Undifferentiated (anaplastic) thyroid carcinoma and iodine intake in Salta, Argentina.

This study was conducted to investigate the natural history of undifferentiated thyroid carcinoma (UTC) in the iodine-deficient province of Salta, Argentina, in relation to salt iodization and health care standards. Five hundred ninety-three thyroid cancers diagnosed from 1958 to2012 were reviewed based mainly on the WHO classification and grouped into three periods, one before and two after iodine prophylaxis. The incidence of UTC was analyzed in relation to changing concentrations of potassium iodide (KI) in salt during the prophylaxis period (from 40 to 33.3 mg KI/kg salt), establishment of primary health care centers throughout the region, and use of fine needle aspiration (FNA) cytology. Twenty-nine UTCs were found in the whole series. The frequency of UTC decreased from 15.2 % (9/59 cases) in the first period to 2.6 % (10/381 cases) well after salt iodination (x (2) Fisher's test, p < 0.0002), and the incidence from 1.4/10(6)/year to 0.1/10(6)/year (Student's t test, p < 0.06), respectively. The decline of UTC after iodine prophylaxis occurred even after decreasing concentrations of KI in salt and timely coincided with the establishment of primary health care centers throughout the region and routine use of FNA. The lower rate of UTC after iodine prophylaxis in the province of Salta is mostly related to earlier detection of more differentiated thyroid tumors rather than higher salt iodization.

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.

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.

Frequent RET rearrangements in thyroid papillary microcarcinoma detected by interphase fluorescence in situ hybridization.

Papillary thyroid microcarcinomas (measuring 1 cm or less in diameter) are very common thyroid tumors, which are present in 10% to 35% of post-mortem histopathological examinations of individuals whose death was due to a cause other than thyroid cancer. The molecular basis of this tumor is still poorly understood. Somatic mutations are better characterized in clinically evident papillary thyroid carcinomas (PTCs), the most common involving the proto-oncogene RET, which maps to 10q11.2. Molecular alterations of RET always lead to intra- or interchromosomal rearrangements. In this study we have investigated the status of RET in 21 microcarcinomas, by means of interphase fluorescence in situ hybridization (FISH). RET was rearranged in 52% of microcarcinomas, a statistically significant higher frequency than that found previously in clinically evident PTCs using the same technique. Moreover, interphase FISH allowed us to detect a putative novel type of rearrangement in a microcarcinoma, and we observed trisomies of chromosome 10 and other chromosomes in two adenomas surrounding two of the microcarcinomas. The strikingly high frequency of RET rearrangements in microcarcinomas strongly suggests that RET plays a role in the initiation of thyroid tumorigenesis but does not seem to be necessary for the further progression of the tumor.

Thyroid pathologic findings in patients with Cowden disease.

We describe the histologic findings in thyroid glands from six female and five male patients with Cowden disease. The patients were aged 9 to 43 years (mean age, 26 years). The salient thyroid lesions in this syndrome were multicentric follicular adenomas and adenomatous (parenchymatous, hyperplastic) nodules showing a wide range of nonspecific cytoarchitectural patterns. Multiple tiny cellular foci, so-called microadenomas, were also a feature. Specific lesions composed of oxyphil or clear cells, a tumor with features of hyalinizing trabecular adenoma, and an adenolipoma also occurred. Two cases showed a follicular carcinoma in addition to multiple benign follicular cell proliferations. The follicular carcinomas occurred at an older age and were larger in size than the clinically significant benign nodular lesions, suggesting tumor progression. All tumors showed thyroglobulin immunoreactivity and were negative for calcitonin. The histologic findings of a multiple adenomatous goiter or multiple follicular adenomas, particularly in children and young adults, should alert the pathologist and physician to the possibility of an inherited trait, such as Cowden disease, with its implications for family screening. The tumors are usually benign and well demarcated, but, because of multicentricity and increased risk of recurrence or progression to carcinoma, total thyroidectomy should be advocated.

