The thyroids from 101 consecutive autopsies from Finland were subserially sectioned at 2-to 3-mm intervals. From 36 thyroids, 52 foci of occult papillary carcinoma (O K) were found, giving a prevalence rate of 35.6%. the highest reported rate in the world. The rate was higher, although not significantly, in males (43.3%) than in females (27.1%), but it did not correlate to the age of the patients. Twenty-six glands contained one tumor focus and ten glands contained two to five tumor foci. Only a minority of the smallest tumors can be detected with the method used. The probable number of O K s over 0.15 mm in diameter was calculated to be about 300 in this material. The tumor diameter varied from 0.15 mm to 14.0 mm, with 67% of tumors under 1.0 mm. The smallest tumors were usually circumscribed and were composed almost solely of follicles. Imrger tumors had more papillary structures and were often invasive. Fibrosis and, in the largest O K s , lymphocytic reaction were seen around the invasive islands. All tumors were positively stained for thyroglohulin and all but one of the tumors stained positively for epidermal keratin. OPC appears to arise from follicular cells of normal follicles. Apparently the great majority of the tumors remain small and circumscribed and even from those few tumors that grow larger and become invasive O K s only a minimal proportion will ever become a clinical carcinoma. According to the study, OPC can be regarded a s a normal finding which should not be treated when incidentally found. In order to avoid unnecessary operations it is suggested that incidentally found small O K s (less than 5 mm in diameter) were called occult papillary tumor instead of iarcinoma. Cuncer 56531-538, 1985. HYROID CARCINOMA is not a common disease; its T incidence rates range in different countries from 0.5 to 10 per lo5 persons.' In most countries, papillary carcinoma is the most common histologic type that comprises about 40% to 70% of all cases.'-5 Its incidence rates in the Scandinavian countries vary between 0.4 and 3.4 per 10' persons.6 Although papillary carcinoma is not common compared to many other human cancers, the prevalence rate of occult papillary carcinoma (O K) has been reported to be high, varying between 5.6% and 28.4% in several systematical autopsy studies.'-' '

This review summarizes reports of recurrent DNA sequence copy number losses in human neoplasms detected by comparative genomic hybridization. Recurrent losses that affect each of the chromosome arms in 73 tumor types are tabulated from 169 reports. The tables are available online at http:// www.amjpathol.org and http://www.helsinki.fi/ϳlgl _www/CMG.html. The genes relevant to the lost regions are discussed for each of the chromosomes. The review is supplemented also by a list of known and putative tumor suppressor genes and DNA repair genes (see Table 1 , online). Losses are found in all chromosome arms , but they seem to be relatively rare at 1q , 2p , 3q , 5p , 6p , 7p , 7q , 8q , 12p , and 20q. Losses and their minimal common overlapping areas that were present in a great proportion of the 73 tumor entities reported in Table 2 (see online) are (in descending order of frequency): 9p23-p24 (48%) , 13q21 (47%) , 6q16 (44%) , 6q26-q27 (44%) , 8p23 (37%), 18q22-q23 (37%) , 17p12-p13 (34%) , 1p36.1 (34%), 11q23 (33%) , 1p22 (32%) , 4q32-qter (31%) , 14q22-q23 (25%) , 10q23 (25%) , 10q25-qter (25%) ,15q21 (23%) , 16q22 (23%) , 5q21 (23%) , 3p12-p14 (22%), 22q12 (22%) , Xp21 (21%) , Xq21 (21%) , and 10p12 ( Knowledge of chromosomal deletions has significantly contributed to the detection of tumor suppressor genes, since the inactivation of one allele, according to the twohit hypothesis, often results from a deletion on the chromosomal level.

Purpose:The clinical significance of intratumoral or peritumoral lymph vessel density is not known. LYVE-1, a lymphatic endothelium-specific hyaluronan receptor, is a novel lymphatic vessel marker that is expressed on lymph vessel endothelial cells of both normal and neoplastic tissues.Experimental Design: We investigated expression of LYVE-1 by immunhistochemistry in 180 unilateral, invasive ductal breast carcinomas and assessed the presence and density of lymph vessels within the tumor and at the tumor periphery.Results: A minority (12%) of breast carcinomas had intratumoral lymph vessels, whereas peritumoral lymph vessels were identified in almost all cases (94%). No substantial association was found between the number of LYVE-1-positive vessels and the number of CD31 or vascular endothelial growth factor receptor-3-positive vessels, or vascular endothelial growth factor-C expression. The number of metastatic axillary lymph nodes increased in parallel with increasing lymph vessel counts (P ‫؍‬ 0.033). A higher than the median lymph vessel count at the tumor periphery was significantly associated with unfavorable distant disease-free survival and overall survival. Women with high peritumoral lymph vessel density had only 58% (95% confidence interval, 46 -70%) 5-year distant disease-free survival as compared with 74% (66 -83%) among those with a low peritumoral lymph vessel density (P ‫؍‬ 0.0088). In contrast, the presence of intratumoral lymph vessels was associated with neither axillary nodal status nor survival. Lymph vessel density was not an independent prognostic factor in a multivariate survival analysis.Conclusions: A high peritumoral lymph vessel density is associated with a poor outcome in ductal breast cancer.

Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3%) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer.

The genetic changes leading to thyroid cancer are poorly characterized. We studied DNA copy number changes by comparative genomic hybridization (CGH) in 69 primary thyroid carcinomas. In papillary carcinoma , DNA copy number changes were rare (3 of 26 , 12%). The changes were all gains , and they were associated with old age (P ‫؍‬ 0.01) and the presence of cervical lymph node metastases at presentation (P ‫؍‬ 0.08). DNA copy number changes were much more frequent in follicular carcinoma (16 of 20, 80%) than in papillary carcinoma (P < 0.0001), and follicular carcinomas had more often deletions (13/20 versus 0/26 , P < 0.0001). Loss of chromosome 22 was common in follicular carcinoma (n ‫؍‬ 7 , 35%) , it was more often seen in widely invasive than in minimally invasive follicular carcinoma (54% versus 0% , P ‫؍‬ 0.04) , and it was associated with old age at presentation (P ‫؍‬ 0.01). In three of the four patients with follicular carcinoma who died of cancer , the tumor had loss of chromosome 22. DNA copy number changes were found in 5 (50%) of the 10 medullary carcinomas studied. Four of these five carcinomas had deletions , and in two of them there was deletion of chromosome 22. Eleven (85%) of the thirteen anaplastic carcinomas investigated had DNA copy number changes , of which five had deletions , and one had deletion of chromosome 22. The most common gains in anaplastic carcinoma were in chromosomes 7p (p22-pter , 31%) , 8q (q22-qter , 23%) , and 9q (q34-qter , 23%). We conclude that DNA copy number changes are frequent in follicular , medullary, and anaplastic thyroid carcinoma but rare in papillary carcinoma when studied by CGH. Loss of chromosome 22 is particularly common in follicular carcinoma , and it is associated with the widely invasive type. (Am J Pathol 1999, 154:1539 -1547)The great majority of all thyroid cancers are either papillary, follicular, or anaplastic carcinomas, which are thought to be derived from follicular cells. Only 5% to 10% are medullary carcinomas, which originate from the C-cells.1 This histopathological classification of thyroid carcinomas into four major subtypes has been considered as established, and each of the four entities have typical clinical features. Papillary carcinoma frequently gives rise to cervical lymph node metastases, but distant metastases are rare. This pattern is reversed in follicular carcinoma, which often has distant bone metastases, but cervical lymph node metastases are rare. Papillary and follicular carcinoma are frequently found in the same thyroid as anaplastic carcinoma, suggesting that some anaplastic carcinomas originate from pre-existing differentiated carcinoma. 2,3The molecular genetic events in the evolution of different types of thyroid carcinomas are poorly characterized. However, the central role of mutations in the RET protooncogene, located at 10q11.2, in the genesis of hereditary medullary thyroid carcinoma is now well recognized, and used in screening of this disorder. More than 95% of patients with MEN 2A have missense germ line mu...

