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Review Article: The Familial Counterparts of Follicular Cell--Derived Thyroid Tumors
Abstract
The follicular cell-derived thyroid cancers (termed nonmedullary thyroid cancers-NMTCs) occur mostly sporadically, but intriguingly, NMTC has the highest familial risk among all cancer sites. This epidemiological observation is strengthened by the clinical occurrence of NMTC in familial aggregation (FNMTC) and by the detection of chromosomal loci in linkage with the disease phenotype. FNMTC loci have been proposed at 14q, 1q21, 19p13.2, 2q21, 8p23, 8q24, 1q21, and 6q22, but to date, no causative mutations have been linked to FNMTCs. In this review, the authors focus on the clinical, morphological, and molecular aspects that characterize familial tumors. Some morphological patterns may alert for a familial disease. FNMTCs share several of the somatic molecular changes associated with sporadic tumors. New genes affected by somatic changes have been disclosed within regions harboring FNMTC loci.
... 19p13.2 deletions are more frequently reported in HCT rather than in other tumors [4,20,[22][23][24]. ...
Hurthle cell tumors (HCTs) are rare thyroid neoplasia. To date, capsular and/or vascular invasion are the only findings predicting malignancy. Recently, mutation of 19p13, encoding two proteins involved in cell proliferation and apoptosis (GRIM-19 and p19), has been described. The aim of our study is to evaluate the cellular proliferation index (Ki67), GRIM-19 and p19 expression as diagnostic markers of malignancy in HCT.
Eighty patients with HCT (32 carcinomas, 48 adenomas) whom underwent surgery in our center were included. Samples of both neoplastic lesions and adjacent normal thyroid tissue were analyzed by means of tissue micro-arrays. Correlations between expressions of Ki67, GRIM-19 and p19 and final histology were analyzed.
Mean size of the lesion was higher in carcinomas than in adenomas (p = 0.01). GRIM-19 and p19 were significantly underexpressed in Hurthle cells tumors compared to normal tissue (p = 0.0004 and p = 0.0001, respectively). Ki67 and GRIM-19 were, respectively, higher and down-expressed in carcinomas compared to adenomas (p = 0.0004 and p = 0.005, respectively). On multivariate analysis, size correlates with carcinoma diagnosis. Neither GRIM-19 nor Ki67 index was related to size. The expression of p19 was reduced in both adenoma and carcinoma but differences were not statistically significant (p = 0.13).
Our study suggest that Ki67 and GRIM-19 correlate with malignancy in HCT. The expression of p19 is down-regulated in HCT, but it is not diagnostic of carcinoma. Ki67 and GRIM-19 may potentially help as cytological markers of malignancy in HCT.
Cancer derived from thyroid follicular epithelial cells is common; it represents the most common endocrine malignancy. The molecular features of sporadic tumors have been clarified in the past decade. However the incidence of familial disease has not been emphasized and is often overlooked in routine practice. A careful clinical documentation of family history or familial syndromes that can be associated with thyroid disease can help identify germline susceptibility-driven thyroid neoplasia. In this review, we summarize a large body of information about both syndromic and non-syndromic familial thyroid carcinomas. A significant number of patients with inherited non-medullary thyroid carcinomas manifest disease that appears to be sporadic disease even in some syndromic cases. The cytomorphology of the tumor(s), molecular immunohistochemistry, the findings in the non-tumorous thyroid parenchyma and other associated lesions may provide insight into the underlying syndromic disorder. However, the increasing evidence of familial predisposition to non-syndromic thyroid cancers is raising questions about the importance of genetics and epigenetics. What appears to be “sporadic” is becoming less often truly so and more often an opportunity to identify and understand novel genetic variants that underlie tumorigenesis. Pathologists must be aware of the unusual morphologic features that should prompt germline screening. Therefore, recognition of harbingers of specific germline susceptibility syndromes can assist in providing information to facilitate early detection to prevent aggressive disease.
Our current approach to evaluation and treatment of PTC in children and adolescents has been extrapolated from the treatment of PTC in adults. While the histology of the cancer is the same, the clinical behavior of PTC in children is very different and the potential short- and long-term risks of complications from treatment are expressed over a greater period of time. As the pediatric community continues to search for the safest and most effective treatment options for children, one must be cognizant that our current knowledge and approach to care is based on retrospective chart reviews. These reviews often cover decades of time with great variations in age of patient, degree of iodine sufficiency, and details of surgical as well as medical evaluation and management. While the last decade has witnessed a marked increase in the number of reports on pediatric thyroid cancer, information on 30–40-year posttreatment follow-up remains quite limited. These disparities and unknowns continue to create controversy in treatment as we strive to balance and individualize the use of aggressive surgical and medical treatment for a cancer that on presentation appears aggressive, with an increased frequency of regional and pulmonary metastasis, but, in contrast to adults, appears to have a more indolent, long-term natural history and lower incidence of disease-specific mortality.
Thyroid nodules are diagnosed less frequently in children and adolescents when compared to adults. However, similar to adults, the incidence of both thyroid nodules and thyroid cancer in pediatric patients has increased over the last several decades. The reason for the increase is not entirely clear but is likely related to a combination of several factors, to include an increase in incidentally discovered thyroid nodules found during non-thyroid-related head and neck imaging (ultrasound (US), CT, and MRI), increased use of radiological surveillance for children at risk of developing thyroid malignancy (i.e., survivors of primary malignancy exposed to radiation therapy), and variety of additional factors with unknown but confounding impact such as the presence of autoimmune thyroid disease, the degree of iodine sufficiency, and exposure to medical and environmental ionizing radiation. In adult patients, there is controversy whether the increasing incidence of thyroid cancer is related to the identification of subclinical disease. This same concern is relevant to the pediatric age as well, however, because of a fivefold risk of malignancy for a nodule discovered in a child or adolescent when compared to an adult patient (25 % vs 5 %, respectively). Thorough evaluation of the nodule found in a child or adolescent should be based on individual risk factors and ultrasound features rather than on the method of discovery.
These considerations highlight the importance of establishing appropriate clinical expertise and resources in order to perform accurate evaluation and management.
Non‐medullary thyroid carcinoma (NMTC) represents over 90% of thyroid neoplasms. This may be associated to various syndromes or arise in non‐syndromic families called, in this case, familial non‐medullary thyroid carcinoma (FNMTC).Objectives
This paper aims to review the incidence, pathogenesis and clinical guidance of the familial forms of NMTC.Method
The literature research, made at the PubMed database, was conducted between January 2008 and December 2013 using as key search terms: «familial nonmedullary thyroid carcinoma» and « FNMTC ».Conclusion
This theme has been target of intense research; however the genes involved in its pathogenesis are still poorly known. Consequently, in order to understand the mechanisms involved and eventual therapeutic modifications, new tests and studies are needed.
The biology and the genetics of Hürthle cell tumors are reviewed starting from the characterization and differential diagnosis of the numerous benign and malignant, neoplastic and nonneoplastic lesions of the thyroid in which Hürthle cell transformation is frequently observed. The clinicopathologic and molecular evidence obtained from the comparative study of the aforementioned conditions indicate that Hürthle cell appearance represents a phenotype that is superimposed on the genotypic and conventional histopathologic features of the tumors. Hürthle cell tumors differ from their non-Hürthle counterparts regarding the prevalence of large deletions of mitochondrial DNA (mtDNA), mutations of mtDNA genes coding for oxidative phosphorylation (OXPHOS) proteins (namely mutations of complex I subunit genes) and mutations of nuclear genes coding also for mitochondrial OXPHOS proteins. Such mitochondrial alterations lead to energy production defects in Hürthle cell tumors; the increased proliferation of mitochondria may reflect a compensatory mechanism for such defects and is associated with the overexpression of factors involved in mitochondrial biogenesis. The mitochondrial abnormalities are also thought to play a major role in the predisposition for necrosis instead of apoptosis which seems to be blocked in most Hürthle cell tumors. Finally, the results obtained in experimental models using cybrid cell lines and the data obtained from histopathologic and molecular studies of familial Hürthle cell tumors are used, together with the aforementioned genetic and epigenetic alterations, to progress in the understanding of the mechanisms through which mitochondrial abnormalities may be involved in the different steps of thyroid carcinogenesis, from tumor initiation to metastization.
