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Activating Thyrotropin Receptor Mutations Are Present in Nonadenomatous Hyperfunctioning Nodules of Toxic or Autonomous Multinodular Goiter*

Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del Lavoro (M.T., P.A., L.C., V.R., G.C., A.Pe., A.Pi., P.Vit.), Dipartimento di Oncologia Divisione di Anatomia Patologica (P.Via., A.N.), and Dipartimento di Clinica Chirurgica (P.M.), Università di Pisa, 56124, Cisanello, Pisa, Italy

Address correspondence and requests for reprints to: Massimo Tonacchera, Dipartimento di Endocrinologia, Università degli Studi di Pisa, Via Paradisa 2, 56124, Cisanello, Pisa, Italy. E-mail: mtonacchera{at}hot-mail.com * Supported by the National

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Toxic multinodular goiter, a heterogeneous disease producing hyperthyroidism, is frequently found in iodine-deficient areas. The pathogenesis of this common clinical entity is still unclear. The aim of the present study was to search for activating TSH receptor (TSHr) or Gs mutations in areas of toxic or functionally autonomous multinodular goiters that appeared hyperfunctioning at thyroid scintiscan but did not clearly correspond to definite nodules at physical or ultrasonographic examination. Surgical tissue specimens from nine patients were carefully dissected, matching thyroid scintiscan and thyroid ultrasonography, to isolate hyperfunctioning and nonfunctioning areas even if they did not correspond to well-defined nodules.

TSHr and Gs mutations were searched for by direct sequencing after PCR amplification of genomic DNA. Only 2 adenomas were identified at microscopic examination, whereas the remaining 18 hyperfunctioning areas corresponded to hyperplastic nodules containing multiple aggregates of micromacrofollicules not surrounded by a capsule. Activating TSHr mutations were detected in 14 of these 20 hyperfunctioning areas, whereas no mutation was identified in nonfunctioning nodules or areas contained in the same gland. No Gs mutation was found.

In conclusion, activating TSHr mutations are present in the majority of nonadenomatous hyperfunctioning nodules scattered throughout the gland in patients with toxic or functionally autonomous multinodular goiter.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
TOXIC MULTINODULAR goiter is a heterogeneous disease producing hyperthyroidism, the pathogenesis of which is still debated (1). The term "toxic multinodular goiter" encompasses a spectrum of different clinical entities, ranging from a single hyperfunctioning nodule within an enlarged thyroid that also contains nonfunctioning nodules to multiple hyperfunctioning areas scattered throughout the gland, barely distinguishable from nonfunctioning nodules and extranodular parenchyma (2, 3). Recently, we (4) have reported that similar to toxic thyroid adenoma (5, 6), activating TSH receptor (TSHr) mutations are present in single hyperfunctioning nodules (either adenoma or hyperplastic nodules) within a toxic multinodular goiter in which nonfunctioning nodules also coexist. The presence of activating TSHr mutations in few cases of multiple adenomatosis has also been reported (7, 8, 9). However, in areas of iodine deficiency, most patients with toxic or autonomous multinodular goiter show thyroid scintigraphic patterns in which hyperfunctioning areas are not superimposable onto nodules found at physical and ultrasound examination. This implies that the boundaries of scintigraphic areas with increased radioiodine uptake do not necessarily correspond to the anatomic boundaries of thyroid nodules (2, 3). The molecular mechanisms leading to the appearance of hyperfunctioning areas in multinodular goiter are still poorly understood (1, 10, 11). A role of activating TSHr mutations has been postulated (10), but in a recent study from Gabriel et al. (12) no activating TSHr mutations were identified in hyperfunctioning nodules from patients with toxic multinodular goiters.

The aim of the present study was to search for activating TSHr or Gs mutations in areas of toxic or functionally autonomous multinodular goiter that appeared hyperfunctioning at thyroid scintiscan but did not clearly correspond to definite nodules at physical or ultrasonographic examination. TSHr mutations were identified by direct sequencing of the entire exons 9 and 10 of the TSHr gene and of codons 201 and 227 of Gs after PCR amplification of genomic DNA obtained from surgical specimens. Of 20 hyperfunctioning areas contained in nine toxic or functionally autonomous multinodular goiters, only two adenomas were identified at microscopic examination, whereas the remaining hyperfunctioning areas at thyroid scintiscan corresponded to micromacrofollicular hyperplastic nodules not surrounded by a capsule. Activating TSHr mutations were detected in the majority of hyperfunctioning areas scattered throughout multinodular goiters, whereas none was identified in adenomatous or hyperplastic nonfunctioning nodules or areas contained in the same glands.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Included in this study were nine patients [four females (mean age, 39 ± 7 yr) and five males (mean age, 53 ± 9 yr)] who were submitted to surgery for toxic or functionally autonomous goiter. In these goiters hyperfunctioning areas at thyroid scintiscan did not clearly correspond to nodules at physical or ultrasonographic examination.

