Frequency of primary cutaneous lymphoma variants in Austria: retrospective data from a dermatology referral centre between 2006 and 2013.

BACKGROUND: Primary cutaneous lymphomas (PCL) are a heterogenous group of rare lymphoid neoplasms with incomplete information on global and regional prevalence. The recently introduced lymphoma classifications define distinctive clinicopathological disease entities that should allow for more accurate epidemiological assessment. OBJECTIVE: The aim of this study was to evaluate the prevalence and clinical spectrum of PCL diagnosed and treated at the Department of Dermatology and Venereology in St. Pölten, Lower Austria, a dermatology referral centre providing secondary and tertiary care for a population of about 600 000. METHODS: In this retrospective study pathology reports, electronically archived between 2006 and 2013, were screened for the terms lymphoma, mycosis fungoides (MF) and lymphomatoid papulosis (LyP). Patients were diagnosed according to the current WHO-EORTC classification for cutaneous lymphomas and results were compared with data from European, US and Asian centres. RESULTS: Among 86 patients with PCL (age 58.3 ± 17.35 years, mean ± SD; women 38%, n = 33; men 62%, n = 53) 83% (n = 71) were classified as cutaneous T-cell lymphomas (CTCL) and 17% (n = 15) as cutaneous B-cell lymphomas (CBCL). Nine patients with CTCL showed associated haematological disorders and malignomas. Among 47 MF patients following variants were observed: pilotropic MF (n = 2), follicular mucinosis (n = 1), unilesional MF (n = 1), large-cell transformation (n = 3), erythrodermic MF (n = 1), poikilodermatous MF (n = 2) and posttransplant lymphoproliferative disorder (CD8(+) MF with gamma/delta phenotype after renal transplantation) (n = 1). One patient had MF concurrent with lymphomatoid papulosis. The group of CBCL comprised six cases (40%) of PCMZL and PCFCL each, 20% (n = 3) were classified as PCLBCL, LT. CONCLUSION: This study for the first time provides data on the distribution of PCL clinicopathologic variants and stages according to the latest classification and staging systems in an Austrian referral centre.

Relative survival of patients with non-malignant central nervous system tumours: a descriptive study by the Austrian Brain Tumour Registry.

BACKGROUND: Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival. METHODS: We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival. RESULTS: Overall 5-year relative survival was 96.1% (95% CI 95.1-97.1%), being significantly lower in tumours of borderline (90.2%, 87.2-92.7%) than benign behaviour (97.4%, 96.3-98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%). CONCLUSION: The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.

The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients.

BACKGROUND: ER+/HER2- breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy. METHODS: A total of 1702 postmenopausal ER+/HER2- breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan-Meier method and Cox regression analysis were used in an early (0-5 years) and late time interval (>5 years post diagnosis). RESULTS: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up. CONCLUSION: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer.

BACKGROUND: In early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed. PATIENTS AND METHODS: We assigned risk groups to 1702 ER-positive/HER2-negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan-Meier survival analysis. RESULTS: After 10 years, absolute risk reductions (ARR) between the high- and low-risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%-61% of women classified as high-/intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years. CONCLUSION: The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.

Osteopontin expression in ductal adenocarcinomas and undifferentiated carcinomas of the pancreas.

Osteopontin (OPN) is a non-collagenous extracellular matrix protein with pleiotropic functions, including mediation of cell adhesion and migration. Recently, high OPN serum levels were found in pancreatic ductal adenocarcinomas (PDACs) in which OPN mRNA was identified in macrophages. We investigated OPN expression at the protein level in 15 PDACs and 10 undifferentiated pancreatic carcinomas (UCs), 4 of them with osteoclast-like giant cells (OCGCs), to find out whether the degree of OPN expression is related to tumor infiltration by macrophages and the adhesive capacity of tumor cells. With regard to its potential adhesive function, we compared OPN expression in PDACs and UCs with that of E-cadherin and beta-catenin, two well-known adhesive molecules. OPN positivity was observed in two-thirds of PDACs (10/15) and in 7 UCs (7/10), including all 4 UCs with OCGCs. Apart from tumor cells, OPN was expressed in macrophages and OCGCs. When we assessed the relationship between the number of OPN-positive macrophages and tumor cells, we did not find any statistically significant correlation. There was also no correlation, either positive or negative, between OPN expression and E-cadherin and beta-catenin expression. The results demonstrated that, in PDACs and UCs, OPN is expressed in both tumor-associated macrophages and tumor cells. The biological significance of this dual expression pattern is not yet known. It is, however, unlikely that OPN has an adhesive function, since its expression pattern differs distinctly from that of E-cadherin or beta-catenin.

Pancreatic diseases past and present: a historical examination of exhibition specimens from the Collectio Rokitansky in Vienna.

