Somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid. (49/183)

Oxyphil or Hurthle cell tumours of the thyroid are characterised by their consistent excessive number of mitochondria. A recently discovered gene, GRIM-19 has been found to fulfil two roles within the cell: as a member of the interferon-beta and retinoic acid-induced pathway of cell death, and as part of the mitochondrial Complex I assembly. In addition, a gene predisposing to thyroid tumours with cell oxyphilia (TCO) has been mapped to chromosome 19p13.2 in one family. A cluster of genes involved in mitochondrial metabolism occurs in this region; one of these is GRIM-19. We have searched for GRIM-19 mutations in a series of 52 thyroid tumours. Somatic missense mutations in GRIM-19 were detected in three of 20 sporadic Hurthle cell carcinomas. A germline mutation was detected in a Hurthle cell papillary carcinoma arising in a thyroid with multiple Hurthle cell nodules. No mutations were detected in any of the 20 non-Hurthle cell carcinomas tested, nor in any of 96 blood donor samples. In one of the sporadic Hurthle cell papillary carcinomas positive for GRIM-19 mutation, we have also detected a ret/PTC-1 rearrangement. No GRIM-19 mutations were detected in any of the six cases of known familial Hurthle cell tumour tested, so that our results do not support the identification of GRIM-19 as the TCO gene. The GRIM-19 mutations we have detected are the first nuclear gene mutations specific to Hurthle cell tumours to be reported to date; we propose that such mutations can be involved in the genesis of sporadic or familial Hurthle cell tumours through the dual function of GRIM-19 in mitochondrial metabolism and cell death.  (+info)

Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome. (50/183)

Birt-Hogg-Dube syndrome (BHD), a genodermatosis characterized by multiple hamartomas of the hair follicle (fibrofolliculoma), predisposes individuals to an increased risk of developing renal neoplasms and spontaneous pneumothorax. Previously, we localized the BHD locus (also known as FLCN) to chromosome 17p11.2 by linkage analysis and subsequently identified germline mutations in a novel gene in probands from eight of the nine families with BHD in our screening panel. Affected members of five of the families inherited an insertion/deletion of a cytosine in a C8 tract in exon 11. This mutation was also identified by exon 11 screening in probands from 22 of 52 additional families with BHD and therefore represents a hypermutable "hotspot" for mutation in BHD. Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study. Mutations were located along the entire length of the coding region, including 16 insertion/deletion, 3 nonsense, and 3 splice-site mutations. The majority of BHD mutations were predicted to truncate the BHD protein, folliculin. Among patients with a mutation in the exon 11 hotspot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Coding-sequence mutations were not found, however, in probands from two large families with BHD whose affected members shared their family's BHD-affected haplotype. Of the 53 families with BHD whose members inherited either a germline mutation or the affected haplotype, 24 (45%) had at least one member with renal neoplasms. Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm. This study expands the BHD-mutation spectrum and evaluates genotype-phenotype correlations among families with BHD.  (+info)

Initial experience in use of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography in thyroid carcinoma patients with elevated serum thyroglobulin but negative iodine-131 whole body scans. (51/183)

INTRODUCTION: This study aims to examine the usefulness of fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in thyroid carcinoma patients with elevated serum thyroglobulin (Tg) but negative iodine-131 (I-131) whole body scans. METHODS: 17 patients with differentiated thyroid carcinoma who underwent FDG PET/CT scans were reviewed retrospectively over a period of one year from July 2003 to June 2004. All these patients had completion thyroidectomy and subsequently presented with elevated serum Tg but negative post-therapy I-131 whole body scans. Nine of these patients underwent FDG PET/CT in a hypothyroid state, while the remainder underwent FDG PET/CT while on thyroxine replacement. RESULTS: 15 out of 17 PET/CT scans revealed lesions consistent with metastases, giving a sensitivity of 88.2 percent. Four of these patients were amendable to surgical treatment. Two scans were negative. CONCLUSION: FDG PET/CT is a sensitive diagnostic tool to detect radioiodine-negative recurrences/metastases in patients with thyroid carcinoma. Our preliminary results are comparable with published results based on PET.  (+info)

