little is known about blood flow in sarcomas. Our purpose was to study glucose metabolism and blood flow in untreated localized musculoskeletal tumors of the extremities using [ 18 F]fluorodeoxyglucose (FDG), oxygen-15 labeled water ([15O]H 2 O) and positron emission tomography (PET). Methods Six patients with high-grade osteosarcoma (OS), two with soft-tissue sarcoma (STS) and one with aneurysmal bone cyst had PET studies with [15O]H 2 O and FDG. Arterial blood sampling and autoradiography calculation method were used to define blood flow as milliliters per 100 g times minutes. Tumor FDG uptake was measured as standardized uptake values (SUVs) and regional metabolic rates for FDG (rMRFDG). Two patients also had FDG PET studies during (one patient) and after (two patients) preoperative chemotherapy. All patients underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The PET findings were compared with the clinical follow-up data and results of DCE-MRI. Results Blood flow in bone tumors was 31.7–75.2 ml/(100 g×min) and in STS 9.0–45.9 ml/(100 g×min). [ 18 F]-Fluorodeoxyglucose uptake and rMRFDG in untreated bone tumors were 5.4–18.4 and 10.9–57.4 μmol/100 g/min, respectively. [ 18 F]-Fluorodeoxyglucose uptake and rMRFDG in STS were 2.6–11.5 and 5.6–32.2 μmol/100 g/min, respectively. Four of five sarcomas with SUV>9.0 have already relapsed. High blood flow in untreated OS was related to long overall survival, while the predictive power of glucose metabolism was less apparent. Good histopathological response to therapy was not associated with long survival. Conclusions Measurement of blood flow in musculoskeletal tumors appears to be feasible by PET and [ 15 O]H 2 O. The influence of tumor blood flow and glucose metabolism on the final outcome in sarcoma is variable and needs further research.

Undifferentiated pleomorphic sarcoma of bone (UPSb) is a rare tumor often difficult to differentiate from fibrosarcoma of bone (FSb), diagnostically. We applied array comparative genomic hybridization (array CGH) to screen for genes with potential importance in the tumor and compared the results with alterations seen in FSb. Twenty-two fresh frozen tissue specimens from 20 patients (18 primary tumors and 4 local recurrences) with UPSb were studied. DNA was isolated and hybridized onto Agilent 244K CGH oligoarrays. The hybridization data were analyzed using Agilent DNA Analytics Software. The number of changes ranged from 2 to 168 (average ¼ 66). Losses were most frequently seen at 8p, 9p, 10, 13q, and 18q, and gains at 4q, 5p, 6p, 7p, 8q, 12p, 14q, 17q, 19p, 20q, 22q, and X. Homozygous deletions of CDKN2A, RB1, TP53, and ING1 were seen in 8/20, 7/20, 3/20, and 2/20 cases, respectively. Hypermethylation of both p16 INK4a and p14 ARF was found in two cases with loss at CDKN2A. Inactivation either of CDKN2A, RB1 ,o rTP53 was detected in 18/20 cases. One case showed high level gains of CDK4 and MDM2. Frequent gains were seen at MYC, PDGFRA, KIT, and KDR. Immunohistochemical positivity of KIT, PDGFRA, KDR, and PDGFRB was found in 8/14, 5/14, 4/14, and 4/14 cases, respectively. The regions most significantly discriminating between UPSb and FSb included RB1 and MYC. No homozygous deletions of RB1 were found in FSb. In conclusion, our analysis showed the disruption of G1/S checkpoint regulation to be crucial for the oncogenesis of UPSb. V C 2011 Wiley-Liss, Inc.

Most Merkel cell carcinomas (MCCs) contain Merkel cell polyomavirus (MCPyV) DNA, and the virus likely has a pivotal role in tumor pathogenesis. p53 and the KIT receptor tyrosine kinase have also been implicated in MCC pathogenesis, but little is known about their association with MCPyV infection. We identified 207 patients diagnosed with MCC in Finland in 1979-2004 and reviewed the histological diagnoses. Adequate clinical information, tumor tissue and DNA were available from 87 confirmed MCC cases. Presence of MCPyV DNA was assessed using quantitative PCR; p53, KIT, phospho-KIT, stem cell factor (SCF) and PDGFRα expression using immunohistochemistry and presence of mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 10, 12, 14 and 18 using DNA sequencing. Most (77.0%) of the 87 tumors contained MCPyV DNA and 37 (42.5%) expressed KIT, whereas PDGFRα, p53, SCF and pKIT expression was less common (31.9, 22.8, 8.6 and 4.8%, respectively). No KIT or PFGFRA mutations were detected, but 10 (12.5%) of the 80 tumors studied harbored common PDGFRA exon 10 S478P substitution. Tumor p53 and KIT expression were associated with absence of MCPyV DNA (p = 0.01 and 0.009, respectively). Tumor p53 expression was associated with unfavorable MCC-specific survival (p = 0.021) and overall survival (p = 0.046), but tumor KIT expression only when stratified by presence of MCPyV DNA. The results suggest that p53 and KIT expression are associated with absence of MCPyV DNA in MCC, and that the molecular pathogenesis of MCC is multifactorial.