The Viennese collection of pathological specimens (Collectio Rokitansky) comprises a large number of objects from all fields of pathological anatomy and is one of the largest historical collections in the entire world. We reviewed the original diagnoses in a series of pancreatic specimens using modern histopathological techniques. It was found that the histological structure of eleven pancreatic specimens was surprisingly well preserved. In three cases of extrapancreatic pseudocysts, we identified chronic pancreatitis as the underlying disease. Two specimens contained tumours that proved to be ductal adenocarcinomas. A third, rather large tumour was identified as a solid-pseudopapillary carcinoma and a fourth one as a neuroendocrine carcinoma. The remaining cases were classified as fibrotic atrophy, congenital cysts, microcystic serous cystadenoma, and necrotic sequestration of the pancreas. The application of immunohistochemical methods failed. In conclusion, the surprisingly well-preserved exhibits from the Collectio Rokitansky, which have been on display for more than 100 years, are accessible to modern histopathological investigation without the use of immunohistochemical techniques. Such examinations allow us to assess the occurrence of diseases and tumours in the sociocultural environment of the 19th century.

Prognostic relevance of intracytoplasmic cytokeratin pattern, hormone expression profile, and cell proliferation in pituitary adenomas of akromegalic patients.

Seventy-six pituitary adenomas of akromegalic patients were investigated to find out the prognostic relevance of the intracytoplasmic distribution of cytokeratins (CK), immunohistochemically defined hormone production profile, proliferative activity and clinical presentation. CK distribution, growth fraction (MIB1 index) and hormone production profile were analyzed by means of immunohistochemistry. Apoptotic activity was investigated by the TUNEL method. Two different CK distribution patterns were seen: a dot-like pattern in 29 cases (type 1 adenomas), and a perinuclear fibrillary pattern in 47 cases (type 2 adenomas). Type 2 adenomas showed more prominent coexpression of prolactin (p < 0.0001), luteotrophic hormone (p < 0.002), follicle-stimulating hormone (p < 0.005), thyroid-stimulating hormone (p < 0.0001), and alpha-subunit (p < 0.005), as compared to type 1 adenomas. The mean MIB1 index was significantly higher in type 1 vs. type 2 tumors (4.23%, range: 1.93% - 9.83% vs. 2.07%, range: 0.67% - 4.87%, p < 0.0001). Apoptotic activity was too low in both examined groups to be used for balancing of tumor cell turnover. Clinical analysis of patients with type 1 adenomas revealed female predominance, younger age, larger tumor size, and more frequently aggressive growth with higher incidence of suprasellar extension (p < 0.0001) and cavernous sinus infiltration (p < 0.0001), as well as larger proportions of re-operations and incomplete resections (34.5% vs. 8.51%). Additionally, the interval until re-operation was shorter in type 1 adenomas (mean: 16 months, range: 9 - 21 months vs. mean: 57 months, range: 18- 158 months). We conclude that classification of adenomas of akromegalic patients based on intracytoplasmic CK distribution, combined with examination of proliferative activity, and immunohistochemically defined hormone production profile, provides important prognostic information for the management of akromegalic patients.

Spatial distribution of prostate cancers undetected on initial needle biopsies.

OBJECTIVES: The spatial distribution of cancer foci of prostate carcinomas with negative initial biopsies was compared to that of prostate carcinomas with positive initial biopsies to detect areas in which carcinomas were more frequently located when the initial biopsy was negative. METHODS: Twenty patients with prostate cancer and a negative initial biopsy trial were detected among 218 patients with preceding systematic biopsies (9.2%) in our hospital. Analysis of the prostatectomy specimens regarding cancer distribution, multifocality, tumour size, Gleason score, and stage was performed using pathohistological techniques and three-dimensional computer reconstruction. RESULTS: Prostatectomy specimens with negative initial biopsies showed more frequently cancer foci in apical (p<0.0001) and dorsal (p<0.02) prostatic compartments, higher incidence of multifocality (p<0.01), and smaller size of carcinoma foci (p<0.00003) compared to carcinomas in 81 stage-matched prostatectomy specimens with positive initial biopsies. Comparing both groups, no significant differences were noted in Gleason score of preoperative biopsies and prostatectomies, prostate weight, prostate-specific antigen (PSA) level, digital rectal examination, and patients age. CONCLUSIONS: Missing the cancer in clinically significant prostate carcinomas by current systematic biopsy techniques may also be due to an apico-dorsal cancer location, particularly in combination with multifocality and small size of carcinoma foci in large prostates. In case of reasonable clinical suspicion of prostate cancer and negative initial biopsy, an early repeat biopsy with special emphasis on the apico-dorsal peripheral zone should be envisaged.

Reverse transcriptase template switching during reverse transcriptase-polymerase chain reaction: artificial generation of deletions in ribonucleotide reductase mRNA.