We describe the cloning and characterization of a new cytoplasmic protein designated epidermal growth factor receptor-associated protein with SH3-and TAM domains (EAST). It contains an Src homology 3 domain in its midregion and a tyrosine-based activation motif in its COOH terminus. Antibodies to EAST recognize a 68-kDa protein that is present in most chicken tissues. An epidermal growth factor (EGF)-dependent association between the EGF receptor (EGFR) and EAST was shown by reciprocal immunoprecipitation/immunoblotting studies with specific antibodies. Activated EGFR catalyzed the tyrosine phosphorylation of EAST, as judged by an in vitro kinase assay with both immunoprecipitated and purified EGFR. Immunoprecipitation/immunoblotting experiments also demonstrated an association between EAST and eps15, an EGFR substrate associated with clathrin-coated pits and vesicles, which is essential in the endocytotic pathway. The association between EAST and eps15 was not affected by EGF treatment. In immunofluorescence microscopy, EAST was shown to partially colocalize with clathrin. The sequence of the NH 2 -terminal portion of EAST shows a high degree of similarity with a group of proteins involved in endocytosis or vesicle trafficking. Thus, EAST is a novel signal transduction component probably involved in EGF signaling and in the endocytotic machinery.Signal transduction proteins are characterized by their capacity to specifically associate with other proteins to form multimolecular assemblies (1). In the case of receptor tyrosine kinases and receptor tyrosine kinase-induced intracellular signaling, such protein interactions are mediated by distinct protein domains. Among these, the Src homology 2 (SH2) 1 domain, which binds Tyr(P) residues in a specific context, and the Src homology 3 (SH3) domain, which binds sequences characterized by polyproline tracts, are the best known (2). In the epidermal growth factor receptor (EGFR), for instance, binding of the epidermal growth factor (EGF) leads to the phosphorylation of multiple tyrosine residues by the kinase activity of the receptor. These Tyr(P) residues serve as docking sites for various downstream, SH2-containing, signaling elements (3). These, in turn, can associate with other signaling proteins or substrates via other binding modules, such as SH3 domains.As new proteins and interactions are being discovered, new motifs are also disclosed. Thus, the phosphotyrosine-binding domain present in Shc and IRS-1, for example, recognizes Tyr(P) in a manner different from SH2 domains (4). Similarly, a distinct new type of tyrosine-containing, SH2-binding domain, termed tyrosine-based activation motif (TAM), has been found in antigen receptor molecules (5). TAM-containing receptors lack an intrinsic kinase activity and use TAM motifs to recruit and activate nonreceptor protein tyrosine kinases, such as members of the Src and Syk families (6), as their effectors.Many of the known signaling pathways are still only partially characterized, and their regulation is poorly underst...

Clinical and morphological features of three cases of primary mucoepidermoid carcinoma of the thyroid are described. The tumours were composed of two cell types. One of these resembled squamous epithelium and ultrastructurally showed tonofilaments and numerous desmosomes. The other cell type contained Alcian blue and mucicarmine positive mucin and, on electron microscopy, showed mucigen granules. Marked stromal fibrosis and psammoma bodies were seen in all tumours. Immunohistochemical studies showed that the tumour cells were negative for thyroglobulin. A few calcitonin-containing cells were seen in one metastatic tumour. One tumour showed, in addition to the histological features of mucoepidermoid carcinoma, anaplastic areas with obvious transition between the two histological patterns. The same thyroid also had a small thyroglobulin-positive papillary carcinoma in the opposite lobe. All tumours presented lymph node metastases. In two cases the primary tumour was confined within the thyroid capsule but that with anaplastic areas invaded surrounding structures. This patient died 13 months after diagnosis; the other patients are alive and symptomless one and 10 years since diagnosis. Mucoepidermoid carcinoma of the thyroid appears to be a clinicopathological entity that resembles papillary carcinoma in its natural history. The origin of the tumour is unclear. There is, however, some histological and immunohistological data suggesting that the tumour might be related to the ultimobranchial system although some histological features also appear to favour a common origin with papillary carcinoma.

Src-homology 3 (SH3) domain is a 60 -70-amino acid motif present in a large variety of signal transduction and cytoskeletal proteins. We used reverse transcriptase-polymerase chain reaction with degenerate and specific primers and chicken brain mRNA to clone a cDNA that codes for a novel SH3 domain-containing protein. The sequence predicts a 448-amino acid polypeptide with a molecular mass of 51,971 daltons. In the amino terminus, it shows a very high propensity for ␣-helicity, suggesting coiled-coil and possibly a higher order oligomeric arrangement. In the carboxyl terminus, there is a unique SH3 sequence. In Northern blotting, a major 3.7-kilobase and a minor 7.2-kilobase transcript was detected in most chicken tissues. In immunofluorescence microscopy and immunoelectron microscopy on cultured chicken fibroblasts, the protein was localized to focal adhesions in which it showed a distinct codistribution with the focal adhesion proteins vinculin, talin, and paxillin. Phosphoamino acid analysis showed that in cultured chicken heart fibroblasts, the protein contains phosphoserine, but no phosphothreonine or phosphotyrosine, and that the phosphorylation is not dependent on fibronectin. We propose this protein the name FAP52, for Focal Adhesion Protein of 52 kDa, and suggest that it forms part of the multimolecular complex constituting focal adhesion sites.