Prognostic Significance of Immunohistochemical Markers and Genetic Alterations in Malignant Peripheral Nerve Sheath Tumors: A Systematic Review

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with dis

Histological findings in unclassified sudden infant death, including sudden infant death syndrome

Our objective was to study histological variations and abnormalities in unclassified sudden infant death (USID), including sudden infant death syndrome (SIDS), in The Netherlands. Two hundred Dutch USID cases between 1984 and 2005 were identified. The histology slides and autopsy reports of 187 cases were available for systematic review, including brain autopsy in 135 cases. An explanation for the cause of death in 19 patients (10.2+ACU-) was found. Twelve patients had bronchopneumonia, 3 showed extensive aspiration, 2 had signs of a metabolic disorder, 1 had sepsis, and 1 had meningitis. Frequent nonspecific findings were congestion (66+ACU-), edema (47+ACU-), small hemorrhages (18+ACU-), and lymphoid aggregates (51+ACU-) in the lungs; congestion of the liver (23+ACU-); and asphyctic bleeding in the kidney (44+ACU-), adrenal gland (23+ACU-), and thymus (17+ACU-). Statistical associations were found for infection with starry sky macrophages in the thymus (P 5 0.004), with calcification (P 5 0.023), or with debris in the Hassal's corpuscles (P 5 0.034). In this study, in 10.2+ACU- of cases the histological findings were incompatible with SIDS or USID. Furthermore, several frequent nonspecific histological findings in the thymus that point toward an infection were found

The role of EXT1 in nonhereditary osteochondroma: Identification of homozygous deletions

Background: Multiple osteochondromas is a hereditary syndrome that is characterized by the formation of cartilagecapped bony neoplasms (osteochondromas), for which exostosis (multiple)-1 (EXT1) has been identified as a causative gene. However, 85% of all osteochondromas present as solitary (nonhereditary) lesions in which somatic mutations in EXT1 are extremely rare, but loss of heterozygosity and clonal rearrangement of 8q24 (the chromosomal locus of EXT1) are common. We examined whether EXT1 might act as a classical tumor suppressor gene for nonhereditary osteochondromas. Methods: Eight nonhereditary osteochondromas were subjected to high-resolution array-based comparative genomic h

The CpG island methylator phenotype: What's in a name?

Although the CpG island methylator phenotype (CIMP) was first identified and has been most extensively studied in colorectal cancer, the term "CIMP" has been repeatedly used over the past decade to describe CpG island promoter methylation in other tumor types, including bladder, breast, endometrial, gastric, glioblastoma (gliomas), hepatocellular, lung, ovarian, pancreatic, renal cell, and prostate cancers, as well as for leukemia, melanoma, duodenal adenocarninomas, adrenocortical carcinomas, and neuroblastomas. CIMP has been reported to be useful for predicting prognosis and response to treatment in a variety of tumor types, but it remains unclear whether or not CIMP is a universal phenomenon across human neoplasia or if there should be cancer-specific definitions of the phenotype. Recently, it was shown that somatic isocitrate dehydrogenase-1 (IDH1) mutations, frequently observed in gliomas, establish CIMP in primary human astrocytes by remodeling the methylome. Interestingly, somatic IDH1 and IDH2 mutations, and loss-of-function mutations in ten-eleven translocation (TET) methylcytosine dioxygenase-2 (TET2) associated with a hypermethylation phenotype, are also found in multiple enchondromas of patients with Ollier disease and Mafucci syndrome, and leukemia, respectively. These data provide the first clues for the elucidation of a molecular basis for CIMP. Although CIMP appears as a phenomenon that occurs in various cancer types, the definition is poorly defined and differs for each tumor. The current perspective discusses the use of the term CIMP in cancer, its significance in clinical practice, and future directions that may aid in identifying the true cause and definition of CIMP in different forms of human neoplasia

Inactivation of SDH and FH cause loss of 5hmC and increased H3K9me3 in paraganglioma/pheochromocytoma and smooth muscle tumors

Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tricarboxylic acid (TCA) cycle enzymes and tumor suppressors. Loss-of-function mutations give rise to hereditary paragangliomas/pheochromocytomas and hereditary leiomyomatosis and renal cell carcinoma. Inactivation of SDH and FH results in an abnormal accumulation of their substrates succinate and fumarate, leading to inhibition of numerous a-ketoglutarate dependent dioxygenases, including histone demethylases and the ten-eleven-translocation (TET) family of 5-methylcytosine (5mC) hydroxylases. To evaluate the distribution of DNA and histone methylation, we used immunohistochemistry to analyze the expression of 5mC, 5-hydroxymethylcytosine (5hmC), TET1, H3K4me3, H3K9me3, and H3K27me3 on tissue microarrays containing paragangliomas/pheochromocytomas (n = 134) and hereditary and sporadic smooth muscle tumors (n = 56) in comparison to their normal counterparts. Our results demonstrate distinct loss of 5hmC in tumor cells in SDH- and FH-deficient tumors. Loss of 5hmC in SDH-deficient tumors was associated with nuclear exclusion of TET1, a known regulator of 5hmC levels. Moreover, increased methylation of H3K9me3 occurred predominantly in the chief cell component of SDH mutant tumors, while no changes were seen in H3K4me3 and H3K27me3, data supported by in vitro knockdown of SDH genes. We also show for the first time that FH-deficient smooth muscle tumors exhibit increased H3K9me3 methylation compared to wildtype tumors. Our findings reveal broadly similar patterns of epigenetic deregulation in both