Using reverse transcriptase-polymerase chain reaction (RT-PCR), we have recently described a bona fide deletion within the coding sequence of the large subunit of ribonucleotide reductase (R1) mRNA in colon cancer. Consecutive studies have raised questions about the nature of this phenomenon, because the corresponding genomic alteration at the DNA level or an aberrant protein could not be detected. Thus we considered an in vitro artifact during RT-PCR as a possible explanation for this observation. In contrast to reverse transcriptase, Taq DNA polymerase or C. therm DNA polymerase did not generate the aberrant product, suggesting the demand for the template switching activity intrinsic to retroviral reverse transcriptases. In fact, virtually the same deletion was observed in RT-PCR experiments when in vitro transcribed R1 mRNA was used. Considering structural prerequisites for template switching within R1 mRNA, we show that two direct repeats adjacent to a strong stem-loop secondary structure flank the deleted region of 1851 base pairs. Because several mRNAs encoding proteins of clinical and diagnostic importance fulfill these criteria, template switching enhances the potential risk of observing artifacts when interpreting results from RT-PCR studies. As shown in the present example, this may involve the artificial generation and the misinterpretation of PCR fragments amplified from targets relevant to tumor biology or cancer pharmacology. As a possible solution, one-step PCR with C. therm polymerase should be considered. This polymerase eliminates the artificial generation of aberrant mRNA signals observed during cDNA synthesis.

Genetic analysis of multiple synchronous lesions of the colon adenoma-carcinoma sequence.

The colorectal adenoma-carcinoma sequence represents a well-known paradigm for the sequential development of cancer driven by the accumulation of genomic defects. Although the colorectal adenoma-carcinoma sequence is well investigated, studies about tumours of different dignity co-existent in the same patient are seldom. In order to address the distribution of genetic alterations in different lesions of the same patient, we coincidently investigated carcinomas, adenomas and aberrant crypt foci in patients with sporadic colon cancer. By utilizing polymerase chain reaction, single-strand conformation polymorphism, heteroduplex-analysis, restriction fragment length polymorphism, protein truncation test and sequencing techniques we looked for mutations and microsatellite instability of APC, H-ras, K-ras, p53, DCC and the DNA repair genes hMLH1/hMSH2. In accordance with the suggested adenoma-carcinoma sequence of the colon, four patients reflected the progressive accumulation of genetic defects in synchronously appearing tumours during carcinogenesis. However, two patients with non-hereditary malignomas presented different genetic instabilities in different but synchronously appearing tumours suggesting non-clonal growth under almost identical conditions of the environment. Thus, sporadically manifesting multiple lesions of the colon were not necessarily driven by similar genetic mechanisms. Premalignant lesions may transform into malignant tumours starting from different types of genetic instability, which indicates independent and simultaneous tumorigenesis within the same organ.

Fractal analysis: an objective method for identifying atypical nuclei in dysplastic lesions of the cervix uteri.

OBJECTIVES: Fractal geometry is a tool used to characterize irregularly shaped and complex figures. It can be used not only to generate biological structures (e.g., the human renal artery tree), but also to derive parameters such as the fractal dimension in order to quantify the shapes of structures. As such, it allows user-independent evaluation and does not rely on the experience level of the examiner. METHODS: We applied a box-counting algorithm to determine the fractal dimension of atypical nuclei in dysplastic cervical epithelium. An automatic algorithm was used to determine the fractal dimension of nuclei in order to prevent errors from manual segmentation. Four groups of patients (CIN 1-3 and control) with 10 subjects each were examined. In total, the fractal dimensions of 1200 nuclei were calculated. RESULTS: We found that the fractal dimensions of the nuclei increased as the degree of dysplasia increased. There were significant differences between control and atypical nuclei found by an analysis of variance. Atypical nuclei associated with CIN 1, CIN 2, and CIN 3 also differed significantly among these groups. CONCLUSION: We conclude that the fractal dimension is a valuable tool for detecting irregularities in atypical nuclei of the cervix uteri and thus allows objective nuclear grading.

Chaodynamic loss of complexity and self-similarity in cancer.

'Omnis cellula a cellula': each cell descends from another cell--and most complex organ structures are built up of multiple cells at least. Even the underlying mechanisms of physiological as well as pathological processes reflect complexity in a pronounced manner. Loss of complexity, however, has been detected in aging and apparently also in the case of a number of diseases. This paper describes the loss of complexity in both carcinogenesis and the related growth pattern of cancer. After disruption of the cell's stability as a result of mutations, a decrease in the ability of the cell to induce a self-organized response is associated with the loss of control parameters at the cellular and molecular level. Complexity, understood as a principle of order, is altered in certain malignant tumors, as is indicated by a loss of the golden mean and by the disappearance of self-similarity. The lack of self-similarity could, therefore, be an ideal practical marker of malignancy in medical image analysis.