This study investigated vascular and especially lymphovascular invasion in primary Merkel cell carcinoma and its value as a prognostic factor. Paraffin-embedded blocks prepared from tumor samples obtained from 126 patients diagnosed with Merkel cell carcinoma in 1979-2004 were immunohistochemically stained using antibodies CD31 and D2-40 to detect intravascular tumor emboli. This finding was compared with the clinical data and the disease outcome. Intravascular tumor cells were observed in 117 (93%) of the samples. The majority, 83 (66%), showed only lymphovascular invasion. Only blood vascular invasion was seen in four (3%) samples. In all, 30 (24%) samples demonstrated both lymphovascular invasion and blood vascular invasion. In only nine (7%) samples, there was no invasion within the vascular structures. The tumors lacking invasion were significantly smaller (P0.01 and alpha=0.050) than those with vascular invasion, although lymphovascular invasion was observed even in the smallest tumor (0.3 cm) of this study. Already in the early stages of the disease, Merkel cell carcinoma seems to have the capacity to penetrate vessel walls. Our finding of the high frequency of lymphovascular invasion might therefore explain the extremely aggressive clinical behavior of Merkel cell carcinoma. This may support the role of sentinel node biopsy even in the case of very small primary Merkel cell carcinoma tumors.

The aim of the present study was to investigate whether the expression of ezrin, a membrane-cytoskeleton linker and regulator of cellular signaling, is associated with clinical features of chondrosarcoma. For this purpose, we studied the expression of ezrin in 54 chondrosarcomas by immunohistochemistry and correlated the expression with other tumor characteristics, markers of proliferation, apoptosis and with clinical parameters. The intensity of ezrin staining increased with the histologic grade, and a significant positive association existed between the tumor grade and ezrin expression (p = 0.0475). In addition, there was a positive correlation between the expression of ezrin and Bcl-2, an anti-apoptotic protein (r = 0.83, p < 0.0001), as well as between ezrin expression and increased proliferation as measured by Ki-67 index (r = 0.70, p < 0.0001). The positive correlation of ezrin expression with Bcl-2 and Ki-67 as well as with tumor grade suggests that an aggressive behavior of chondrosarcoma may be related to activation of ezrin and that ezrin inhibitors could provide a much needed adjuvant therapy in chondrosarcomas. In conclusion, our results indicate that high ezrin expression correlates with aggressive features of chondrosarcomas. Further analyses on the pathways downstream of ezrin are warranted.

Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma typically affecting the elderly. Only 5% to 10% of the patients are younger than 50 years at the time of the diagnosis. The purpose of this study was to compare the tumour and disease characteristics between exceptionally young and the typical elderly MCC population. Further, quantitative polymerase chain reaction analysis was used to study for Merkel cell polyomavirus (MCPyV) in their primary MCC tumours. Patients diagnosed with MCC in Finland from 1979 to 2004 were identified from the files of the Finnish Cancer Registry. Presence of MCPyV DNA in tumour samples was investigated using quantitative polymerase chain reaction. Six of 181 MCC patients were ≤50 years, with male-to-female ratio of 1:1. An altered immune condition state was observed in five patients. The Kaplan–Meier analysis showed a trend towards worse MCC-specific survival both in 5- and 10-year surveillance for younger patients. Five primary tumour tissue samples, available for analysis, contained MCPyV DNA. Our data shows that MCC, ≤50 years of age, is rarer then previously estimated. Moreover, our data showed marked differences both in patient demographics and in primary tumour characteristics as compared to surveys including older MCC patients. Course of disease seemed to be worse in the exceptionally young patients. All MCC primary tumours in this study contained MCPyV DNA.