Histology of familial thyroid tumours linked to a gene mapping to chromosome 19p13.2.

This paper describes the pathology of thyroid tumours showing an autosomal mode of inheritance linked to a gene that maps to chromosome 19p13.2. All the affected members from the family (seven males and two females; mean age 23 years) were clinically euthyroid and presented with nodular goitre; tumour recurrence after thyroidectomy was observed in four. In four of the five patients studied, the tumours were multifocal, bilateral well demarcated or encapsulated and composed of follicles, papillae, trabeculae/solid areas (often resembling hyalinizing trabecular adenoma of the thyroid) or an admixture, formed by cells with pale to intense cytoplasmic eosinophilia. A diagnosis of multiple adenomatous goitre was made in the thyroidectomy specimen from two patients, while the other two patients showed, in addition to multiple adenomas, a co-existent oxyphil papillary carcinoma. The fifth patient had an oxyphil cell carcinoma. All tumours were of follicular cell origin as shown by immunocytochemistry. Less than a third of the benign tumours and all three carcinomas showed a variable number of neoplastic cells diffusely immunostained for mitochondria. Histological findings of a 'multiple adenomatous goitre', non-endemic 'multinodular goitre' or multiple neoplasms of follicular cell origin with the morphology of those described here, particularly in young patients, should alert the pathologist and physician to the possibility of an inherited trait, with its implications for family screening. The tumours are usually benign and well demarcated but because of multicentricity and consequently increased risk of recurrence and/or progression to carcinoma, total thyroidectomy should be advocated.

Adrenocortical oncocytoma.

The histopathology and ultrastructural features of an adrenocortical oncocytoma are reported. The tumour was discovered incidentally during investigation for hypertension in a 72 year old female. Oncocytic tumours of the adrenal cortex are rare, with only 20 examples described in English language reports. Most have been non-functioning and benign, like the present example. Molecular studies may help assess the significance of oncocytic change in the pathogenesis and behaviour of oncocytic neoplasms.

A gene predisposing to familial thyroid tumors with cell oxyphilia maps to chromosome 19p13.2.

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.

Solitary, multiple, and familial oxyphil tumours of the thyroid gland.

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.

Thyroid cancer and thyroiditis in the goitrous region of Salta, Argentina, before and after iodine prophylaxis.

OBJECTIVE: The importance of iodine intake and thyroiditis in the pathogenesis of thyroid cancer remains controversial. We have investigated the natural history of thyroid cancer and thyroiditis in a goitrous region before and after iodine prophylaxis over a 31-year period. DESIGN: For the analysis of thyroid cancer the material was divided in two periods. The first 15 years (59 cases), including 5 years before prophylaxis, was compared with the second 16 years (85 cases), a period well after iodine supplementation of salt. Histological diagnosis of the tumours was based on the WHO system. Moderate to severe thyroiditis in the non-tumoral surrounding thyroid from female patients was recorded. For this, the material was analysed in the two periods in relation to the introduction of iodine prophylaxis in 1963, taking account of the age of the patients. RESULTS: Papillary carcinomas formed the largest group of tumours in both periods, with nearly twice as many in the second period as the first, while the numbers of follicular and medullary carcinomas remained about the same. The ratio of papillary to follicular carcinoma rose from 1.7:1 in the first period to 3.1:1 in the second. All three thyroid lymphomas were of the non-Hodgkin's type, and all occurred in the second period in females aged over 50. A severe lymphoid thyroiditis was present in the two cases with assessable background thyroid tissue. The frequency of lymphoid infiltrate in females rose from 8% (1/12) before 1963 to 25% (18/72) after prophylaxis in the whole series. After salt prophylaxis, thyroiditis was more frequent in patients with papillary carcinoma in general (31%), and clinically significant papillary carcinomas in particular (35%), than in those with non-papillary tumours (6%) (chi 2, P < 0.05 and P < 0.025, respectively). CONCLUSIONS: Our observations indicate that a high dietary intake of iodine may be associated with a high frequency of papillary carcinoma and thyroiditis, and that thyroiditis is more commonly associated with papillary carcinoma than with other thyroid tumours. The occurrence of non-Hodgkin's lymphomas only in the post-prophylaxis period may be linked to an increase in thyroiditis.