Background: Papillary thyroid carcinoma can have familial aggregation. Aim: To compare retrospectively familial non medullary thyroid carcinoma (FNMTC) with sporadic papillary thyroid carcinoma (PTC). Material and methods: Retrospective analysis of medical records of patients with thyroid carcinoma. An index case was defined as a subject with the diagnosis of differentiated thyroid carcinoma with one or more first degree relatives with the same type of cancer. Seventeen such patients were identified and were compared with 352 subjects with PTC. Results: The most common affected relatives were sisters. Patients with FNMTC were younger than those with PTC. No differences were observed in gender, single or multiple foci, thyroid capsule involvement, surgical border involvement, number of affected lymph nodes and coexistence of follicular hyperplasia. Patients with FNMTC had smaller tumors and had a nine times more common association with lymphocytic thyroiditis. Five patients with FNMTC had local recurrence during 4.8 years of follow up. Conclusions: Patients with FNMTC commonly have an associated chronic thyroiditis, are younger and have smaller tumors than patients with PTC
Familial adenomatous polyposis (FAP) is caused by germ-line mutations of the apc gene, and it is associated with an increased risk of developing papillary thyroid carcinomas. We have previously reported that a significant fraction of sporadic human papillary thyroid carcinomas is characterized by gene rearrangements affecting the ret protooncogene. These rearrangements generate chimeric transforming oncogenes designated ret/ptc. By a combined immunohistochemical and RT-PCR approach, we analyzed, for ret/ptc oncogene activation, papillary thyroid carcinomas occurred in two FAP kindreds, both showing typical apc gene mutations. Kindred 1 had seven members affected by FAP, and among these, three patients showed papillary thyroid carcinomas. Kindred 2 had two patients, mother and daughter, affected by colonic polyposis; the 20-yr-old daughter showed also a papillary carcinoma. Here we report that ret/ptc1 oncogene was activated in two of the three papillary carcinomas of FAP kindred 1 and in the papillary carcinoma of FAP kindred 2. These findings document that loss of function of apc coexists with gain of function of ret in some papillary thyroid carcinomas, suggesting that ret/ptc1 oncogene activation could be a progression step in the development of FAP-associated thyroid tumors.
Papillary thyroid carcinoma (PTC) displays higher heritability than most other cancers. To search for genes predisposing to PTC, we performed a genome-wide linkage analysis in a large family with PTC and melanoma. Among several peaks the highest was at 8q24, with a maximum nonparametric linkage (NPL) score of 7.03. Linkage analysis was then broadened to comprise 25 additional PTC families that produced a maximum NPL score of 3.2, P = 0.007 at the 8q24 locus. Fine mapping with microsatellite markers was compatible with linkage to the 8q24 locus in 10 of the 26 families. In the large family, a approximately 320 Kb haplotype was shared by individuals with PTC, melanoma, or benign thyroid disease, but not by unaffected individuals. A 12 Kb haplotype of 8 SNP markers within the larger haplotype was shared by 9 of the 10 families in which the 8q24 locus was compatible with linkage. The shared haplotype is located within 2 known overlapping protein-coding genes, thyroglobulin (TG) and Src-like adaptor (SLA). Resequencing of the coding and control regions of TG and SLA did not disclose putative mutations in PTC patients. Embedded in the TG-SLA region are three likely noncoding RNA genes, one of which (AK023948) harbors the 8-SNP haplotype. Resequencing of AK023948 and one of the other RNA genes did not reveal candidate mutations. Gene expression analysis indicated that AK023948 is significantly down-regulated in most PTC tumors. The putative noncoding RNA gene AK023948 is a candidate susceptibility gene for PTC.
Non-medullary thyroid carcinoma (NMTC) is mostly sporadic, but familial clustering is described. We aimed to compare the features of patients with sporadic and familial NMTC (FNMTC) patients and to assess whether FNMTC patients with parent-child relationship exhibit the 'anticipation' phenomenon (earlier age at disease onset and increased severity in successive generations). Among 300 NMTCs followed in the Section of Endocrinology (University of Siena, Italy), 34 (11.3%) patients, all with the papillary histotype, (16 kindred), met the criteria of FNMTC. Twenty-seven of them (79.4%) exhibited a parent-child relationship and seven (20.6%) a sibling relationship. These patients were compared with 235 patients with sporadic papillary thyroid cancer (PTCs). To analyze the features of FNMTC of the first and second generations, we cumulated the series of Siena with 32 additional FNMTC patients (15 kindred) from the Department of Endocrinology-Endocrine Oncology, Thessaloniki, Greece. Significant difference between sporadic PTC and FNMTC patients included more frequent tumor multifocality (P=0.001) and worse final outcome in FNMTC patients (P=0.001). Among 47 FNMTC with parent-child relationship, we found an earlier age at disease presentation (P<0.0001), diagnosis (P<0.0001), and disease onset (P=0.04) in the second generation when compared with the first generation. Patients in the second generation were more frequently males (P=0.02); their tumors were more frequently multifocal (P=0.003) and bilateral (P=0.01), had higher rate of lymph node metastases at surgery (P=0.02) and worse outcome (P=0.04) when compared with the first generation. In conclusion, FNMTC displays the features of clinical 'anticipation' with the second generation acquiring the disease at an earlier age and having more advanced disease at presentation.
Familial nonmedullary thyroid carcinoma (FNMTC) accounts for approximately 5% of all thyroid tumors. Genetic mapping studies have identified four different chromosomal regions predisposing to FNMTC: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32), and TCO (19p13.2).
Our objective was to map the gene predisposing to familial thyroid epithelial neoplasia in a large Portuguese family.
The clinical screening of a Portuguese family identified 11 members affected with benign thyroid lesions and five affected with thyroid carcinomas. Linkage analysis excluded the involvement of the fPTC/PRN, NMTC1, MNG1, and TCO loci. To map the gene predisposing to thyroid epithelial neoplasia in this family, a genome-wide linkage analysis was conducted, using DNA samples from 17 family members and high-density single-nucleotide polymorphism arrays. A genome-wide significant evidence of linkage, to a single region on chromosome 8p23.1-p22 was obtained, with a maximum parametric haplotype-based LOD score of 4.41 (theta=0.00). Linkage analysis with microsatellite markers confirmed linkage to 8q23.1-p22, and recombination events delimited the minimal region to a 7.46-Mb span. Seventeen suggestive candidate genes located in the minimal region were excluded as susceptibility genes by mutational analysis. Allelic losses in the 8p23.1-p22 region were absent in seven thyroid tumors from family members, suggesting that the inactivation of a putative tumor suppressor gene may have occurred through other mechanisms.
Our results present evidence for the existence of a novel familial thyroid epithelial neoplasia susceptibility locus on chromosome 8p23.1-p22, providing the basis for the identification of a gene for this disease.
