Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas.

Primary carcinomas of the small intestine are rare and the mechanism of their pathogenesis is poorly understood. Patients with familial adenomatous polyposis (FAP) have a high risk of developing duodenal carcinomas. The aim of this study is to gain more insight into the development of duodenal carcinomas. Therefore, five FAP-related duodenal carcinomas were characterized for chromosomal and methylation alterations, which were compared to those observed in sporadic duodenal carcinomas. Comparative genomic hybridization (CGH) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed in 10 primary sporadic and five primary FAP-related duodenal carcinomas. In the FAP-related carcinomas, frequent gains were observed on chromosomes 8, 17 and 19, whereas in sporadic carcinomas they occurred on chromosomes 8, 12, 13 and 20. In 60% of the sporadic carcinomas, gains in the regions of chromosome 12 were observed which were absent in the FAP-related carcinomas (P=0.04). Hypermethylation was observed in the immunoglobulin superfamily genes member 4 (IGSF4), TIMP metallopeptidase inhibitor 3 (TIMP3), Estrogen receptor 1 (ESR1), adenomatous polyposis coli (APC), H-cadherin (CDH13) and paired box gene 6 (PAX6) genes. Hypermethylation of PAX6 was only observed in FAP-related carcinomas (3/5) and not in sporadic carcinomas (P=0.02). In conclusion, in contrast to sporadic duodenal carcinomas, gains on chromosome 12 were not observed in duodenal carcinomas of patients with FAP. Identification of the genes in these regions of chromosome 12 could lead to a better understanding of the carcinogenesis pathways leading to sporadic and FAP-related duodenal carcinomas. Furthermore, hypermethylation seems to be a general feature of both FAP-related duodenal carcinomas as well as sporadic duodenal carcinomas with the exception of the PAX6 gene, which is methylated only in FAP-related carcinomas.

Lethal African trypanosomiasis in a traveler: MRI and neuropathology.

The authors report a case of human African trypanosomiasis with CNS involvement caused by Trypanosoma brucei rhodesiense in a 52-year-old woman, which relapsed after melarsoprol treatment. After a second regimen, she developed a severe toxic polyneuropathy, progressing to coma and eventually death. MRI revealed rapidly progressive multiple white matter lesions as well as damage of the central gray matter and cortex. The autopsy results confirmed the diagnosis of human African trypanosomiasis.

Expression of a colorectal antigen defined by a new monoclonal antibody, CO-TL1.

A murine monoclonal antibody (MoAb CO-TL1, IgG1) has been raised by differential screening of hybridoma supernatants on sections of human large and small intestines, followed by screening on colon adenomas as well as on colorectal carcinomas. In both paraffin sections and cryostat sections, the antibody stained strongly all cell types in adult, neonatal and fetal human colorectal epithelium, that is, the goblet cells, the columnar cells and the endocrine cells. No staining was observed in the remaining parts of the normal gastrointestinal tract and other tissues. As revealed by immuno electron microscopy the epitope was present in the apical and basolateral cell membranes, the Golgi complex, secretory vesicles of goblet and columnar cells, and also in granules of the endocrine cells. The epitope in colorectal tissue sections was resistant to the deglycosylation enzymes neuramidase, diastase and hyaluronidase indicating its proteinaceous nature. This colorectal antigen remained expressed in 100% of colorectal adenomas (n = 39) and 86% (n = 29) of colorectal carcinomas. The expression was reduced in undifferentiated carcinomas. The CO-TL1 antibody detected also most other gastrointestinal adenocarcinomas and a few carcinomas of the ovary, uterus, breast, gallbladder and pancreas. However, it never detected carcinomas derived from the thyroid, lung, liver, bladder, kidney, prostate, testis, serous membranes of body cavities and skin. A wild-type variant protein of > 300 kDa of the colorectal antigen was identified in normal colorectal epithelium. In colorectal tumours, however, two tumour variant forms were found of 160-200 and 115-140 kDa, respectively. Our data indicate that this new MoAb CO-TL1 can be considered as a useful marker, which identifies normal colorectal epithelium and gastrointestinal tumours and especially colorectal tumours with high accuracy and excludes tumours originated from thyroid, lung, liver, bladder, kidney, prostate, testis, mesothelium and skin.

Spitz naevi may express components of the plasminogen activation system.

The plasminogen activation (PA) system is involved in the process of invasion and metastasis. Its major components are urokinase (uPA) and tissue-type plasminogen activator (tPA), plasminogen activation inhibitor type 1 and 2 (PAI-1 and PAI-2) and a receptor for urokinase (uPAR). In this study, the expression of plasminogen activation components in Spitz naevi was compared with that in common and dysplastic naevi on the one hand and primary cutaneous melanomas on the other. Spitz naevi had melanocytic positivity for uPA in 0% (0/36), tPA in 30% (6/20), PAI-1 in 10% (3/35), PAI-2 in 40% (8/21) and uPAR in 60% (13/21) of cases. This far exceeded the expression found in common (n = 25) and dysplastic (n = 15) naevi, which only showed melanocytic positivity for PAI-2 (20% and 15% respectively) and in one dysplastic naevus also for uPAR. This was much (for most components significantly) less than the proportion of primary melanomas with tumour cell positivity, which was 30% (11/38) for uPA, 80% (19/24) for tPA, 75% (28/38) for PAI-1, 80% (19/24) for PAI-2 and 80% (19/24) for uPAR. The main findings of this study are that Spitz naevi, firstly, may express plasminogen activator (tPA), inhibitors and the receptor of the PA system, but in a much smaller proportion than cutaneous melanomas; and secondly, do not express urokinase, whereas some of the melanomas do. uPA positivity may therefore be suggestive of melanoma. However, overlapping staining results imply that the PA system has limited value in the differential diagnosis between Spitz naevus and primary melanoma. As serine protease components are expressed, Spitz naevi may use this proteolytic machinery to accomplish matrix degradation, although in a more restricted, possibly transient manner than melanomas.

Allelic imbalance in the diagnosis of benign, atypical and malignant Spitz tumours.

To test the diagnostic usefulness of allelic imbalance (AI) analysis based on routinely paraffin-embedded tissue, a series of 55 benign Spitz naevi, Spitz tumours with uncertain malignant potential, and malignant Spitzoid melanomas was investigated. Laser microdissection was used to ensure representative sampling of lesional cells and to investigate AI in separate tumour areas of four melanomas. AI was found in 2/12 (17%) typical Spitz naevi, 3/9 (33%) atypical Spitz tumours, 12/17 (65%) atypical Spitz tumours suspicious for melanoma and 15/17 (88%) Spitzoid melanomas. Additional immunohistochemical staining for Ki-67 using the MIB-1 antibody revealed positive deeply situated lesional cells in 0/6 (0%) Spitz naevi, 1/8 (13%) atypical Spitz tumours, 5/14 (35%) atypical Spitz tumours suspicious for melanoma, and 7/14 (50%) Spitzoid melanomas, respectively. Two of the melanomas examined for AI in separate tumour areas showed intratumoural genetic heterogeneity. In view of the finding of AI and deeply situated Ki-67 positive cells not only in melanomas but also in Spitz tumours with uncertain malignant potential, these approaches appear to have no direct diagnostic applicability for the distinction between benign and malignant Spitz tumours. Further molecular studies will be required to determine whether Spitz tumours and Spitzoid melanomas are unrelated entities, or whether there is a true spectrum of tumour progression.