Hans Kristian Haugland

Diagnostic and prognostic markers for gastrointestinal stromal tumors in Norway

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tract. The diagnosis of GIST is based on histology together with a panel of immunohistochemical markers; the most important is KIT (CD117). A total of 434 cases of GISTs were confirmed by histology and immunohistochemistry, and incorporated into tissue microarrays. Validation of histological features as well as the prognostic value of two immunohistochemical biomarkers (p16 and L1) was assessed. High mitotic rate, large tumor size, nuclear atypia, and small bowel primary site were all validated as negative prognostic factors in GISTs. Expression of p16 was significantly correlated with unfavorable prognosis, whereas L1 expression was not.

Genomic Evolution of Breast Cancer Metastasis and Relapse

Summary Patterns of genomic evolution between primary and metastatic breast cancer have not been studied in large numbers, despite patients with metastatic breast cancer having dismal survival. We sequenced whole genomes or a panel of 365 genes on 299 samples from 170 patients with locally relapsed or metastatic breast cancer. Several lines of analysis indicate that clones seeding metastasis or relapse disseminate late from primary tumors, but continue to acquire mutations, mostly accessing the same mutational processes active in the primary tumor. Most distant metastases acquired driver mutations not seen in the primary tumor, drawing from a wider repertoire of cancer genes than early drivers. These include a number of clinically actionable alterations and mutations inactivating SWI-SNF and JAK2-STAT3 pathways.

Time-trends on incidence and survival in a nationwide and unselected cohort of patients with skeletal osteosarcoma

Abstract Background. This study describes time-trends on epidemiology, subtypes and histopathological entities of osteosarcoma (OS) in a nationwide and unselected cohort of OS patients in Norway between 1975 and 2009. Few nationwide studies are published, and we still have particularly limited knowledge regarding patients not included in clinical trials comprising about half of the OS population. Method. Histologically verified skeletal OS for all subgroups were included, resulting in 473 eligible cases from a total of 702 evaluated patients. To ensure completeness, the present cohort was based on all cases reported to the Norwegian Cancer Registry, complemented with data from all Norwegian hospitals involved in sarcoma management. Survival analyses were performed with overall and sarcoma-specific survival as endpoints. Results. Mean annual age-standard incidence amounted to about 3.8 per million in male and 2.8 per million in female with no clear time-trends. The male to female ratio was 1.4. Peak incidence was observed in the second decade for both genders. Conventional OS comprised 71.2% of all cases, while low grade OS represented 10.4% and telangiectatic OS only 1.3%. The most common primary site of OS was femur and tibia, respectively. The axial to appendicular ratio increased with the age. The overall 10-year survival did increase from about 30% during the late 1970s to around 50% 20 years later, with no subsequent improvement during the last two decades. Axial tumours, age above 40 years and overt metastatic disease at time of diagnosis were all negative prognostic factors. Conclusion. No improvement in the overall survival for OS since the 1990s was documented. The survival rates are still poor for elderly people, patients with axial disease and in the primary metastatic setting. The average incidence rate of skeletal OS in Norway was in line with international figures.

Laminin expression by glial fibrillary acidic protein positive cells in human gliomas.

Extracellular matrix components are regarded as important substrates for invasive tumor cells. The present work focuses on the expression of laminin in the brain in response to invading brain tumors. Biopsies obtained from tissue macroscopically evaluated as the border zone between tumor and normal brain, in 5 patients undergoing surgery for glioblastoma multiforme, were examined by immunocytochemistry and scanning confocal microscopy for the expression of laminin and glial fibrillary acidic protein. Laminin was mainly found in all the specimens associated with the basal lamina of blood vessels, but a variable degree of punctate laminin deposits were also observed in the parenchyma not associated with blood vessels. In the specimens with substantial deposits, scanning confocal microscopy showed that some of the laminin co‐localized with intracellular glial fibrillary acidic protein.