Characterization of human pituitary adenomas in cell cultures by light and electron microscopic morphology and immunolabeling. (52/183)

The morphology and hormone production of pituitary adenoma cell cultures were compared in order to highlight their characteristic in vitro features. Cell suspensions were prepared from 494 surgical specimens. The 319 viable monolayer cultures were analyzed in detail by light microscopy and immunocytochemistry within two weeks of cultivation. Some cultures were further characterized by scanning, transmission and immunogold electron microscopy. The viability and detailed in vitro morphology of adenoma cells were found to be characteristic for the various types of pituitary tumors. The sparsely granulated growth hormone, the corticotroph and the acidophil stem cell adenomas provided the highest ratio of viable cultures. Occasionally, prolonged maintenance of cells resulted in long-term cultures. Furthermore, a variety of particular distributions of different hormone-containing granules were found in several cases. Both light microscopic and ultrastructural analyses proved that the primary cultures of adenoma cells retain their physiological features during in vitro cultivations. Our in vitro findings correlated with the routine histopathological examination. These results prove that monolayer cultures of pituitary adenoma cells can contribute to the correct diagnosis and are valid model systems for various oncological and neuroendocrinological studies.  (+info)

A metachronous, atypical, multifocal renal oncocytoma with a concomitant renal cell carcinoma of the contralateral side and bilateral multifocal oncocytomas: two case reports and review of literature. (53/183)

We present one case of a metachronous, atypical, multifocal renal oncocytoma with a concomitant chromophobe renal cell carcinoma (RCC) of the contralateral side and one case of bilateral and multifocal oncocytomas. Oncocytomas are benign renal tumours that rarely appear bilateral or multifocal or with coexisting RCC. A common pathogenic denominator of oncoytomas and RCC is being discussed. The first case was a 63 years old patient presenting with a history of nephrectomy for a pT1 G1 pN0 R0 papillary RCC 4 years prior to presentation, showed two tumours of a singular kidney. Upon nephron-sparing surgery one typical and one atypical oncocytoma with an invasion of the perinephric fat were found. Comparative genomic hybridisation was performed. Both tumours revealed genetic alterations with loss of genetic material on chromosome 1p. The second case was a 62 years old patient presenting with multifocal and bilateral renal tumours of undeclared dignity upon imaging. During open exploration all tumours could be removed by nephron-sparing surgery and were identified as oncocytomas. Again comparative genomic hybridisation was performed. All 4 tumours revealed genetic alterations with loss of genetic material on chromosome 1p, one of the tumours an additional loss of chromosome 10.  (+info)

Messenger RNA expression ratios among four genes predict subtypes of renal cell carcinoma and distinguish oncocytoma from carcinoma. (54/183)

PURPOSE: Morphologic distinction among clear cell, papillary, and chromophobe types of renal cell carcinoma (RCC) can be difficult, as is the differential diagnosis between oncocytoma and RCC. Whether these renal tumors can be distinguished by their mRNA expression profile of a few selected genes was examined. EXPERIMENTAL DESIGN: The expression of four genes in renal tumor was evaluated by quantitative reverse transcription-PCR: carbonic anhydrase IX (CA9), methylacyl-CoA racemase (AMACR), parvalbumin (PVALB), and chloride channel kb (CLCNKB). Thirty-one fresh-frozen and 63 formalin-fixed, paraffin-embedded tumor specimens were analyzed. RESULTS: CA9 expression was highest in clear cell carcinoma and lowest in chromophobe RCC and in oncocytoma. AMACR expression was highest in papillary RCC, and CLCNKB was highest in chromophobe RCC/oncocytoma. PVALB was highest in chromophobe RCC, variable in oncocytoma, and low in clear cell and papillary types. Similar findings were observed in fresh-frozen and formalin-fixed specimens. The mRNA expression ratios among these genes (i.e., CA9/AMACR and AMACR/CLCNKB ratios) further accentuate the gene expression differences among these tumors, and a molecular diagnostic algorithm was established. This algorithm accurately classified the 31 fresh-frozen tumors into 14 clear cell, 5 papillary, 6 chromophobe, and 6 oncocytomas. In the formalin-fixed group, the molecular criteria accurately classified the cases into 15 clear cell, 16 papillary, and 32 in the chromophobe/oncocytoma group but could only separate some, but not all, oncocytomas from chromophobe RCC. CONCLUSIONS: RNA expression ratios based on the four-gene panel can accurately classify subtypes of RCC as well as help distinguish some oncocytomas from chromophobe RCC.  (+info)