Very little is known about the genetics of fibrosarcoma (FS) of bone. We applied array comparative genomic hybridization (CGH) to identify genes and genomic regions with potential role in the pathogenesis of this tumor. Seventeen patients with FS of bone were included in the study. Array CGH analysis was carried out in 13 fresh frozen tissue specimens from 11 of these patients (nine primary tumors and four local recurrences). DNA was extracted and hybridizations were performed on Agilent 244K CGH oligoarrays. The data were analyzed using Agilent DNA Analytics Software. The number of changes per patient ranged from 0 to 132 (average = 43). Losses were most commonly detected at 6q, 8p, 9p, 10, 13q, and 20p. CDKN2A was homozygously deleted in 7/11 patients. Hypermethylation of both p16(INK4a) and p14(ARF) was found in 1/14 patients. An internal deletion of STARD13 was found in a region with common losses at 13q13.1. The most frequent gains were seen at 1q, 4q, 5p, 8q, 12p, 15q, 16q, 17q, 20q, 22q, and Xp. Single recurrent high level amplification was detected at 4q12, including KIT, PDGFRA, and KDR. No activating mutations were found in any of them. Immunohistochemistry revealed expression of PDGFRA and/or PDGFRB in 12/17 samples. Moreover, small regions of gains pinpointed genes of particular interest, such as IGF1R at 15q26.3 and CHD1L at 1q21.1. In conclusion, our analysis provided novel findings that can be exploited when searching for markers for diagnosis and prognosis, and targets of therapy in this tumor type.

Background: Immunosuppression and Merkel-cell polyomavirus (MCPyV) infection may have a role in the pathogenesis of Merkel-cell carcinoma (MCC), a rare neuroendocrine carcinoma of the skin. Methods: We studied incidence of chronic lymphocytic leukaemia (CLL) and MCC from the files of the Finnish Cancer Registry and the largest hospital of Finland, Helsinki University Central Hospital, from 1979 to 2006. Presence of MCPyV DNA in MCCs was investigated by quantitative PCR. Results: We identified 4164 patients diagnosed with CLL and 172 diagnosed with MCC. Six patients diagnosed with both diseases were found; CLL was the first diagnosis in four cases and MCC in two. The standardised incidence ratio (SIR) for CLL after the diagnosis of MCC was highly elevated, 17.9 (95% confidence interval (CI), 2.2–64.6; P

Leiomyosarcoma (LMS) is the third most common type of soft tissue sarcoma after malignant fibrous histiocytoma (MFH) and liposarcoma. Comparative genomic hybridization (CGH) has shown similar DNA copy number imbalances in LMS and MFH. It has been suggested that both tumors may correspond to different differentiation states of a single tumor entity and that a large proportion of MFHs could correspond to undifferentiated LMS. We report CGH results from 102 MFH and 82 LMS cases, as well as a subsequent clustering analysis. The distribution pattern of DNA copy number changes could not differentiate LMS from MFH, suggesting that most MFHs could represent an ultimate state of tumor progression of LMS. Even if an oncogenic pattern common to LMS and MFH is valid, the genes relevant to smooth muscle cell differentiation may reside in one or more chromosomal imbalances that are not shared by both tumor types. Further explorative analysis identified a small cluster of tumors (9% of the samples: 2 LMS and 10 MFH) characterized by the presence of high-level amplifications at 1p33 approximately p34.3, 17q22 approximately q23, 17q25 approximately qter, 19p, 22p, and 22q, and associated with a higher proportion of tumors located in the thigh (P=0.003) and with male sex (P=0.079).

Introduction Despite the diagnostic advancements, some clinically important diagnoses remain undetected during intensive care in burn patients. The aim of this study was to compare the premortem clinical diagnoses and autopsy findings. Patients and methods A retrospective review of all burn deaths during 1995–2005 was conducted. The clinical diagnoses and autopsy reports were reviewed, and diagnostic discrepancies were classified into four categories, according to the impact on the treatment. Results Overall mortality during the study period was 5.4%. Altogether 74 deaths were recorded, of which 71 were included in the study. Typical patient was a 58-year-old male with flame burn of %TBSA 49, ABSI 10. Clinical diagnostic discrepancies were found in 14.1% of the patients; one diagnostic discrepancy was recorded in each of the patients. Of these diagnostic discrepancies, 8.5% were considered major, and 5.6% would have altered the clinical outcome or therapy, if known at the time. Diagnostic discrepancies consisted of one cardiovascular, seven respiratory and two gastrointestinal missed diagnosis. The most common missed diagnosis was pneumonia. Conclusion This study emphasizes the usefulness of autopsies to provide valuable clinical data for the treatment of burn patients. It also highlights the few missed diagnoses which may occur in burn patients.

