Diagnostic accuracy of SSR-PET/CT compared to histopathology in the identification of liver metastases from well-differentiated neuroendocrine tumors.

BACKGROUND: Histopathology is the reference standard for diagnosing liver metastases of neuroendocrine tumors (NETs). Somatostatin receptor-positron emission tomography / computed tomography (SSR-PET/CT) has emerged as a promising non-invasive imaging modality for staging NETs. We aimed to assess the diagnostic accuracy of SSR-PET/CT in the identification of liver metastases in patients with proven NETs compared to histopathology. METHODS: Histopathologic reports of 139 resected or biopsied liver lesions of patients with known NET were correlated with matching SSR-PET/CTs and the positive/negative predictive value (PPV/NPV), sensitivity, specificity, and diagnostic accuracy of SSR-PET/CT were evaluated. PET/CT reading was performed by one expert reader blinded to histopathology and clinical data. RESULTS: 133 of 139 (95.7%) liver lesions showed malignant SSR-uptake in PET/CT while initial histopathology reported on 'liver metastases of NET´ in 127 (91.4%) cases, giving a PPV of 91.0%. Re-biopsy of the initially histopathologically negative lesions (reference standard) nevertheless diagnosed 'liver metastases of NET' in 6 cases, improving the PPV of PET/CT to 95.5%. Reasons for initial false-negative histopathology were inadequate sampling in the sense of non-target biopsies. The 6 (4.3%) SSR-negative lesions were all G2 NETs with a Ki-67 between 2-15%. CONCLUSION: SSR-PET/CT is a highly accurate imaging modality for the diagnosis of liver metastases in patients with proven NETs. However, we found that due to the well-known tumor heterogeneity of NETs, specifically in G2 NETs approximately 4-5% are SSR-negative and may require additional imaging with [18F]FDG PET/CT.

[Modern sonographic imaging of abdominal neuroendocrine tumors]. / Moderne sonographische Bildgebung bei neuroendokrinen Tumoren des Abdomens.

BACKGROUND: Radiological and nuclear medical diagnostics play an important role in the work-up of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET). The sonographic examination, including contrast-enhanced examination, depicts an initial imaging modality to screen for NET. This report describes the sonomorphological behavior of ileal and pancreatic NET as well as hepatic metastases from NET. CLINICAL/METHODICAL ISSUE: Sonographic evaluation of NET of the small intestine, pancreas and neuroendocrine hepatic metastases. STANDARD RADIOLOGICAL METHODS: Contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), unenhanced ultrasonography. METHODICAL INNOVATIONS: Contrast-enhanced ultrasound (CEUS). PERFORMANCE: CEUS supports unenhanced ultrasound in the detection of NET and the differential diagnosis of unclear lesions, and is more sensitive for liver metastases (sensitivity according to the literature, 99% vs. 68%) PRACTICAL RECOMMENDATIONS: CEUS allows initial evaluation of NET and differentiation of benign vs. malignant lesions. Nevertheless, CEUS cannot replace more elaborate imaging modalities like CT or MRI for thorough staging examinations.

[Neuroendocrine neoplasia of the stomach : What is new?] / Neuroendokrine Neoplasien des Magens : Was ist neu?

INTRODUCTION: Neuroendocrine Neoplasms are classified according to the new WHO classification in (1.) well differentiated neuroendocrine tumors G1 (NET G1, Ki67 ≤ 2 or mitosis count <2) and (2.) well differentiated neuroendocrine tumors G2 (NET G2, Ki67 3-20 or mitosis count 2-20) and (3.) poorly differentiated neuroendocrine carcinomas G3 (NEC G3, Ki67 > 20 or mitosis count >20). MATERIAL AND METHODS: In this study 310 NENs of the Ludwig-Maximilians-University in Munich were reevaluated according to the new WHO classification. RESULTS: 7% of the analyzed NENs were presented as neoplasias of the stomach. In NENs of the stomach three distinct subtypes are recognized: (1) type 1 associated with autoimmune chronic atrophic gastritis (2) type 2, associated with multiple endocrine neoplasia (MEN1) and Zollinger-Ellison Syndrom; and (3) type 3, sporadic tumors. DISCUSSION: Precursor lesions (i. e. hyperplasia of the ECL cells) are found in patients with hypergastrinaemia (type 1 and 2). This article should provide insights into the diagnosis of NENs of the stomach with emphasis on the new international standard.

[Tyrosine kinases in soft tissue tumors]. / Tyrosinkinasen in Weichgewebstumoren.