PURPOSES OF THE STUDY: In contrast to familial medullary carcinoma, familial nonmedullary thyroid carcinoma (FNMTC) is less frequent and has been less investigated. The aim of this study was to determine the frequency of FNMTC and analyse the main demographic and clinical characteristics of the patients.
Data on 1411 patients surgically treated for nonmedullary thyroid carcinoma, in the Center for Endocrine Surgery in Belgrade, from 1995 to 2006 were analysed. The possible presence of malignant tumours of the thyroid gland was investigated in their closest relatives in order to identify cases of FNMTC. Only data on first-degree relatives (parents and children) and second-degree relatives (grandparents, grandchildren and siblings) were taken into account in the analysis.
Thirteen patients (11 females and 2 males) (0.92% of those with nonmedullary carcinoma of the thyroid gland) had a familial form of the disease. In five families two members had a tumour, and in one family three members. In five out of six families it was a papillary carcinoma and in one family a follicular carcinoma. Patient age varied from 20 to 79 years, with a mean age of 40 years. The tumour size ranged from 5 to 60 mm (mean 25 mm). In two of the thirteen cases the tumour penetrated the capsule of the thyroid gland. In four cases the tumour was multicentric and bilateral, and in a further two metastases were present in regional lymph nodes. During the follow-up period, which lasted from 2 to 12 years (mean 8.5 years), two relapses were detected.
Familial nonmedullary carcinoma of the thyroid gland occurs very rarely.
Eighteen members of an extended pedigree have been found to have a form of euthyroid adolescent multinodular goiter. Histological examination showed multiple adenomata with areas of epithelial hyperplasia, hemorrhage, and calcification. In two subjects there were focal areas of epithelial hyperplasia reminiscent of low-grade papillary carcinoma, but capsular and vascular invasion was not found. The pattern of inheritance appeared to be autosomal dominant, with diminished penetrance in males. Although the patients were euthyroid, the likely basis for this disorder is an abnormality in thyroglobulin structure and function.
In a population-based case-control study in the Uppsala-Orebro Health Care Region of Sweden, the histories of cancer among parents of 517 histologically confirmed cases of papillary and follicular carcinoma and of a similar number of sex- and age-matched controls were compared. The parental history of cancer was compiled through information from death certificates and from the nationwide Cancer Register. The incidence of malignancies in a cohort of parents of cases of thyroid cancer was also compared with the incidence in the whole Swedish population. A maternal history of cancer was more common among women with follicular carcinoma than among their controls (OR 2.11, 95% CI 0.96-4.67). Parents of probands with papillary carcinoma had an increased risk of thyroid cancer (OR 4.25, 95% CI 1.16-10.89), and mothers of probands with follicular carcinoma had an increased risk of stomach cancer (OR 3.65, 95% CI 0.99-9.35) compared with the general population. Cancer of the lung, breast, and pancreas were less common than in the general population. Familial cases of thyroid cancer were not limited to the papillary type. An inheritable pattern of carcinogenesis is possible for certain differentiated non-medullary thyroid cancers, but shared environmental exposures may also explain the parent-child associations of cancer in this study.
Papillary carcinoma of the thyroid (PTC) is the most prevalent malignancy of the thyroid gland. Although the majority of lesions are sporadic tumors, an established relationship exists between familial adenomatous polyposis (FAP) and PTC. Moreover, some authors postulate the existence of familial PTC as a distinct entity. Evidence for this is limited, however, there being few well characterized descriptions of pedigrees with high prevalence of PTC.
The objective of the present study was to examine an apparent heritable predisposition to PTC occurring in two Tasmanian families in which PTC occurs commonly.
Pedigree charts were constructed for both families and the medical records of the members reviewed.
In Pedigree I, 7 of 25 members had PTC (6 of these had coexisting multinodular goiter (MNG), and 11 others had MNG. In Pedigree II, identical male twins and their daughters had PTC.
In both families there is evidence of autosomal dominant inheritance of PTC. The association of PTC with MNG suggests a possible role for MNG in tumor pathogenesis in hereditary PTC. The majority of the patients were diagnosed with PTC before commencement of prospective screening, indicating clinically relevant disease in the families described.
A high frequency (about 60%) of ret rearrangements in papillary thyroid carcinomas of children exposed to radioactive fallout in Belarus after the Chernobyl accident, has been reported by three recent studies (Fugazzola et al., 1995; Ito et al., 1994; Klugbauer et al., 1995). These studies suggested that the radiation exposure may be a direct inducer of activating rearrangements in the ret gene. In order to confirm the postulated link between irradiation and the role of the ret proto-oncogene in thyroid tumorigenesis, we analysed for the presence of ret activating rearrangements using RT-PCR, XL-PCR, Southern blot and direct sequencing techniques, 39 human thyroid tumors (19 papillary carcinomas and 20 follicular adenomas), from patients who had received external radiation for benign or malignant conditions. As controls, we studied 39 'spontaneous' tumors (20 papillary carcinomas and 19 follicular adenomas). Our data concerning the radiation-associated tumors, showed that: (1) the overall frequency of ret rearrangements was 84% in papillary carcinomas (16/19) and 45% (9/20) in follicular adenomas; (2) in contrast with the results obtained in the Chernobyl tumors, the most frequently observed chimeric gene was RET/PTC1 instead of the RET/PTC3 and (3) all the tumors were negative for RET/PTC2. In the 'spontaneous' tumors, only the papillary carcinomas presented a ret rearrangement (15%:3/20): 1 RET/PTC1, 1 RET/ PTC3 and 1 uncharacterized. In conclusion, our results confirm the crucial role played by the ret proto-oncogene activating rearrangements in the development of radiation-associated thyroid tumors appearing after therapeutic or accidental ionizing irradiation, and show, for the first time, the presence of RET/PTC genes in follicular adenomas appeared after external irradiation.
The papillary carcinoma family (PCF) of thyroid tumors includes a wide variety of neoplastic entities regarded as well-differentiated, poorly differentiated, and undifferentiated papillary thyroid carcinomas. Recent studies have established the presence of alternative oncogenic rearrangements of the RET and NTRK1 genes in a consistent fraction (< or = 50%) of papillary thyroid tumors. RET oncogenic rearrangements are also very frequent (approximately 60%) in Chernobyl radiation-associated papillary thyroid neoplasias, which show an increased aggressiveness in terms of pathological stage at disease onset. These observations prompted us to study the relationship between the presence or absence of RET and NTRK1 oncogenes and the clinicopathological features (age, sex, histopathology, and pTNMC2 staging) of 76 consecutive, non-radiation-related tumors of the PCF. As previously reported, statistical univariate analysis revealed a correlation between the combination of RET and NTRK1 (RET/NTRK1) positivity and young age of patients at diagnosis. In addition, a significant association was found between RET/NTRK1 positivity and locally advanced stage of disease at presentation (pT4: P < 0.015). The multivariate analysis confirmed that RET/NTRK1 activation parallels an unfavorable disease presentation, which may correlate with a less favorable disease outcome. Furthermore, within the PCF, the frequency of RET/NTRK1 positivity was not influenced by the different neoplastic subtypes or the tumor versus degree of differentiation.
Werner syndrome (WS), an autosomal recessive disease characterized by premature aging, has a high frequency of association with six rare neoplasms in Japanese patients, and only four of these neoplasms also occur excessively in whites. Several differ from what is usual in their epidemiology and/or histology. Described in this article are peculiarities in the occurrences of follicular and papillary thyroid carcinomas among Japanese patients and the possible genotype-phenotype relations pertaining to cell types and the absence of excess thyroid carcinoma occurrence in whites with WS.