[Stereotactic breast biopsy: comparison of vacuum punch biopsy versus high speed core biopsy]. / Stereotaktische Mammabiopsie: Vergleich von Vakuumstanzbiopsie versus Hochgeschwindigkeits-Corebiopsie.

Since few years a new vacuum-assisted biopsy is used in addition to the common gun-needle biopsy in suspicious lesions of the mamma. Aim of our study was to compare these two techniques in regard to their histological outcome. Retrospectively, 149 of the 1997 performed biopsies and the corresponding operation specimens were evaluated. The biopsied lesions were divided in star-like densities, roundish opacities and different forms of microcalcifications. We found both stereotactical methods very accurate. In vacuum-assisted biopsies more representative material could be obtained in cases of microcalcifications. The better quality of the tissues made the histological result more reliable. In concern to other lesions in the mammogram there was no difference between the two techniques at all. In summary, both stereotactical methods revealed comparable and valuable results whereas in any form of microcalcifications we suggest to apply the vacuum-assisted method.

[Fractal analysis of a breast carcinoma--presentation of a modern morphometric method]. / Fraktale Analyse eines Mammakarzinoms--Vorstellung einer modernen morphometrischen Methode.

Fractal analysis techniques are common tools in physics and image processing. In the past few years they have gained increasing attention in medical sciences, e.g., cardiology, pathology and radiology, respectively. This article intends to describe this new technique by applying fractal analysis to the instant of a breast carcinoma. One of the advantages of fractal analysis is the ability to describe an irregular and complex object by a measureable value, called the fractal dimension. The fractal dimension can be determined by using the box-counting method. We applied this technique to the mammography as well as to the histologic section of a breast carcinoma. The application of fractal analysis provides a specific measureable value of the growth pattern of a tumor. Thus, the fractal dimension serves in addition to the common used metric diameter.

[Actinic brachial plexus lesion]. / Aktinische Plexus brachialis-Läsion.

Radiation-induced brachial plexus lesions are progressive and irreversible complications. Until now, there is no way to successful prevention and treatment of this problem. In our series, relief of pain could be achieved by neurolysis in some cases, but there was no recovery of sensory and motor function. In order to improve the vascularity and nerve tissue regeneration, we performed muscle or gliding tissue flaps after neurolysis in our department. Since 1975, 25 patients who developed radiation-induced plexopathy were treated in our department. We followed 18 patients to evaluate the benefits of our surgical intervention. None of the patients had improvement of their sensory or motor impairment. Relief of severe pain was achieved in 83% either by neurolysis only with or without muscle or gliding tissue flap. In some cases, paresis worsened postoperatively. We also observed a return of severe pain after the operation.

Survival of normal colonic epithelial cells from both rats and humans is prolonged by coculture with rat embryo colonic fibroblasts.

Primary cultures of normal colonic epithelial cells from both humans (HCEC) and rats (RCEC) have been established using coculture with colon fibroblasts isolated from rat term embryos. While no other factors we have analyzed had any effect on the survival of epithelial cells, which is normally 3-4 days, coculture with viable fibroblasts extended this period to at least 2 weeks. The effects depended on early passages and low seeding densities of the fibroblasts and on direct cell-cell contact. We have obtained cultures of epithelial cells expressing keratin, laminin, and uvomorulin, displaying a polygonal, epithelial morphology and forming microvilli. DNA synthesis as measured by BrdU uptake into DNA varied widely between colonies of the same culture depending on cell morphology: flat colonies of RCECs contained 5.7% +/- 0.56% BrdU-positive cells, while the proportion in dense three-dimensional colonies reached 50.3% +/- 2.6%. In HCECs the growth fraction was lower, but showed the same distribution between classes of colonies. In the presence of rat embryonic colon fibroblasts, growth factors exerted survival activity on colonic epithelial cells. Consecutive addition of insulin and epidermal growth factor/fibroblast growth factor (EGF/FGF) increased colony number (15.0 +/- 1.0 and 23.0 +/- 2.0 colonies/well respectively; p < or = 0.05 increased above control) and size (1022 +/- 155 and 1207 +/- 158 cells/colony respectively; p < or = 0.05 increased above control) compared to serum-free control medium and basic MEM without growth factors. BrdU labeling index was not increased, however: EGF/FGF actually decreased BrdU labeling from 33.2% +/- 3.9% in controls to 21.3% +/- 3.8% in the EGF/FGF group (p < or = 0.05) owing to the high proportion of flat colonies consisting of resting cells. The newly established culture model can now be used to investigate growth control mechanisms in colonic mucosa and the effects of toxic and/or tumor-promoting substances on these mechanisms.