The development of therapeutic agents that specifically target the molecular alterations critical for tumorigenesis has a tremendous impact on the management of cancer patients. The successful treatment of advanced gastrointestinal stromal tumors (GIST) with receptor tyrosine kinase (RTK) inhibitors has raised the hope that other malignancies could also benefit from a similar treatment. Tyrosine kinase receptors are promising targets for personalized medicine and new drugs are currently in phase 2 and phase 3 clinical trials. We analyzed a large cohort of soft tissue sarcomas for different tyrosine kinase receptors and correlated the results with clinicopathological parameters. A total of 275 soft tissue sarcomas from the Ludwig-Maximilians University (LMU) were revisited and catagorized according to the current World Health Organization (WHO) classification system. Different entities showed distinct survival curves in 10-year long-term survival. Furthermore, different subtypes of sarcomas showed distinct expression profiles at the protein level. The expression of vascular endothelial growth factor (VEGF) receptors is associated with tumor progression. Due to the fact that not all patients respond to RTK inhibitor therapy, protein signatures should be evaluated before targeting therapy to give a rationale for a viable personalized therapy.

The search for the primary tumor in metastasized gastroenteropancreatic neuroendocrine neoplasm.

Gastroenteropancreatic neuroendocrine tumors (NETs) often present as liver metastasis from a carcinoma of unknown primary. We recently showed that primary NETs from the pancreas, small intestine and stomach as well as their respective liver metastases differ from each other by the expression profile of the three genes CD302, PPWD1 and ABHB14B. The gene and protein expression of CD302, PPWD1, and ABHB14B was studied in abdominal NET metastases to identify the site of the respective primary tumors. Cryopreserved tissue from NET metastases collected in different institutions (group A: 29, group B: 50, group C: 132 specimens) were examined by comparative genomic hybridization (Agilent 105 K), gene expression analysis (Agilent 44 K) (groups A and B) and immunohistochemistry (group C). The data were blindly evaluated, i.e. without knowing the site of the primary. Gene expression analysis correctly revealed the primary in the ileum in 94 % of the cases of group A and in 58 % of group B. A pancreatic primary was predicted in 83 % (group A) and 20 % (group B), respectively. The combined sensitivity of group A and B was 75 % for ileal NETs and 38 % for pancreatic NETs. Immunohistochemical analysis of group C revealed an overall sensitivity of 80 %. Gene and protein expression analysis of CD302 and PPWD1 in NET metastases correctly identifies the primary in the pancreas or the ileum in 80 % of the cases, provided that the tissue is well preserved. Immunohistochemical profiling revealed CD302 as the best marker for ileal and PPWD1 for pancreatic detection.

[Diagnostic procedures and results in surgical therapy for cholangiocarcinoma]. / Diagnostisches Vorgehen und Ergebnisse in der chirurgischen Therapie von Gallenwegstumoren.

INTRODUCTION: Despite a rising incidence worldwide, cholangiocarcinoma (CCC) is one of the infrequent malignancies of the gastrointestinal tract. The surgical approach depends largely on the location of the tumour. PATIENTS AND METHODS: Since 1995, 425 consecutive patients with cholangiocarcinoma were seen at our hospital; their data were prospectively entered in our cancer registry. Tumour-specific data were now retrospectively analysed for prognostic value. RESULTS: Resection with primarily curative intent was performed in 183 of the 425 patients; resection rates were 36 % for intrahepatic (66 patients), 44 % for hilar (69 patients) and 56 % for distal cholangiocarcinoma (48 patients). R0-resection was achieved in 152 patients (83 %) and was found to be the most important factor determining survival. With respect to intrahepatic cholangiocarcinoma, clinical T3- and T4-categories, lymph node metastases as well as UICC stages III and IV had negative predictive value; in hilar carcinomas, this was only seen for the last two factors. In distal cholangiocarcinoma, a low degree of differentiation was associated with a poor prognosis. No differences in survival were seen in the presence of perineural infiltration, angioinvasion or elevation of tumour marker CA 19 - 9.  Regarding the surgical techniques, we found a survival benefit for limited liver resection in intrahepatic cholangiocarcinomas, which is explained by earlier tumour stages seen in these cases, as well as the performance of trisectionectomy or liver transplantation in hilar carcinomas. CONCLUSIONS: Comparable to other malignant gastrointestinal tumours, radical surgery represents the most important prognostic factor in cholangiocarcinomas; for hilar tumours, a survival advantage is seen after extended resections (trisectionectomy or liver transplantation) if compared to more limited resections. At the time of presentation, however, the stage of disease was incurable in most patients, thus accounting for the low overall resection rates.

