Intraductal carcinoma (IC) is the new World Health Organization designation for tumors previously called "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma is controversial, but they now are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in situ, that shows diffuse S100 protein and mammaglobin positivity and is only partially defined genetically. (Mammary analogue) secretory carcinoma harboring ETV6-NTRK3, and in rare cases ETV6-RET fusion, shares histomorphologic and immunophenotypical features with IC. Recently, RET rearrangements and NCOA4-RET have been described in IC, suggesting a partial genetic overlap with mammary analogue secretory carcinoma. Here, we genetically characterize the largest cohort of IC to date to further explore this relationship. Seventeen cases of IC were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). Identified fusions were confirmed using fluorescence in situ hybridization break apart and, in some cases, fusion probes, and a reverse transcription polymerase chain reaction designed specifically to the detected breakpoints. All analyzed cases were known to be negative for ETV6 rearrangement by fluorescence in situ hybridization and for ETV6-NTRK3 fusion by reverse transcription polymerase chain reaction. Next-generation sequencing analysis detected a NCOA4-RET fusion transcript joining exon 7 or 8 of NCOA4 gene and exon 12 of RET gene in 6 cases of intercalated duct type IC; and a novel TRIM27-RET fusion transcript between exons 3 and 12 in 2 cases of salivary gland tumors displaying histologic and immunohistochemical features typical of apocrine IC. A total of 47% of IC harbored a fusion involving RET. In conclusion, we have confirmed the presence of NCOA4-RET as the dominant fusion in intercalated duct type IC. A novel finding in our study has been a discovery of a subset of IC patients with apocrine variant IC harboring a novel TRIM27-RET.

Intraductal carcinoma (IC) is the new WHO designation for tumors previously encompassed by "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma (SDC) is controversial, even though they are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with histopathological features reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast, showing diffuse S100 protein and mammaglobin positivity, while it is partially defined genetically. Recently, RET rearrangements including NCOA4-RET and TRIM27-RET have been described in IC. Here, we genetically characterize the largest cohort of IC to date (33 cases) including 8 cases with focal or widespread invasive growth and 1 case with lymph node metastasis. Thirty-three cases of IC were analyzed by next-generation sequencing (NGS) using the FusionPlex Solid Tumor kit (ArcherDX). Identified gene fusions were confirmed using fluorescence in situ hybridization break-apart and fusion probes and an reverse transcription polymerase chain reaction designed specifically for the detected breakpoints. Ten cases of SDC were analyzed for comparison using NGS panels that detect mutations and fusion transcripts. NGS analysis detected an NCOA4-RET fusion transcript in 11 cases of intercalated duct-type IC joining exon 7 or 8 of NCOA4 gene and exon 12 of the RET gene. Eight cases of IC had an invasive growth pattern, including one with widespread invasion and lymph node metastasis. Three invasive ICs harbored an NCOA4-RET fusion transcript, while 1 case was negative, and 2 cases were not analyzable. In addition, a novel TRIM27-RET fusion transcript between exon 3 of TRIM27 and exon 12 of RET was identified in 2 cases of IC with apocrine features, and one of them displayed invasive growth. Two IC cases with invasive growth harbored novel fusions TUT1-ETV5 and KIAA1217-RET, respectively. A total of 42.4% of the cases in this series of IC harbored fusions involving RET. Such fusion transcripts were not detected in any of the 10 SDC cases. We have confirmed NCOA4-RET as a predominant fusion in intercalated duct-type IC, including 3 cases with invasive growth pattern. A novel finding in our series was a case of widely invasive intercalated duct-type IC, with a single lymph node metastasis that revealed an NCOA4-RET fusion transcript. We also demonstrated that a subset of apocrine ICs harbored a TRIM27-RET gene fusion, including one case with invasive growth. In contrast, neither NCOA4-RET nor TRIM27-RET fusions were detected in any tested SDCs. Thus, the distinct molecular findings in IC and SDC support that the tumors are separate malignant salivary tumor entities. The presence of tumor-type-specific NCOA4-RET or TRIM27-RET translocations in a subset of widely invasive carcinomas with intercalated duct-like immunoprofiles suggests that a recharacterization of IC including its redesignation as "intercalated duct carcinoma, invasive or noninvasive" may be a...