Childhood thyroid cancer in England and Wales.

A total of 154 cases of thyroid cancer in children under 15 were registered in England and Wales over a period of 30 years, an incidence of about 0.5 per million per year. A total of 4.5 cases per year were registered in 1963-72, 4.9 in 1973-82 and 5.8 in 1983-92. A rapid rise in incidence with age occurred after the age of 5. Malignancy was confirmed in 92% of the cases in which tissue was available. Of these, 68% were papillary carcinomas, 11% follicular carcinomas and 17% medullary carcinomas. There were two spindle cell tumours with mucous cysts and one teratoma. The increased frequency but small size of medullary carcinomas in the second half of the period suggested that this increase was due to the introduction of screening; it accounted for most of the rise in crude incidence rats with time. The sex ratio (F:M) in all registered cases in the differentiated follicular cell carcinoma groups in children aged under 10 was 1.2:1, and 3.6:1 in the older children. Five children with differentiated thyroid cancer of follicular cell origin died up to 17 years after diagnosis. Two of the eight children aged 9 or less with a 20 year follow-up died, compared with three of 28 older children. An unusual group of differentiated carcinomas showed solid or follicular architecture. These tumours were unencapsulated, often widely invasive, contained psammoma bodies but little or no papillary architecture and the nuclei often lacked prominent grooving. This childhood type of papillary carcinoma contrasted with the classical type commonly found in the adult, which was present in one of 13 confirmed papillary carcinomas in children aged less than 10, compared with 20 of 35 older children. These observations show that thyroid carcinoma in very young children has a different spectrum of histological types from both older children and adults. From the age of about 10 well-differentiated papillary carcinomas rapidly increase in frequency in females, so that the other types come to form only a small proportion of the total. These differences, and the lower incidence but poorer prognosis of thyroid carcinoma in men and the poorer prognosis in post- as compared with premenopausal women, are compatible with a major role for sex hormones in thyroid carcinogenesis in females during the reproductive period. This study documents the incidence of childhood thyroid cancer in England and Wales, explains the rise in crude incidence rates, shows differences between carcinomas in children under and over the age of ten which may correlate with puberty, and draws attention to an unusual aggressive type of childhood papillary carcinoma. It illustrates the value to crude registry data of a pathology review.

Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm.

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.

Thyroid/cervical teratomas in children: immunohistochemical studies for specific thyroid epithelial cell markers.

Pathological and immunohistochemical findings for specific thyroid epithelial cell markers in thyroid/cervical teratomas from four children are reported. All tumors showed components from the three germinal cell layers. Neoplastic thyroglobulin-immunoreactive thyroid follicles occurred in three intrathyroid teratomas, but the findings were negative in a cervical teratoma in which evidence of its thyroid origin could not be ascertained. As previously suggested on histological grounds, thyroid tissue, other than normal trapped thyroid follicles, is not an infrequent component of cervical teratomas. We found no evidence to support an ultimobranchial origin for these tumors, as previously suggested by Roediger et al. (19), because no calcitonin immunoreaction was observed.

Intrathyroidal thymic tissue: an autopsy study in fetuses with some emphasis on pathological implications.

Fifty-eight human thyroid glands obtained at autopsy from fetuses with proven retrosternal thymus were systematically studied for the presence of intrathyroidal thymic tissue. The latter was found in one thyroid lobe in each of three fetuses (5.1%). It was located in a subcapsular position in two cases (3.4%) and lying deep in thyroid tissue in one (1.7%). Our findings would support a IV-V pharyngeal pouch origin for some accessory thymic tissue and would provide an explanation of the histogenesis of intrathyroid thymomas.