Both STAT1 and STAT3 are favourable prognostic determinants in colorectal carcinoma.

BACKGROUND: Aberrant activities of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathways have been implicated in the development and spread of various cancer entities, among them colorectal carcinoma (CRC). Transcription factors STAT3 and STAT1, both downstream effectors of interleukin (IL)-6 and its receptor, are involved in growth and developmental control of CRC cells. Constituents of the signalling network around IL-6 and STAT activation are discussed as potential biomarkers and therapeutic targets in CRC. METHODS: By immunohistochemical analysis of a tissue microarray covering >400 CRC biopsies, the expression and activity status of STAT1, STAT3 as well as of IL-6 and the IL-6 receptor α-chain was determined. The outcome was correlated with clinical information and patients' survival data. Colorectal carcinoma biopsies were also analysed for specific DNA-binding activity of STATs. RESULTS: Statistical analysis showed tendential associations between individual STATs, IL-6/IL-6 receptor-α and clinicopathological parameters. The study revealed a significant correlation of high STAT1 activity with longer patient overall survival. Surprisingly, strong STAT3 expression in surgical specimens was correlated with an increase in median overall survival by about 30 months. Statistical analysis revealed that high expression levels of STAT1 and STAT3 were associated. This finding was backed up by biochemical data that showed simultaneous STAT1 and STAT3 DNA-binding activity in randomly selected CRC biopsies. CONCLUSION: By multivariate data analysis, we could show that STAT3 expression and activity constitutes an independent favourable prognostic marker for CRC.

DSC3 expression is regulated by p53, and methylation of DSC3 DNA is a prognostic marker in human colorectal cancer.

BACKGROUND: Desmocollin 3 (DSC3), a member of the cadherin superfamily and integral component of desmosomes, is involved in carcinogenesis. However, the role of DSC3 in colorectal cancer (CRC) has not yet been established. METHODS: Desmocollin 3 expression in CRC cell lines was analysed by RT-PCR and western blotting. Methylation status of DSC3 was examined by demethylation tests, methylation-specific PCR, and bisulphite sequencing (BS). The regulatory role of p53 was investigated by transfection. RESULTS: Desmocollin 3 was downregulated in CRC cells at mRNA and protein levels. Desmocollin 3 expression was restored in five out of seven cell lines after 5-aza-2'-deoxycytidine (DAC) treatment. A heterogeneous methylation pattern was detected by BS in promoter region and exon 1 of DSC3. Methylation of DSC3 genomic sequences was found in 41% (41 out of 99) of primary CRC, being associated with poor prognosis (P=0.002). Transfection of p53 alone or in combination of DAC increased the DSC3 expression. Similarly, treatment with p53 inducer adriamycin alone or in combination with DAC enhanced DSC3 expression. CONCLUSIONS: DNA methylation contributes to downregulation of DSC3 in CRC cell lines. Methylation status of DSC3 DNA is a prognostic marker for CRC. P53 appears to have an important role in regulating DSC3 expression.

[Update from the soft tissue tumour registry in Jena]. / Neues aus dem Jenaer Weichteiltumor-Register.

The Jena Institute of Pathology has been serving as a consultation and reference center for soft tissue tumors in Germany since 1978. The present study provides an overview of the clinicopathological data from a two-year period and an update on diagnostics and research. Retrospectively, 7043 cases sent to the institute in the years 2006 and 2007 were analyzed. The majority of cases (>77.7%) were soft tissue tumors, of which 49% were categorized as malignant, 11.4% as intermediate, 35% as benign and 4.6% as tumors of uncertain biological potential. Neoplasms with fibroblastic differentiation were the most frequent. The mean age of patients with a sarcoma was 63 years. The molecular pathological analysis of soft tissue tumors has attained a major role in diagnosis. This is further advanced at the Jena institute in the context of a German Federal Ministry of Education and Research (BMBF) project for molecular sarcoma diagnosis with the aim of developing and validating DNA probes for in situ hybridization detection of translocations and their associated chromosomal breaks on the one hand, and DNA chips for the detection of fusion transcripts on the other. Research projects relate to the analysis of specific biomarkers in large tumor collectives and the pathomechanisms in several sarcoma entities.

[Solitary fibrous tumor and haemangiopericytoma: what is new?]. / Solitärer fibröser Tumor und Hämangioperizytom : Was ist neu?