Epidemiologic features of 23 histologically diagnosed thyroid carcinomas from a series of 150 cancers in 845 Japanese patients with WS were compared with those of 19,446 tumors in a Japanese national registry of thyroid carcinomas from 1977-1991. Germline mutations had been determined by molecular studies of peripheral blood.
The average age of patients with thyroid carcinoma was 39 years for those with WS and 49 years for the registry patients. The female-to-male ratios were 2.3:1 and 6.6:1, respectively. The rates of occurrence of papillary, follicular, and anaplastic carcinomas were 35%, 48%, and 13% for Japanese patients with WS and 78%, 14%, and 2% in the general Japanese population. All four cases of follicular carcinoma had germline mutations of the WS gene in the C-terminal region, and the germline mutation for the only papillary carcinoma was in the N-terminal region.
This study suggests two possible WS genotype-phenotype relations. One concerns thyroid carcinoma histology; the other concerns frequent mutations that occur in the C-terminal region in Japanese patients, but not in white patients, with WS. These may account for the excess thyroid carcinoma occurrence among Japanese.
Context.—Cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) is one of the rare types of papillary carcinoma. It has been associated with familial adenomatous polyposis, though it can also occur sporadically. The molecular pathogenesis of this tumor is incompletely understood. It appears that there can be molecular contributions from the RET/PTC translocations and from mutations in the APC gene and β-catenin gene, which are both part of the Wnt signaling pathway. However, one of the most common mutations in papillary carcinoma, the BRAF mutation, has not been reported in this variant of papillary carcinoma.
Objective.—To investigate the BRAF mutational status in CMVPTC.
Design.—Four cases of CMVPTC (1 associated with familial adenomatous polyposis and the others apparently sporadic) were identified from the files of 3 large centers. Deoxyribonucleic acid was extracted and successfully amplified from each case. The polymerase chain reaction products were sequenced and evaluated for the T1799A BRAF mutation.
Results.—None of the 4 cases harbored the T1799A BRAF mutation (0/4).
Conclusions.—The T1799A BRAF mutation does not appear to play a role in the tumorigenesis of CMVPTC.
• Although the number of reported cases of papillary carcinoma of the thyroid in families is few, a review of the literature and the three cases presented here strongly suggest the characteristics of hereditary cancer. Further study and reportage of similar cases is indicated to confirm whether this is indeed a familial cancer.(Arch Surg 1981;116:836-837)
BACKGROUND
Werner syndrome (WS), an autosomal recessive disease characterized by premature aging, has a high frequency of association with six rare neoplasms in Japanese patients, and only four of these neoplasms also occur excessively in whites. Several differ from what is usual in their epidemiology and/or histology. Described in this article are peculiarities in the occurrences of follicular and papillary thyroid carcinomas among Japanese patients and the possible genotype–phenotype relations pertaining to cell types and the absence of excess thyroid carcinoma occurrence in whites with WS.METHODS
Epidemiologic features of 23 histologically diagnosed thyroid carcinomas from a series of 150 cancers in 845 Japanese patients with WS were compared with those of 19,446 tumors in a Japanese national registry of thyroid carcinomas from 1977–1991. Germline mutations had been determined by molecular studies of peripheral blood.RESULTSThe average age of patients with thyroid carcinoma was 39 years for those with WS and 49 years for the registry patients. The female-to-male ratios were 2.3 : 1 and 6.6 : 1, respectively. The rates of occurrence of papillary, follicular, and anaplastic carcinomas were 35%, 48%, and 13% for Japanese patients with WS and 78%, 14%, and 2% in the general Japanese population. All four cases of follicular carcinoma had germline mutations of the WS gene in the C-terminal region, and the germline mutation for the only papillary carcinoma was in the N-terminal region.CONCLUSIONS
This study suggests two possible WS genotype–phenotype relations. One concerns thyroid carcinoma histology; the other concerns frequent mutations that occur in the C-terminal region in Japanese patients, but not in white patients, with WS. These may account for the excess thyroid carcinoma occurrence among Japanese. Cancer 1999;85:1345–52. © 1999 American Cancer Society.
A study of 169 oxyphil tumours of the thyroid, correlating histological features with age, sex, thyroiditis, and available clinical history, has shown two significant findings relevant to pathogenesis, diagnosis, and treatment. Oxyphil tumours with a papillary architecture can be divided into papillary carcinomas with secondary oxyphilia and true oxyphil tumours. The tumours of the former group are typically unencapsulated, invasive, show nuclei characteristic of papillary carcinoma generally, are associated with thyroiditis, and frequently show psammoma bodies. The tumours of the latter group are typically encapsulated, with nuclei similar to those found in other oxyphil tumours; usually lack psammoma bodies; and some show capsular and vascular invasion. Papillary architecture alone is not thought to justify a diagnosis of malignancy in this group of tumours, and further study with follow-up is needed to determine the appropriate treatment. It is suggested that oxyphilia in the first group is secondary to the accompanying thyroiditis, comparable to the oxyphilia in follicular cells in Hashimoto's thyroiditis, while the oxyphilia in the latter group, as in other oxyphil tumours, is due to a somatic mutation leading to an increase in mitochondrial number. About 20 per cent of all cases showed multiple oxyphil tumours. These were more frequently female, more often associated with thyroiditis, younger, and less often malignant than solitary tumours. The occurrence of multiple tumours of the same uncommon histological type in these patients is compatible with a germline mutation conferring a liability to oxyphil follicular cell tumours. This is supported by the occurrence of oxyphil tumours in families; the present series of cases included two mother–daughter pairs and similar examples have been reported, including multiple oxyphil tumours in identical twins. Further studies are needed to identify the gene involved and any co-operating genes. Oxyphil carcinoma in patients with multiple oxyphil tumours occurred at a mean age 10 years greater than that for multiple adenomas, suggesting that the carcinomas arose by progression from adenomas. It is important to complete thyroidectomy in a case with multiple oxyphil tumours if there is evidence of the presence of lesions in both lobes. It is necessary to consider the differences between primary and secondary oxyphilia, and between sporadic and multiple or familial oxyphil tumours in future studies of these lesions.Copyright © 1998 John Wiley & Sons, Ltd.
Comparisons of cancer risks in persons by sibling cancers and those by parental cancers are informative of elucidating the potential genetic modes in the etiology of the cancers. The Swedish Family-Cancer Database was used to systematically estimate the effects of parental and sibling cancers on the cancer risks in the individuals born after 1934 (offspring). The study population included 5,520,756 offspring and their parents from 2,112,616 nuclear families. Standardized incidence ratios (SIRs) were calculated to analyze the risks for cancers in offspring by parental cancers (offspring risk) and by sibling cancers (sibling risk). For 20 concordant sites, all offspring and sibling risks were significantly increased except for sibling risks for squamous cell carcinoma of the skin and myeloma. Apart from breast cancer, the SIRs were more than 10 when offspring had both an affected parent and an affected sib at the concordant site. The ratio for the sibling to offspring risk was around 2.0 or more for gastric, renal, non-thyroid endocrine, urinary bladder, colon, testicular and prostate cancers and leukemia. For discordant sites, many reported across-site associations were confirmed and several consistent novel associations (rectum-skin, breast-endocrine and lung-endocrine) were found only among sibs. Our findings suggested that low-penetrance polygenic dominant effects or dominant genes of high penetrance but low mutant allele frequency in the population may be involved in the observed familial cancers at many sites. Recessive or X-linked effects may contribute particularly to gastric, renal, non-thyroid endocrine, bladder, colon, testicular and prostate cancers and leukemia. The search for pleiotropic recessive/X-linked susceptibility genes should be well motivated based on our results. © 2001 Wiley-Liss, Inc.