There have only been a few nationwide studies on the epidemiology and outcome of osteosarcoma. We report the clinical features, treatment, and prognosis of osteosarcoma in Finland for the period 1971-1990.The study material was derived from population-based data from the national Finnish Cancer Registry. 302 osteosarcomas were reported during the study period. Histological slides could be retrieved for 199 cases and from histological re-examination, 139 (83%) of these cases were confirmed as osteosarcoma and were included in the analysis. The mean length of follow-up was 8 (0.1-28) years.The overall 5-year survival for the whole study population was 58%, with an improvement in survival during 1981-1990 (65%) compared to the period 1971-1980 (47%) (p=0.01). More chemotherapy was administered in the later time period. For metastasis-free survival, diagnosis in the 1970s as opposed to the 1980s (p=0.01) and large tumor size worsened outcome in univariate analysis. Patients who developed metastatic relapse within 10 months of the diagnosis had worse sarcoma-specific survival than those who developed metastases later. Limb-salvage surgery increased from 12% to 23% for patients with a peripheral tumor, with no increase in local relapses.We recommend aggressive approach to treat recurrent disease, with a view to further improving survival. In a small country such as Finland it is necessary to concentrate treatment to only a few centers, to ensure a high quality of treatment.

Background: Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of the skin with a tendency to recur locally after inadequate excision. Treatment has traditionally been wide excision with a 2- to 3-cm gross margin. Because of the variable results presented in mainly retrospective reports, it has been queried whether local control can be as good with conventional surgery as with micrographic surgery. Methods: Forty patients with dermatofibrosarcoma protuberans treated by surgical excision were operated on at our center from 1987 to 2001. Data were recorded prospectively. Twenty-seven patients presented with a primary tumor and 13 with a locally recurrent tumor primarily operated on elsewhere. Gross and histologic margins were studied in detail. Results: At a mean follow-up of 40 months, there were no recurrences. Thirty-four patients required single, five patients two, and one patient three operations before the margins were adequate (mean, 1.2 stages per patient). Twenty-three patients (58 percent) needed reconstructions. Tumor-free margins were obtained in 39 patients. The average thickness of surgical gross margins was 3.1 cm; histologically defined margins averaged 1.6 cm. Conclusions: Good local control can be achieved with wide surgery. Histologic tumor-free margins differ greatly from gross margins and are difficult to assess clinically and macroscopically. Careful postoperative histologic examination with margins measured in millimeters should be carried out to define the adequacy of excision in all directions. On average, a 1.6-cm histologic margin was adequate for complete local control. Most patients can be operated on in one stage. Reconstructions are often needed.

The amplification or gain of the p-arm of chromosome 17 is common in sarcomas, suggesting its role in carcinogenesis. Here, we report the architectural structure and targets of 17p aberrations commonly shared by osteosarcoma (OS), leiomyosarcoma (LMS) and malignant fibrous histiocytoma (MFH) of soft tissue. Two low-grade and two high-grade soft tissue LMS, three OS, and two MFH samples were studied using fine-resolution oligonucleotide-based microarray comparative genomic hybridization. Eight of the nine samples showed a loss of 17pter→p13, the locus of tumor suppressor TP53 preceding the amplified area 17p12→p11.2. The size and detailed architecture of the amplified region of 17p differed between the studied sarcoma entities. OS and high-grade LMS showed similar complex patterns of discontinuous amplifications with regions of gain in between. MFH and low-grade LMS showed continuous regions of gains and amplifications. Precise boundaries of the lost or gained regions were determined, and in addition to the previously suggested targets of the region, ELAC and FLCN were amplified in all the sarcoma entities.