Gliomas are the most frequently occurring central nervous system (CNS) tumours and include astrocytomas, anaplastic astrocytomas and glioblastoma multiforme. They are severely disabling, producing symptoms of headaches, fits, confusion, personality changes and neurological deficits which impair the patients' quality of life. Despite advances in the diagnosis and treatment of gliomas the prognosis remains poor, with only 10-15% survival for patients with high-grade gliomas at 30+ months (Brada et al, 1998). Nevertheless, considerable variation exists with respect to post-operative survival. Identification of prognostic variables to assist in clinical management is thus of considerable value to both patients and clinicians.Historically, prognostic models for gliomas have used clinical variables and patient characteristics to determine factors that predict response to therapy and survival. In 1990, the Medical Research Council (MRC) working party developed a clinical scoring system that predicted a better prognosis for patients less than 45 years old at diagnosis, with longer duration of fits, debulking surgery and a better performance status (Report of the MRC Brain Tumour Working Party, 1990). Although adverse histological features including high proliferative activity (Bruner, 1994), the presence of necrosis (Barker et al, 1996) and a gemistocyte population of greater than 20% (Krouer et al, 1991) have been identified in univariate analysis of small series, these have not been evaluated in larger series and are not widely employed.The development of gliomas, in common with many tumours, is a multistep process involving the accumulation of several genetic events which involve the activation of oncogenes (Collins, 1995) and the loss of tumour suppressor genes (Jen et al, 1994;Louis and Gusella, 1995;von Deimling et al, 1995). The commonest genetic abnormality observed in gliomas is loss, often involving a whole homologue, of chromosome 10 (Bigner at al, 1990). This loss is associated with high-grade tumours, being rare in low-grade astrocytomas but present in some 60-85% of high-grade gliomas (Louis and Gusella, 1995). Recent studies have led to the identification of at least three tumour suppressor genes, PTEN (MMAC1), DMBT1 and LGI1 (Li et al, 1997;Mollenhauser et al, 1997;Steck et al, 1997;Chernova et al, 1998) on chromosome 10, which may be involved in glioma progression. The aim of this study was to determine whether loss of heterozygosity (LOH) for chromosome 10 is an important prognostic variable in high-grade gliomas and whether it provides additional predictive information to the previously defined clinical prognostic indices. MATERIALS AND METHODS PatientsBetween January 1994 and April 1997, blood samples and pathological blocks of tumour material were collected prospectively from 42 patients diagnosed with high-grade glioma. Blood tumour Loss of chromosome 10 is an independent prognostic factor in high-grade gliomas Summary Loss of heterozygosity (LOH) for chromosome 10 is the most frequent genetic abn...

The in vivo monitoring of erosive wear is difficult because lesions mostly progress relatively slowly and reliable reference points are difficult to obtain. To date, only a few methods for clinical monitoring of erosive loss have been described, which either require extensive equipment or do not provide sufficient sensitivity. The aim of the present study was to evaluate, using study models (epoxy resin material), a procedure that permits the reliable and accurate monitoring of erosive substance loss within acceptable observation periods. The method is the profilometric measurement of erosive tissue loss using acid-resistant markers, which represent both a reference area and a structure for the defined retracing of a given erosive lesion surface. The study model magnified values slightly (2.8%; not significant), the precision was < 4 microm, and the repeatability was good (95% limits of repeatability ranging from -4.7 to 5.2 microm). The estimated detection threshold for erosive loss is 15 microm, which appears to be adequate for monitoring. The method is indicated for special dental care in cases of severe dental erosion (e.g. eating disorders) and for clinical studies.

This case is believed to be the first reported recurrent intracranial ganglioglioma with purely neuroblastomatous malignant transformation. A complete macroscopic resection of a right frontal lobe tumor in an 18-year-old woman revealed differentiated ganglioglioma. Seven years later a large, well-demarcated recurrent tumor was again macroscopically totally resected in the same patient. Histological analysis showed malignant transformation in only the neuronal component of the original tumor. A review of the literature on recurrent gangliogliomas and their malignant transformation is included.