Familial nonmedullary thyroid cancer (FNMTC) is associated with earlier onset and more aggressive behavior than its sporadic counterpart. Although candidate chromosomal loci have been proposed for isolated families with variants of FNMTC, the etiology of most cases is unknown. We aimed to identify loci linked to FNMTC susceptibility using single-nucleotide polymorphism (SNP) array-based linkage analysis in a broad sampling of affected families.
We enrolled and pedigreed 38 FNMTC families. Genomic DNA was extracted from the peripheral blood of 110 relatives, and hybridized to Affymetrix SNP arrays. We performed genotyping and linkage analysis, calculating exponential logarithm-of-the-odds (LOD) scores to identify chromosomal loci with a significant likelihood of linkage.
Forty-nine affected and 61 unaffected members of FNMTC families were genotyped. In pooled linkage analysis of all families, 2 distinct loci with significant linkage were detected at 6q22 and 1q21 (LOD=3.3 and 3.04, respectively).
We have identified 2 loci on chromosomes 1 and 6 that demonstrate linkage in a broad sampling of FNMTC families. Our findings suggest the presence of germline mutations in heretofore-undiscovered genes at these loci, which may potentially lead to accurate genetic tests. Future studies will consist of technical validation and subset analyses of higher-risk pedigrees.
Cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) is one of the rare types of papillary carcinoma. It has been associated with familial adenomatous polyposis, though it can also occur sporadically. The molecular pathogenesis of this tumor is incompletely understood. It appears that there can be molecular contributions from the RET/PTC translocations and from mutations in the APC gene and beta-catenin gene, which are both part of the Wnt signaling pathway. However, one of the most common mutations in papillary carcinoma, the BRAF mutation, has not been reported in this variant of papillary carcinoma.
To investigate the BRAF mutational status in CMVPTC.
Four cases of CMVPTC (1 associated with familial adenomatous polyposis and the others apparently sporadic) were identified from the files of 3 large centers. Deoxyribonucleic acid was extracted and successfully amplified from each case. The polymerase chain reaction products were sequenced and evaluated for the T1799A BRAF mutation.
None of the 4 cases harbored the T1799A BRAF mutation (0/4). Conclusions.-The T1799A BRAF mutation does not appear to play a role in the tumorigenesis of CMVPTC.
Although the responsible genes have not yet been identified, it is known that the risk of nonmedullary thyroid carcinoma is elevated in individuals with 1st-degree relatives with nonmedullary thyroid carcinoma. However, it remains controversial whether the biological character of familial nonmedullary carcinoma (FNMTC) differs from that of sporadic carcinoma. In this study, we investigated the prevalence of familial papillary carcinoma and its biological behavior.
Between 1987 and 2004, 6,015 patients underwent initial surgical treatment for papillary carcinoma at Kuma Hospital and 273 (4.5%) were classified as having familial carcinoma. We compared the biological characteristics including prognosis between familial and sporadic papillary carcinomas.
Disease-free survival and cause-specific survival rates of familial carcinoma did not differ from those of sporadic carcinoma. Familial papillary carcinoma showed multicentricity and recurrence to the thyroid more frequently than sporadic carcinoma. There were no differences in other clinicopathological parameters between the 2 groups.
Prognosis of patients with familial papillary carcinoma did not differ from that of those with sporadic papillary carcinoma. Although routine total thyroidectomy is recommended for familial papillary carcinoma, its therapeutic strategy can otherwise be the same as that for sporadic papillary carcinoma.
Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p < 0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p < 0.001), thyroid (5/10 versus 15/106, p < 0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.
Differentiated thyroid cancers were found in mother and son. The diagnosis was made first in the boy where papillary and follicular cancer with lymph node involvement and lung metastatic dissemination was diagnosed at the age of 9. Treatment by surgery, radioiodine and thyroid hormones was highly effective. 1 year later, thyroid surgery was performed on his mother but the diagnosis of poorly differentiated follicular thyroid cancer was made only 4 years later when the primary tumour was already unresectable and distant metastases present. In spite of treatment, the disease followed a lethal course in the mother. The familial occurrence of differentiated thyroid cancer is extremely rare and this report is the first where neither previous radiation exposure nor familial colonic polyposis were detected.
A 38-year-old woman had bilateral papillary thyroid carcinoma. Her brother and mother also had papillary thyroid carcinoma. The literature on familial papillary thyroid carcinoma is reviewed briefly.
We recently detected a novel activated oncogene by transfection analysis on NIH 3T3 cells in five out of 20 primary human thyroid papillary carcinomas and in the available lymph node metastases. We designated this transforming gene PTC (for papillary thyroid carcinoma). Here we describe the molecular cloning and sequencing of the gene. The new oncogene resulted from the rearrangement of an unknown amino-terminal sequence to the tyrosine kinase domain of the ret proto-oncogene. This gene rearrangement was detected in all of the transfectants and in all of the original tumor DNAs, but not in normal DNA of the same patients, thus indicating that this genetic lesion occurred in vivo and is specific to somatic tumors. Moreover, the transcript coded for by the fused gene was detected in an additional PTC-positive human papillary carcinoma for which mRNA was available.
Although a higher incidence of medullary carcinoma of the thyroid is well known to occur in families with syndromes of multiple endocrine neoplasia (MEN II and III), an epidemiologic familial component has only very rarely been ascribed to papillary carcinoma. In this report we describe a mother and daughter presenting with neck masses at an early age and subsequently found to have metastatic papillary thyroid carcinoma documented on pathology following thyroidectomy. The occurrence of the neoplasm at an advanced stage in closely related individuals early in life suggests that underlying genetic factors may predispose to this malignancy. Familial papillary carcinoma of the thyroid may have a hereditary basis independent of its association with the syndromes of multiple polyposis and of multiple hamartomas, and thus may represent a new entity with characteristics which distinguish it as a distinct subset of the more common disease.
Familial occurrence of differentiated, nonmedullary thyroid carcinoma in 23 patients from 11 families is reported. Five patients were male and 18 were female. The familial relationship of patients was “parent and child” in 12 cases from 6 families, and “siblings” in 11 cases from 5 families. Carcinoma of other organs was noted in other members in 8 families. Histological examination revealed 18 papillary, 2 follicular, and 2 anaplastic carcinomas (the 2 anaplastic carcinomas were considered to be transformed from preexisting differentiated carcinoma). In 1 case, the histological type was unknown. The average diameter of the primary lesion was 29.9 mm. Cervical lymph node metastasis was found in 77.8% and local recurrence in 28.6% of the patients. Solid and invasive growth was dominant. On HLA typing, phenotypes of B 7 and DR 1 were significantly redominant in familial patients compared with nonfamilial patients and normal Japanese. Moreover, the haplotype of B 7 ‐C w7 ‐DR 1 was observed in 5 of 13 patients tested.
It is suggested from these observations that some types of differentiated, nonmedullary thyroid carcinoma may show familial occurrence and that they may have common factors with regard to the genetic and immunologic basis of the disease .