Deoxyribonucleic acid ploidy in endometrial carcinoma: a reproducible and valid prognostic marker in a routine diagnostic setting

OBJECTIVE The objective of the study was to investigate the prognostic impact of deoxyribonucleic acid (DNA) ploidy in endometrial carcinoma in a routine diagnostic series as compared with a research series. STUDY DESIGN We studied a population-based series of 363 endometrial carcinomas prospectively collected, with long and complete follow-up. The prognostic value of DNA ploidy was investigated in a routine diagnostic series (n=262) and compared with the results from a previous research series (n=101). RESULTS The proportion of DNA aneuploid tumors was 21% in the research series and 25% in the routine diagnostic series (P=NS). In both series, DNA aneuploidy was significantly correlated to higher age at diagnosis, nonendometrioid subtype, and high histologic grade. Patients with DNA aneuploid tumors had significantly poorer survival, adjusted for established clinicopathologic prognostic factors. CONCLUSION DNA ploidy estimation in endometrial carcinoma adds independent prognostic information in a routine diagnostic setting.

Template reporting matters—a nationwide study on histopathology reporting on colorectal carcinoma resections

Complete and accurate histopathology reports are fundamental in providing quality cancer care. The Cancer Registry of Norway and the Norwegian Society of Pathology have previously developed a national electronic template for histopathology reporting on colorectal carcinoma resection specimens. The present study was undertaken to investigate (1) whether quality routines in Norwegian pathology laboratories might affect completeness of such histopathology reports and (2) whether the national electronic template improves completeness of histopathology reports compared with other modes of reporting. A questionnaire on quality routines was sent to the 21 pathology laboratories in Norway. All histopathology reports on colorectal cancer submitted to the Cancer Registry for a 3-month period in the autumn of 2007 were then evaluated on the mode of reporting and the presence of 11 key parameters. Of the 20 laboratories that handled resection specimens, 16 had written guidelines on histopathology reporting. Of these, 4 used the national electronic template, 5 used checklists, 3 used locally developed electronic templates, whereas the remaining 4 had neither obligatory checklists nor templates. Of the 650 histopathology reports submitted to the Cancer Registry in the 3-month period, the national template had been used in 170 cases (26.2%), checklists/locally developed templates in 112 cases (17.2%), and free text in 368 cases (56.6%). Quality routines in the pathology laboratories clearly governed reporting practice and the completeness of the histopathology reports. Use of the national electronic template significantly improved (P < .05) the presence of the 11 key parameters compared with reporting by checklists, locally developed electronic templates, or free text.

Wear particles and ions from cemented and uncemented titanium-based hip prostheses—A histological and chemical analysis of retrieval material

Wear debris-induced inflammation is considered to be the main cause for periprosthetic osteolysis in total hip replacements (THR). The objective of this retrieval study was to examine the tissue reactions and exposure to metal ions and wear particles in periprosthetic tissues and blood samples from patients with titanium (Ti)-based hip prostheses that were revised due to wear, osteolysis, and/or aseptic loosening. Semiquantitative, histological tissue evaluations in 30 THR-patients revealed numerous wear debris-loaded macrophages, inflammatory cells, and necrosis in both groups. Particle load was highest in tissues adjacent to loosened cemented Ti stems that contained mainly submicron zirconium (Zr) dioxide particles. Particles containing pure Ti and Ti alloy elements were most abundant in tissues near retrieved uncemented cups. Polyethylene particles were also detected, but accounted only for a small portion of the total particle number. The blood concentrations of Ti and Zr were highly elevated in cases with high abrasive wear and osteolysis. Our findings indicate that wear particles of different chemical composition induced similar inflammatory responses, which suggests that particle size and load might be more important than the wear particle composition in periprosthetic inflammation and osteolysis.

Adjuvant radiotherapy in retroperitoneal sarcomas. A Scandinavian Sarcoma Group study of 97 patients

Abstract Background. Currently there is no consensus on the use of adjuvant radiotherapy (RT) in retroperitoneal sarcoma (RPS). We have analysed clinical outcomes in patients with localised RPS treated at two Scandinavian Sarcoma Group (SSG) centres: Haukeland University Hospital (HUH), Bergen, Norway and Skåne University Hospital (SUH), Lund, Sweden to clarify the effects of adjuvant RT on local control and overall survival (OS). Material and methods. Local databases and registers at HUH and SUH as well as the SSG central register were used to identify RPS patients. Patients with localised RPS who underwent surgery in Bergen between 1988 and 2009 and in Lund from 1998 to 2009 were included. Medical records were examined for clinical data, tumour characteristics, treatment factors and follow-up status. Archived tumour sections and tumour tissue were reviewed, and when necessary, restained and reclassified. Cox regression was used to analyse the association of potential prognostic factors with local recurrence-free survival (LRFS), metastasis-free survival (MFS) and OS. Results. The study included 97 patients: 52 from Norway and 45 from Sweden. The proportion of high-grade tumours was 73%. The five-year LRFS, MFS and OS were 55%, 59% and 60%, respectively. RT was significantly associated with improved local control resulting in a five-year LRFS of 77% compared with 39% without (p < 0.001). Furthermore, five-year OS was 71% in the RT group in contrast to 52% with surgery alone (p = 0.019). In the adjusted analysis RT proved to be a significant factor also for MFS (HR = 0.42, 95% CI 0.20–0.88, p = 0.021). In addition, high-grade malignancy, large tumour and positive surgical margin were risk factors for local recurrence. High malignancy grade was the only significant adverse prognostic factor for metastasis. High age and high-grade malignancy were negative prognostic factors for OS. Conclusion. Adjuvant RT was significantly associated with an improved five-year LRFS and OS.