Soft-tissue tumors with haemangiopericytoma (HPC)-like growth patterns can now be divided into three categories: (1) The solitary fibrous tumour (SFT) group with its variants; (2) lesions showing clear evidence of myoid/pericytic differentiation and corresponding to "true" HPCs (myopericytoma/glomangiopericytoma and a subset of sinonasal HPCs); (3) neoplasms that occasionally display HPC-like features (e.g. synovial sarcoma). In this study 268 intrathoracic and extrathoracic SFTs from the German consultation and reference center of soft tissue tumors in Jena were evaluated and analyzed immunohistochemically with antibodies CD34, Bcl-2, CD99, SMA, S100, PanCK and Ki-67. Furthermore, SFTs were categorized into the newly proposed SFT designation: Fibrous variant, cellular variant (more than 90% hypercellularity), fat-forming variant, giant cell-rich variant and malignant SFTs. This article should provide insights into the diagnosis of this entity with emphasis on the new international standard.

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) has potential tumour-suppressive activity in human lung cancer.

The expression of insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is decreased in various tumours, but the role of IGFBP-rP1 in lung cancer is not yet clear. In this study, IGFBP-rP1 expression in lung cancer cell lines was evaluated and reduced expression of IGFBP-rP1 was found. In tissue microarrays containing 138 primary tumours and 20 normal lung tissues analysed by immunohistochemistry, 58 tumours (42%) exhibited no expression of IGFBP-rP1, while all 20 normal lung tissues showed high expression. In squamous cell lung cancer, low expression of IGFBP-rP1 was significantly linked to high-grade tumours. Treatment with 5-aza-2'-deoxycytidine restored the expression of IGFBP-rP1 in three of four lung cancer cell lines. Sequencing of PCR products of sodium bisulphite-treated genomic DNA from the three lung cancer cell lines revealed a heterogeneous methylation pattern in the region of exon 1 and intron 1. Stable transfection of IGFBP-rP1 full-length cDNA into the H2170 lung cancer cell line led to increased expression of IGFBP-rP1 protein. IGFBP-rP1-positive transfectants exhibited remarkably reduced colony-forming ability in soft agar, suppression of tumour growth rate in nude mice, and increased apoptotic cell number as well as activated caspase-3 expression level. The data suggest that IGFBP-rP1 is a tumour suppressor inactivated by DNA methylation in human lung cancer.

[A look beyond urology: vaginal cancer]. / Ein Blick diesseits des Tellerrandes: Das Vaginalkarzinom.

Primary carcinomas of the vagina are very rare. Nevertheless, they need to be included in differential diagnoses when carrying out a urological examination of the pelvic floor and the vagina in patients with micturition problems, also in younger patients: we report a case of a 35-year-old woman with a primary carcinoma of the vagina and present a review of the literature.

Parvovirus B19 infection associated with unilateral cervical lymphadenopathy, apoptotic sinus histiocytosis, and prolonged fatigue.

This report describes the case of a 16 year old girl with a history of high fever, prolonged fatigue, and cervical lymphadenopathy of the right side. In addition, the patient showed neutropenia, thrombopenia, and pronounced reticulopenia. Cervical ultrasound showed unilateral hypoechoic lymph nodes up to 23 mm in diameter suspicious for malignant lymphoma. Histology of a cervical lymph node specimen revealed massive nodular histiocytic proliferation and prominent apoptosis without necrosis. Parvovirus B19 was detected by polymerase chain reaction and immunohistochemistry in the lymph node. In summary, this case is an unusual presentation of parvovirus B19 infection. The virus was identified as the potential causative agent of unilateral cervical lymphoma and apoptotic sinus histocytosis, thus broadening the clinicopathological spectrum of parvovirus B19 induced diseases.

ALCAM/CD166 is overexpressed in colorectal carcinoma and correlates with shortened patient survival.

BACKGROUND: Activated leucocyte cell adhesion molecule (ALCAM) has been implicated in tumorigenesis and tumour progression of malignant melanoma and prostate cancer. AIMS: To clarify the expression patterns of ALCAM in colon cancer and to correlate these with clinicopathological parameters, including patient survival. METHODS: One hundred and eleven colorectal carcinomas were immunostained for ALCAM (clone MOG/07) using a standard detection system. Cytoplasmic and membranous immunoreactivity were scored semiquantitatively. Fisher's exact test, chi2 test for trends, Kaplan-Meier analysis, and Cox's regression were applied. RESULTS: In colorectal cancer, 58.6% and 30.6% of cases showed strong cytoplasmic and membranous expression of ALCAM, respectively. No significant correlation with patient age, tumour grade, stage, or nodal status was apparent. In survival analyses, membranous ALCAM expression correlated significantly (Cox's regression, p=0.028; relative risk, 2.3) with shortened patient survival. CONCLUSIONS: ALCAM is frequently upregulated in colorectal cancer and is a new independent prognostic marker, underscoring the importance of ALCAM in tumour progression in this disease.