A population-based case-control interview study of thyroid cancer (159 cases and 285 controls) was conducted in Connecticut. Prior radiotherapy to the head or neck was reported by 12% of the cases and 4% of the controls [odds ratio (OR) = 2.8; 95% confidence interval = 1.2-6.9]. Risk was inversely related to age at irradiation and was highest among children exposed under age 10. Few persons born after 1945 received prior radiotherapy, consistent with the declining use of radiation to treat benign conditions in the 1950's. Among females the radiogenic risk appeared to be potentiated by the number of subsequent live-births. Other significant risk factors included a history of benign thyroid nodules (OR = 33) or goiter (OR = 5.6). Miscarriage and multiparity increased risk but only among women who developed thyroid cancer before age 35 years. Consumption of shellfish (a rich source of iodine) seemed to increase the risk of follicular thyroid cancer, whereas consumption of goitrogen-containing vegetables appeared to reduce risk of total thyroid cancer, possibly because of their cruciferous nature. A significantly low risk was observed among persons of English descent, whereas Italian ancestry appeared to increase risk. No significant associations were found with a number of suspected risk factors: diagnostic x-rays, radioactive isotope scans, occupational radiation exposure, tonsillectomy, Jewish ethnicity, alcohol intake, cigarette smoking, oral contraceptives, lactation suppressants, menopausal estrogens, most other common medications, and water source. New associations were suggested for obesity among females (OR = 1.5), surgically treated benign breast disease (OR = 1.6), use of spironolactone (OR = 4.3) or vitamin D supplements (OR = 1.8), and a family history of thyroid cancer (OR = 5.2). About 9% of the incident thyroid cancers could be attributed to prior head and neck irradiation, 4% to goiter, and 17% to thyroid nodular disease, leaving the etiology of most thyroid cancers yet to be explained.
Of 226 consecutive papillary carcinoma patients, 14 indicated that at least one other relative was similarly affected. Pathology confirmation was obtained in 8 of the 14 families. Of the eight families with documented familial papillary carcinoma, one had five members, another had four members, and yet another had three members affected. The remaining families had two members affected. In those families with two or more persons with confirmed papillary carcinomas of the thyroid, 20 first- and second-degree relatives were examined. Of those, one had a previously unidentified papillary carcinoma and 6 had a benign thyroid disease (4 primary hypothyroidism and 2 simple goiters). High-resolution chromosome studies of four patients from four different families were normal, and there was no increase in chromosome breakage in a fifth patient from yet another family. Autosomal dominant inheritance is possible. Although there was no family history of lipomas, osteomas, or intestinal polyposis to suggest Gardner syndrome, four parents of our familial papillary carcinoma patients had colon cancer. In addition, three other relatives died of unidentified intra-abdominal cancer. The apparently high frequency of colon cancer and other abdominal cancer in relatives was an additional concern. Based on our observations, three clinical recommendations can be made: obtain a family history of all patients with papillary carcinoma of the thyroid, since between 3.5 to 6.2% will have another affected relative; when two or more persons in a family have papillary carcinoma of the thyroid, all first- and second-degree relatives should have a neck palpation by an experienced examiner; and families with two or more persons with papillary carcinoma should be observed for possible colon cancer.
The occurrence of familial medullary carcinoma in the thyroid is a well-known entity, but cases of familial papillary carcinoma have been rarely reported. A case of thyroid papillary carcinoma which occurred almost synchronously in a mother and her two daughters is presented. No significant difference between familial and nonfamilial papillary carcinoma was noted in clinical, histopathological and chemical findings. The pedigree of our case is considered to show autosomal dominant inheritance.
We report two kindreds from northern Norway with 7 and 4 cases of papillary thyroid carcinoma in otherwise healthy, nonirradiated subjects. While histologic features were comparable the patient's age at the time of diagnosis was lower and lymph node metastases were more frequent in familial than in nonfamilial cases of papillary thyroid carcinoma from the same region. We conclude that genetic factors can predispose the patient for development of papillary thyroid carcinoma. The high local incidence may be due to interaction between susceptibility gene(s) and environmental factors.
Although the number of reported cases of papillary carcinoma of the thyroid in families is few, a review of the literature and the three cases presented here strongly suggest the characteristics of hereditary cancer. Further study and reportage of similar cases is indicated to confirm whether this is indeed a familial cancer.
We report a large kindred of patients with congenital goiter, followed for 15 yr, in which two siblings (one male and one female) developed metastatic follicular thyroid carcinoma. These two patients were evaluated by iodine kinetic analysis. None of the classical defects of T4 biosynthesis was present in either patient. Rather, both patients had extremely rapid rates of iodine turnover, with elevated 131I uptake and excessive spillage of iodide in the urine. Serum iodoalbumin was present, probably as a nonspecific result of glandular hyperplasia. Iodine kinetic analysis after the ingestion of potassium perchlorate and methimazole was compatible with a leak of nonhormonal iodide from the thyroid. It is not possible to determine whether this iodide leak is the primary pathogenetic defect or is secondary to another unidentified abnormality. The unprecedented development of metastatic thyroid cancer in patients with congenital goiter occurred, in both instances years after subtotal thyroidectomy without thyroid hormone replacement therapy, suggesting a role for TSH in the genesis of human thyroid cancer. On the basis of our study of these patients and a review of the literature, we conclude that TSH is likely to be a factor in the induction of human follicular thyroid carcinoma.
To determine whether familial nonmedullary thyroid carcinoma behaves like sporadic carcinoma of follicular cell origin.
Retrospective review.
University medical center.
Fourteen patients were treated for familial nonmedullary thyroid carcinoma between 1980 and 1994. Thirteen families were identified, with 30 affected individuals.
Patients were treated with total or completion total thyroidectomy. Thirteen additional operations were performed to control recurrent disease.
Stage, recurrence, and survival. Patients were followed up for a mean of 6.5 years.
In our 14 patients, 13 tumors were multifocal, and six of these were bilateral. The incidences of lymph node metastasis and local invasion were both 57% (n = 8). Seven patients (50%) had recurrences during follow-up.
Familial nonmedullary thyroid carcinoma has a high incidence of multifocality and invasion and a high rate of local recurrence. Aggressive initial treatment and careful follow-up seem to be indicated.
Thyroid carcinoma has been described as occurring more frequently than expected in association with familial adenomatous polyposis. The histology of these cases has not been described in detail, although the reported cases were usually diagnosed as papillary carcinoma. We now report the pathological features of four cases of thyroid carcinoma associated with familial adenomatous polyposis, and review the findings in the literature. The tumours in these four cases were all of follicular cell origin as shown by thyroglobulin immunohistochemistry. In three they were multifocal. The tumours showed some features of papillary carcinoma--grooved nuclei and papillary architecture, but these were not consistent. They also showed features that were unusual for papillary carcinoma--a cribriform pattern and solid areas with spindle cell component. Commonly the tumours combined both patterns. A review of the reported cases of thyroid cancer associated with familial adenomatous polyposis showed that they also were commonly multifocal and occurred predominantly in young women. When the histology was adequately reported or illustrated it was, in most instances, consistent with the findings in our own cases. We therefore suggest that these thyroid tumours form a distinct type with some unusual features. Clearly it is likely that the APC gene is associated with their pathogenesis, and that other factors contribute to the predominantly female incidence in this as in sporadic tumours. Six of 63 reported cases showed metastasis or died from thyroid carcinoma. In a number of cases the tumours presented before the familial adenomatous polyposis was recognized. The findings of these unusual histological features in a thyroid tumour, and particularly of multicentricity, should alert the pathologist to the possibility of familial adenomatous polyposis with its implications for family screening. The tumours are often well demarcated but, because of the multicentricity, total thyroidectomy should be advocated.
Cancer has long been recognized to have a familial component. Elevated risks for cancers at the same site for relatives of cancer probands have been reported for both common cancers and a number of the rarer cancer sites. For a particular cancer site, however, the estimated risks to relatives have varied considerably depending on criteria for selection of probands, how cancers were determined in relatives, and overall study design. Not surprisingly, the estimated risks of other cancers in relatives of probands with cancer at a given site have been subject to even more variation.