Collecting duct carcinoma associated with oncocytoma. (55/183)

Collecting duct carcinoma (CDC) is a rare, highly aggressive malignant neoplasm that arises from the collecting duct epithelium of the kidney. CDC was reported to coexist with renal cell and transitional cell carcinomas. We report a rare case of CDC associated with oncocytoma, confirmed by the characteristic histological appearance and immunohistochemistry. We also review the epidemiological, histological and immunohistochemical criteria for diagnosis, in addition to the genetic and cytogenetic aberrations reported in the literature. Identification and reporting CDC is important for the establishment of treatment strategies and monitoring prognosis.  (+info)

Fine-needle aspiration biopsy of Hurthle cell lesions of the thyroid gland: A cytomorphologic study of 139 cases with statistical analysis. (56/183)

BACKGROUND: Lesions of the thyroid gland composed of Hurthle cells encompass pathologic entities ranging from hyperplastic nodules with Hurthle cell metaplasia to Hurthle cell carcinomas. The cytologic distinction between these entities can be diagnostically challenging. Many cytologic features of Hurthle cell lesions that distinguish neoplastic Hurthle cell lesions requiring surgery from those that are benign and nonneoplastic have been described, but with variable usefulness. This is due, in part, to the small numbers of cases examined in previous studies and the limited application of statistical analysis. A morphologic study was made of 139 Hurthle cell lesions of the thyroid gland and statistical analysis applied to identify a set of cytomorphologic features that distinguish benign Hurthle cell lesions (BHCL) from Hurthle cell neoplasms (HCN). METHODS: Fine-needle aspiration biopsies (FNABs) of thyroid nodules with a predominant Hurthle cell component and corresponding histologic followup were included in the study. Cases were divided into BHCL and HCN groups on the basis of the histologic diagnosis. All cases were reviewed to assess the following 14 cytologic features: overall cellularity, cytoarchitecture, percentage of Hurthle cells, percentage of single cells, percentage of follicular cells observed as naked Hurthle cell nuclei, background colloid, chronic inflammation, cystic change, transgressing blood vessels (TBV), intracytoplasmic lumina, presence of multinucleated Hurthle cells, nuclear to cytoplasmic ratio, nuclear pleomorphism/atypia, and nucleolar prominence. The results were evaluated by using univariate and stepwise logistic regression (SLR) analysis; statistical significance was achieved at P-values < 0.05. RESULTS: One hundred thirty-nine FNAB specimens, corresponding to 56 HCN and 83 BHCL, fulfilled the study criteria. Six of the 14 cytologic features evaluated were shown by univariate analysis to be statistically significant in predicting HCN: nonmacrofollicular architecture (P < 0.001), absence of background colloid (P < 0.001), absence of chronic inflammation (P < 0.001), presence of TBV (P < 0.001), > 90% Hurthle cells (P < 0.001), and >10% single Hurthle cells (P = 0.014). The first four of these features were also shown to be statistically significant in the SLR analysis (P = 0.005, 0.010, 0.016, and 0.045, respectively), and when all four of these features were present HCN was correctly identified 86% of the time. CONCLUSIONS: In the current study of 139 FNAB specimens of thyroid Hurthle cell nodules, 14 cytologic features were examined and 6 were found to be statistically significant in identifying HCN. The following four features, when found in combination, were found to be highly predictive of HCN: nonmacrofollicular architecture, absence of colloid, absence of inflammation, and presence of TBV.  (+info)