Genetic imbalances with impact on survival in colorectal cancer patients.

AIMS: To investigate the prognostic significance of chromosomal alterations in colorectal cancer patients. Histopathological tumour classification is still considered to be the gold standard for the characterization of solid tumours. However, it is well known that such established parameters do not satisfactorily predict the clinical outcome in individual cases. Markers that reliably predict survival are needed. These markers should guide the clinical treatment of neoplastic disease. METHODS AND RESULTS: Chromosomal imbalances in 61 colorectal carcinoma specimens in 37 patients determined by comparative genomic hybridization were correlated with patient survival using custom-made computer software which enabled the assessment of individual chromosomal loci. Kaplan-Meier analysis revealed that over-representations of 2p14-15, 6q23-6q24, 15q22-15q23, 22q11.2 and deletions of 1p36.1-36.2, 4q31.3, 4q35, 8q12-q21, 8p11.2 and 9p22 were significantly associated with shorter disease-specific survival, whereas over-expression of 20q13.3 and deletion of 18q11.2 were significantly associated with longer disease-specific survival in this collection of colorectal cancers. Multivariate Cox proportional hazards regression models consistently identified gains of 2p14-15, 15q22-23, 22q11.2 and losses of 1p36.1-36.2 and 4q35 as independent markers of shorter patient survival carrying greater significance than the classical clinicopathological parameters of nodal status and tumour grade. CONCLUSIONS: These five markers allow a molecular categorization of patients into high and low clinical risk groups. Thus, the genomic data have refined the histopathological classification highlighting the necessity for a supplementary genetically based stratification of colorectal cancer.

Chromosomal imbalances in brain metastases of solid tumors.

Metastases account for approximately 50% of the malignant tumors in the brain. In order to identify structural alterations that are associated with tumor dissemination into the central nervous system we used Comparative Genomic Hybridization (CGH) to investigate 42 brain metastases and 3 primary tumors of 40 patients. The metastases originated from lung cancer (14 cases), melanomas (7), carcinomas of breast (5), colon (5), kidney (5), adrenal gland (1) and thyroid (1). In addition, tumors of initially unknown primaries were assessed in 3 cases. The highest incidence of DNA gains were observed for the chromosomal regions 1q23, 8q24, 17q24-q25, 20q13 (>80% of cases) followed by the gain on 7p12 (77%). DNA losses were slightly less frequent with 4q22, 4q26, 5q21, 9p21 being affected in at least 70% of the cases followed by deletions at 17p12, 4q32q34, 10q21, 10q23-q24 and 18q21-q22 in 67.5% of cases. Two unusual narrow regional peaks were observed for the gain on 17q24-q25 and loss on 17p12. The incidence at individual loci can be viewed at our CGH online tumor database at http:// amba.charite.de/cgh/. The metastases of each tumor type showed a recurrent pattern of changes. In those cases with primary tumor and metastases available, the CGH pattern exhibited a high degree of conformity. In conclusion, our data suggests that specific genetic lesions are associated with tumor dissemination into the nervous system and that CGH analysis may be a useful supplementary tool for classification of metastases with unknown origin.

[Meniscus replacement using incongruent transplants--an experimental study]. / Der Meniskusersatz mit inkongruenten Transplantaten--eine experimentelle Untersuchung.

The effect of incongruous medial meniscal grafts on the articular surface was studied. We compared the cartilage degeneration in 4 Groups of 25 sheep knees. The histological changes were graded according to the score of Mankin, the morphological alterations by the score of Jackson. In Group 1 no surgery was performed. In group 2, the meniscus was totally detached from its base at the capsule and refixed without changes in the congruity or isometry. This group provided the basic data. In group 3, the contralateral medial meniscus was used as a transplant by reversing it. The reattachment was done according to isometric conditions. With this technique only the congruity of the tibial and femoral surface was modified. In group 4, the medial meniscus was completely removed. The results of group 1 (Mankin grade 0.58; Jackson grade 0.00) and group 2 (grade 0.50 and 0.47) showed no difference. The highest degree of degenerative changes occurred in the meniscectomized knees (group 4, grade 4.47 and 1.73), however considerable changes were also found in the knees with an incongruous meniscal graft (group 3, grade 3.37 and 1.27). The results suggest that incongruous grafts will lead to degeneration of the articular surface but still have a chondroprotective effect.