The aim of this study was to use the Utah Population Database resource to systematically study familial clustering of 28 distinct cancer site definitions among first-degree relatives (parents, siblings, and off-spring) of cancer probands.
We estimated familial relative risks from the Utah Population Database by identifying all cases of cancer in these first-degree relatives. These observed values were compared with those expected based on cohort-specific internal rates calculated from 399,786 relatives of all individuals in the Utah Population Database known to have died in Utah.
All sites showed an excess of cancers of the same site among relatives, with thyroid and colon cancers and lymphocytic leukemia showing the highest familial risks. When the analyses were restricted to cases with early ages at diagnosis, increased familial components for most cancer sites became evident. A significant difference in familial relative risk (FRR) between male (FRR = 4.04; 95% confidence interval [CI] = 3.13-5.07) and female (FRR = 2.24; 95% CI = 1.54-3.08) probands was found for colon cancer. Highly significant familial associations (one-sided; P < .001) were found among breast, colon, and prostate cancers and between breast and thyroid cancers. Statistically significant (one-sided, P < .01) associations were also found between tobacco-associated sites (lung, larynx, lip, and cervix).
This study represents a unique comprehensive population-based study of familial cancer. The familial associations reported here will be useful in generating hypotheses about specific genetic and environmental factors that can be tested in genetic linkage and case-control studies.
Familial occurrence of nonmedullary thyroid carcinoma is extremely rare but this has been increasingly recognized over the recent years. Earlier reports of such occurrence were primarily confined to individuals with previous radiation exposure, history of familial adenomatous polyposis (Gardner's syndrome) or multiple hamartomas (Cowden's syndrome), or monozygotic twins. The author reviews 15 case reports/series of familial nonmedullary thyroid carcinoma available in the literature involving kindreds with no obvious associated pathogenetic factors as mentioned above. There were a total of 87 kindreds with 178 affected individuals available for analysis, with a male to female ratio of 1:2.2. The modal age group at diagnosis was 30-39 years in both gender groups. Papillary thyroid carcinoma constituted 91% of the cases, followed by follicular (6%) and anaplastic (2%) varieties. There was one case (0.5%) each of combined papillary and medullary thyroid carcinoma and Hurthle cell carcinoma, respectively. Six of the 15 series observed that patients with familial history generally have more aggressive tumour characteristics compared to the sporadic counterparts. The incidences of multifocality, local invasion, and distant metastases at diagnosis were 49, 32, and 5%, respectively. The incidences of locoregional recurrence, distant metastases, and deaths were 29, 10, and 5.4%, respectively, at a mean follow-up period of 11 years. The actual prognostic outcome of familial nonmedullary thyroid carcinoma is still unclear in view of the limited clinical data. Although several authors have advocated an aggressive approach in managing these patients, no conclusion can be reached on the basis of this review to support this position. The author recommends that patients with familial disease should be treated according to the disease stage and other risk factors, similar to those with spontaneously occurring well-differentiated papillary or follicular thyroid carcinomas. In addition, one might consider and perform follow-up of first-degree relatives with similar degree of caution as patients who have undergone head and neck irradiation in childhood.
Cowden disease (CD) is an autosomal dominant cancer predisposition syndrome associated with an elevated risk for tumours of the breast, thyroid and skin. Lhermitte-Duclos disease (LDD) cosegregates with a subset of CD families and is associated with macrocephaly, ataxia and dysplastic cerebellar gangliocytomatosis. The common feature of these diseases is a predisposition to hamartomas, benign tumours containing differentiated but disorganized cells indigenous to the tissue of origin. Linkage analysis has determined that a single locus within chromosome 10q23 is likely to be responsible for both of these diseases. A candidate tumour suppressor gene (PTEN) within this region is mutated in sporadic brain, breast and prostate cancer. Another group has independently isolated the same gene, termed MMAC1, and also found somatic mutations throughout the gene in advanced sporadic cancers. Mutational analysis of PTEN in CD kindreds has identified germline mutations in four of five families. We found nonsense and missense mutations that are predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of this gene. Thus, PTEN appears to behave as a tumour suppressor gene in the germline. Our data also imply that PTEN may play a role in organizing the relationship of different cell types within an organ during development.
Carney complex is a multiple neoplasia and lentiginosis syndrome that affects endocrine glands, including the pituitary, adrenals, and testes; thyroid gland involvement has not been unequivocally demonstrated. In the present study, the medical records of 12 families with Carney complex (53 affected patients) were reviewed for evidence of thyroid abnormality; 2 patients with thyroid carcinoma (1 papillary and 1 follicular; 3.8%) and 1 with follicular adenoma were identified in 3 unrelated kindreds. Six affected members of these kindreds were then screened for the presence of thyroid disease (familial cases). We also studied 5 patients with the complex who had no affected relatives (sporadic cases). These 11 patients consisted of 5 adults [mean age, 33.2 +/- 9.2 (+/- SD) yr] and 6 children and adolescents (mean age, 13.8 +/- 2.5 yr). All had normal results of physical and biochemical examination of the thyroid gland (total and free T4, T3, and TSH levels). Thyroid ultrasonography showed hypoechoic, cystic, solid, or mixed lesions in 3 of the 5 adults (60%) and 4 of the 6 children (67%). Two patients underwent fine needle aspiration biopsy, which identified follicular lesions. Thyroid gland abnormalities were documented in 5 siblings and 1 parent-child pair. We conclude that thyroid gland pathology is 1) common in patients with Carney complex; 2) includes a spectrum of abnormalities ranging from follicular hyperplasia and/or cystic changes to carcinoma; and 3) is inherited in an autosomal dominant manner, like the other manifestations of the syndrome, it is therefore, a candidate component of the syndrome. Ultrasonography is useful in the detection and clinical follow-up of these lesions.
We present a patient with hyperthyroidism associated with McCune-Albright syndrome (MAS). MAS is a sporadic genetic disease characterized by polyostotic fibrous dysplasia, cafe au lait cutaneous spots and endocrinopathies (peripheral precocious puberty, thyroidopathies, acromegaly, etc.). It is caused by an activating mutation of the gene for the Gs alpha membrane-associated protein, which mediates the thyrotropin (TSH)-induced and other hormone-induced activation of adenylyl cyclase. A 13-month-old girl was diagnosed with MAS. Precocious puberty was treated initially with testolactone and later with oophorectomy. Subclinical hyperthyroidism was detected biochemically at birth, and 10 months later, it became clinically evident, albeit mild, with absence of goiter. A concomitant liver dysfunction precluded treatment with thionamides and she was sporadically treated with beta-blockers. The combination of increased free thyroxine (T4) and triiodothyronine (T3) with low plasma thyrotropin (TSH) levels in the absence of thyroid-stimulating autoantibodies persisted until the age of 6 years, when she was referred to our unit. Hyperthyroidism was then clinically evident with cardiac hyperactivity, and it was cured with administration of radioiodine (131I). Thyroid disease is the second most common endocrinopathy associated with MAS, and since 1936, 63 cases of thyroidopathies have been described, including 19 nodular (14 with and 5 without hyperthyroidism) and 23 diffuse (20 with and 3 without hyperthyroidism) goiters, and 18 cases of hyperthyroidism without goiter. The previously described somatic activating mutation of the gs alpha gene in the ovaries, the liver and the peripheral blood of our patient, in the absence of stigmata, autoimmunity might be incriminated for the secretory and mitotic activation of the thyroid gland. We suggest the treatment of choice of hyperthyroidism in MAS patients should be 131I administration because: (a) hyperthyroidism is very likely to recur after withdrawal of antithyroid medication; (b) the morbidity of these patients is elevated; (c) oophorectomized patients do not need to be advised to avoid procreation during the months after 131I administration; and (d) finally, even in the usual cases of hyperthyroidism in childhood, 131I treatment is becoming more popular worldwide.