DNA ploidy in curettage specimens identifies high-risk patients and lymph node metastasis in endometrial cancer

Background:Preoperative risk stratification is essential in tailoring endometrial cancer treatment, and biomarkers predicting lymph node metastasis and aggressive disease are aspired in clinical practice. DNA ploidy assessment in hysterectomy specimens is a well-established prognostic marker. DNA ploidy assessment in preoperative curettage specimens is less studied, and in particular in relation to the occurrence of lymph node metastasis.Methods:Curettage image cytometry DNA ploidy in relation to established clinicopathological variables and outcome was investigated in 785 endometrial carcinoma patients prospectively included in the MoMaTEC multicentre trial.Results:Diploid curettage status was found in 72.0%, whereas 28.0% were non-diploid. Non-diploid status significantly correlated with traditional aggressive postoperative clinicopathological features, and was an independent predictor of lymph node metastasis among FIGO stage I–III patients in multivariate analysis (OR 1.94, P=0.033). Non-diploid status was related to shorter disease-specific survival (5-year DSS of 74.4% vs 88.8% for diploid curettage, P<0.001). When stratifying by FIGO stage and lymph node status, the prognostic effect remained. However, in multivariate regression analysis, preoperative histological risk classification was a stronger predictor of DSS than DNA ploidy.Conclusions:Non-diploid curettage is significantly associated with aggressive clinicopathological phenotype, lymph node metastasis, and poor survival in endometrial cancer. The prognostic effect was also observed among subgroups with (presumably) less aggressive traits, such as low FIGO stage and negative lymph node status. Our results indicate curettage DNA ploidy as a possible supplement to existing parameters used to tailor surgical treatment.

Post-PET ultrasound improves specificity of 18F-FDG-PET for recurrent differentiated thyroid cancer while maintaining sensitivity

Background Positron emission tomography (PET) using fluor-18-deoxyglucose (18F-FDG) with or without computed tomography (CT) is generally accepted as the most sensitive imaging modality for diagnosing recurrent differentiated thyroid cancer (DTC) in patients with negative whole body scintigraphy with iodine-131 (I-131). Purpose To assess the potential incremental value of ultrasound (US) over 18F-FDG-PET-CT. Material and Methods Fifty-one consecutive patients with suspected recurrent DTC were prospectively evaluated using the following multimodal imaging protocol: (i) US before PET (pre-US) with or without fine needle biopsy (FNB) of suspicious lesions; (ii) single photon emission computed tomography (≥3 GBq I-131) with co-registered CT (SPECT-CT); (iii) 18F-FDG-PET with co-registered contrast-enhanced CT of the neck; (iv) US in correlation with the other imaging modalities (post-US). Postoperative histology, FNB, and long-term follow-up (median, 2.8 years) were taken as composite gold standard. Results Fifty-eight malignant lesions were identified in 34 patients. Forty lesions were located in the neck or upper mediastinum. On receiver operating characteristics (ROC) analysis, 18F-FDG-PET had a limited lesion-based specificity of 59% at a set sensitivity of 90%. Pre-US had poor sensitivity and specificity of 52% and 53%, respectively, increasing to 85% and 94% on post-US, with knowledge of the PET/CT findings (P < 0.05 vs. PET and pre-US). Multimodal imaging changed therapy in 15 out of 51 patients (30%). Conclusion In patients with suspected recurrent DTC, supplemental targeted US in addition to 18F-FDG-PET-CT increases specificity while maintainin sensitivity, as non-malignant FDG uptake in cervical lesions can be confirmed.