Multiple genetic alterations have been associated with pheochromocytoma (PCC). Most PCCs are sporadic, but they also occur in inherited tumor syndromes, including von Hippel-Lindau disease. Although the etiology of most inherited PCCs is well documented, little is known about the etiology of sporadic tumors. Mutations of those genes that harbor germ-line mutations in familial cases cover only 10% to 15% of somatic mutations in sporadic PCCs. A previous cytogenetic analysis indicated frequent loss of 6q in sporadic PCCs. We therefore investigated in detail 18 PCCs using 22 microsatellite markers spanning 6q to search for the presence of allele deletions and identify specific regions likely to contain tumor suppressor genes involved in PCC. Moreover, we sought to compare PCC with capillary hemangioblastoma, another von Hippel-Lindau disease-associated tumor that we previously found to harbor frequent loss of heterozygosity (LOH) at 6q. Our study revealed a high frequency (13/18; 72%) of overall 6q LOH in PCCs. Loss of heterozygosity at 6q was observed in 6 benign (6/9; 67%) and 7 borderline (7/9; 78%) tumors. We identified 2 regions where LOH or allelic imbalance was common (ie, 6q14 [9/18; 50%] and 6q23-24 [6/18; 33%]). We further focused the search using markers specific for the ZAC1 gene region located at 6q24-25. Altogether, for all 6q23-25 markers, including the ZAC1-specific ones, LOH or allelic imbalance was observed in 50% (9/18) of the PCCs. Similar to our findings for capillary hemangioblastomas, our data for the first time suggest that one or several tumor suppressor genes located at 6q, particularly at 6q23-24, may play a role in the tumorigenesis of PCCs.

DNA copy number changes were investigated in 51 (19 uterine and 32 nonuterine) primary leiomyosarcomas by comparative genomic hybridization. The aim was to evaluate whether true biological differences exist between uterine and nonuterine leiomyosarcoma and whether changes revealed by comparative genomic hybridization have prognostic value. Genomic imbalances were found in 48 (94%) cases. The most frequent DNA copy number changes were losses in 10q (35%), 13q (57%), and 16q (41%), gains in 1q (41%), and gains and high-level amplifications in 17p (39%). Gains were nearly as frequent as losses in both uterine and nonuterine leiomyosarcoma. Correlation-based tree modeling revealed two clusters that segregated significantly a group of uterine (gains at 1q11-q24) and a group of nonuterine (losses at 13q14-q34, 16q11.1-q24, and 10q21-q26) cases. The nonuterine cluster was associated with subcutaneous origin and a trend toward increased metastasis-free survival. Further explorative analyses identified aberrations associated with shorter metastasis-free survival time, including losses at 2q32.1-q37 and gains at 8q24.1-q24.3, whereas the cases with losses at 6cen-p25 showed longer metastasis-free survival time., Facultad de Ciencias Naturales y Museo

Dermatofibrosarcoma protuberans (DFSP) is a rare, slow-growing, low-grade dermal tumor. Cytogenetic and FISH studies have revealed that the chromosomal rearrangements characteristic of DFSP tumors involve both translocations and the formation of a supernumerary ring derived from chromosomes 17 and 22. The t(17;22) (q22;q13.1) translocation generates a gene fusion between COL1A1 and PDGFB, which serves as a diagnostic marker of DFSP. In the present study we performed array-CGH (aCGH) analysis on ten DFSP tumors. The COL1A1 region at 17q was gained in 71% (5/7) of the samples and the PDGFB region at 22q was gained in 43% (3/7) of the individual samples. In addition to the 17q and 22q gains, altogether 17 minimal common regions of gain and one region of loss were detected.

Mutations that may predict response to adenosine 5'-triphosphate (ATP)-mimetic epidermal growth factor receptor (EGFR) inhibitors occur in the EGFR kinase domain in lung adenocarcinomas and bronchioloalveolar carcinomas (BACs). Data on the frequency of EGFR mutations are sparse in other human tumors. Apart from the deletion mutant EGFRvIII, little is known about the frequency of mutations that encode for the EGFR extracellular domains II and IV that participate in receptor dimerization and formation of the tethered (autoinhibited) receptor conformation. We investigated 566 human neoplasms consisting of various histological types for mutations in exons 6, 7 (encode domain II), 14, 15 (domain IV), 18, 19, and 21 (the kinase domain) using denaturing high-performance liquid chromatography (DHPLC). Approximately 4,500 EGFR exons were screened for the presence of a mutation, and samples with an abnormal finding in DHPLC were sequenced. Only one mutation was found in the extracellular domain IV (glioblastoma), and none in domain II. Eight (11%) out of the 40 lung adenocarcinomas, or 33 BACs, investigated had exon 19 or 21 mutation in the kinase domain, but no mutations were found in other tumor types. Most of the lung cancers with mutated EGFR had three to six copies of the mutated gene in fluorescence in situ hybridization. We conclude that mutations of the EGFR kinase domain and the cysteine-rich extracellular domains are infrequent in most types of human cancer apart from lung adenocarcinoma. Mutated EGFR is usually not amplified in lung cancer.