Thyroid goiter is a common condition that is often associated with iodine deficiency. Familial forms of goiter in areas not known to feature iodine deficiency are much less common. We have performed a genomic search on a single large Canadian family with 18 cases of nontoxic multinodular goiter in which 2 individuals also had papillary lesions highly suggestive of papillary carcinoma. A locus on chromosome 14q (MNG1 [multinodular goiter 1]) has been identified, with a maximal two-point LOD score of 3.8 at D14S1030 and a multipoint LOD score of 4.88 at the same marker, defined by D14S1062 (upper boundary) and D14S267 (lower boundary). The gene encoding thyroid-stimulating hormone receptor (TSHR), which is located on chromosome 14q, is outside the linked region. To determine the role of this gene in familial nonmedullary thyroid cancer (NMTC), we studied 37 smaller pedigrees each containing at least two cases of NMTC. Analysis by both parametric and nonparametric methods indicates that only a very small proportion of familial NMTC (point estimate 0.001, support intervals 0-.6 under a dominant model) is attributable to MNG1.
Familial nonmedullary thyroid cancer (FNMTC) is a clinical entity characterized by a phenotype more aggressive than that of its sporadic counterpart. Families with recurrence of nonmedullary thyroid cancer (NMTC) have been repeatedly reported in the literature, and epidemiological data show a very high relative risk for first-degree relatives of probands with thyroid cancer. The transmission of susceptibility to FNMTC is compatible with autosomal dominant inheritance with reduced penetrance, or with complex inheritance. Cases of benign thyroid disease are often found in FNMTC kindreds. We report both the identification of a new entity of FNMTC and the mapping of the responsible gene, named "TCO" (thyroid tumors with cell oxyphilia), in a French pedigree with multiple cases of multinodular goiter and NMTC. TCO was mapped to chromosome 19p13.2 by linkage analysis with a whole-genome panel of microsatellite markers. Interestingly, both the benign and malignant thyroid tumors in this family exhibit some extent of cell oxyphilia, which, until now, had not been described in the FNMTC. These findings suggest that the relatives of patients affected with sporadic NMTC with cell oxyphilia should be carefully investigated.
The autoimmune thyroid diseases [Graves' and Hashimoto's diseases (GD and HT)] develop in genetically susceptible individuals, but the genes responsible for this susceptibility remain unknown. To identify such genes, we have been testing candidate genes and chromosomal regions using highly polymorphic microsatellite markers. We recently reported evidence for the first locus linked to GD (GD-1) on chromosome 14q31 in a small group of families. We have now extended these studies and analyzed 53 multiplex families with GD and/or HT (323 individuals). Chromosome 14 was screened using 16 microsatellite markers spanning the entire chromosome. Three additional markers located inside candidate genes on chromosome 14 were also studied. Microsatellite markers were amplified using fluorescent-labeled primers and separated on an ABI-310 genetic analyzer. The data were analyzed using LIPED software for two-point logarithm of odds (LOD) score analysis and GeneHunter software for multipoint linkage analysis. No linkage of any marker was found to HT or autoimmune thyroid diseases (GD+HT). The previously identified GD-1 locus on 14q31 continued to show evidence of linkage to GD in this much larger set of families. The maximum LOD score was 2.1 obtained for marker D14S81 (theta=0.01), assuming a recessive mode of inheritance and a penetrance of 0.3. Multipoint analysis yielded a maximum LOD score of 2.5 between markers D14S81 and D14S1054. There was no evidence for heterogeneity in our sample. These data again suggest the presence of a major Graves' disease susceptibilitygene (GD-1) on chromosome 14q31. This locus is close to the recently identified multinodular goiter-1 locus.
A study of 169 oxyphil tumours of the thyroid, correlating histological features with age, sex, thyroiditis, and available clinical history, has shown two significant findings relevant to pathogenesis, diagnosis, and treatment. Oxyphil tumours with a papillary architecture can be divided into papillary carcinomas with secondary oxyphilia and true oxyphil tumours. The tumours of the former group are typically unencapsulated, invasive, show nuclei characteristic of papillary carcinoma generally, are associated with thyroiditis, and frequently show psammoma bodies. The tumours of the latter group are typically encapsulated, with nuclei similar to those found in other oxyphil tumours; usually lack psammoma bodies; and some show capsular and vascular invasion. Papillary architecture alone is not thought to justify a diagnosis of malignancy in this group of tumours, and further study with follow-up is needed to determine the appropriate treatment. It is suggested that oxyphilia in the first group is secondary to the accompanying thyroiditis, comparable to the oxyphilia in follicular cells in Hashimoto's thyroiditis, while the oxyphilia in the latter group, as in other oxyphil tumours, is due to a somatic mutation leading to an increase in mitochondrial number. About 20 per cent of all cases showed multiple oxyphil tumours. These were more frequently female, more often associated with thyroiditis, younger, and less often malignant than solitary tumours. The occurrence of multiple tumours of the same uncommon histological type in these patients is compatible with a germline mutation conferring a liability to oxyphil follicular cell tumours. This is supported by the occurrence of oxyphil tumours in families; the present series of cases included two mother-daughter pairs and similar examples have been reported, including multiple oxyphil tumours in identical twins. Further studies are needed to identify the gene involved and any co-operating genes. Oxyphil carcinoma in patients with multiple oxyphil tumours occurred at a mean age 10 years greater than that for multiple adenomas, suggesting that the carcinomas arose by progression from adenomas. It is important to complete thyroidectomy in a case with multiple oxyphil tumours if there is evidence of the presence of lesions in both lobes. It is necessary to consider the differences between primary and secondary oxyphilia, and between sporadic and multiple or familial oxyphil tumours in future studies of these lesions.
Familial papillary thyroid carcinoma (fPTC) is an inherited tumor syndrome characterized by isolated papillary thyroid carcinoma (PTC) in affected subjects. Its etiology is unknown. Large multigeneration families with PTC are very rare, and therefore, modern genetic linkage studies have not been applied extensively to this disorder. Familial adenomatous polyposis coli (FAP) is an inherited tumor syndrome enriched in PTC. FAP is caused by germline mutations of the adenomatous polyposis coli (APC) gene that is located in the 5q21 region. It is not known if fPTC is a phenotypic variant of FAP, or if it is a genetically distinct disorder. We report a large 3-generation fPTC kindred and use linkage analysis to test the hypothesis that fPTC and FAP are genetically distinct. In this kindred there are 25 living informative subjects; 5 have PTC, and 1 is an obligate carrier. Inheritance is autosomal dominant with incomplete penetrance. There is vertical transmission, multifocal disease, an average age of onset of 36 years, and 1 subject has colon cancer. The probability is approximately 1 in 2 billion against the clustering of 5 sporadic PTC cases in this kindred. To test for linkage to the APC gene we used 2 highly polymorphic markers, D5S656 and D5S421, which are located within a maximum distance of 1.7 megabase (Mb) of the APC gene and within an estimated genetic region of less than 1 centimorgan (cM) from each other. After polymerase chain reaction (PCR) amplification 18 family members were genotyped. Construction and inspection of haplotypes showed that the affected subjects do not share the same allelic composition. Using a penetrance ratio of 75%, linkage was excluded at 2 cM and 3 cM on both sides of D5S656 and D5S421, respectively. The combined haplotype of these 2 markers provided an exclusion region of 4 cM. We conclude that fPTC is genetically distinct from FAP.