Subtotal or near total thyroidectomy was performed in all patients. At diagnosis, two patients were overtly hyperthyroid and seven patients had subclinical hyperthyroidism [normal serum concentrations of free T₄ (FT₄) and free T₃ (FT₃) and a subnormal or undetectable serum TSH]. In two patients with multinodular goiter there was humoral evidence of coexisting focal thyroiditis due to the presence in their serum of antithyroglobulin and/or antithyroperoxidase antibodies. Anti-TSHr antibodies were undetectable in all patients. Thyroid glands were studied by physical examination, thyroid ultrasound, scintiscan imaging using iodine-131 (¹³¹I), and histology. All patients were prepared to surgery with methimazole and iodide.

Age, sex, and thyroid hormonal findings in patients with multinodular goiter are described in Table 1. The images of ¹³¹I thyroid scintiscans of the nine patients are shown in Fig. 1. Surgical tissue specimens were carefully dissected matching ¹³¹I scintiscan with the whole gland laid on the pathologist tray in its proper anatomic orientation. Hyperfunctioning and nonfunctioning areas identified by scintiscan were isolated and used for histologic examination and genetic analysis. Thyroid ecography was also taken into account, although it was clearly evident that the boundaries of scintigraphic areas did not necessarily correspond with the anatomic boundaries of the thyroid nodules identified at ultrasonography.

View larger version (61K): [in this window] [in a new window]   Figure 1. 131I thyroid scintiscans of the nine patients with toxic or functionally autonomous multinodular goiter.

Laboratory evaluation of thyroid function.Serum FT₄ and FT₃ were measured by a RIA after chromatographic separation of the free hormone (FT₄ RIA and FT₃ RIA, Lysophase; Technogenetics S.r.l., Milan, Italy). TSH was assessed by a sensitive assay (AutoDelfia hTSH Kit; Pharmacia s.p.a., Milan, Italy). Thyroperoxidase and Thyroglobulin antibodies were measured by passive agglutination (SERODIA-AMC and SERODIA-ATG, Fujirebio, Tokyo, Japan). Anti-TSHr antibodies were searched for using a commercial radioreceptor assay (TRAK assay; B.R.A.H.M.S., Berlin, Germany).

Thyroid scintiscan.Thyroid uptake was measured 3 and 24 h after a tracer dose of ¹³¹I (50 µCi). Thyroid scintiscan was performed after 24 h. Radioactivity was revealed with a gamma camera.

Thyroid ultrasound.Ultrasound evaluation was performed by the same examiner using a linear transducer (7.5 MHz) attached to a real time instrument (AU 590 Asynchronous Apparatus; Esaote Biomedica, Milan, Italy). Patients were examined in the supine position with the neck hyperextended. Thyroid volume was calculated according to the formula of the ellipsoid model (13): width (mm) x length (mm) x thickness (mm) x 0.52 x each lobe = volume (mL). The thyroid volume used as normal reference value, obtained by measurements in 130 healthy adult individuals (65 males and 65 females) residing in urban areas with sufficient iodine intake of the same region, was 11.3 ± 3.4 mL in males and 8.6 ± 2.2 mL in females.

Sequence determination.Genomic DNA was extracted from tissue specimens obtained at surgery, as described previously (4). We sequenced the entire exons 9 and 10 of the TSHr gene and codons 201 and 227 of Gs exactly as described (see Ref. 4). At least two different PCR amplifications from genomic DNA were sequenced on double strand with sense and antisense primers.

Contamination problems were ruled out by including PCR control samples with no DNA as template. Extraction of DNA and pre-PCR reactions were performed in different rooms with respect to post-PCR reactions.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Histology

At microscopic examination all goiters contained multiple nodules, and most hyperfunctioning areas at scintiscan corresponded to hyperplastic nodules constituted by multiple microfollicular and macrofollicular aggregates not confined by a capsule (Table 1). Nodules were separated by irregular strands of apparently normal micromacrofollicular parenchyma, but in few cases nodules were in intimate contact. Areas of fibrosis, hemorrhage, and calcium depositions were also observed.

At microscopy only two hyperfunctioning areas at scintiscan corresponded to well-defined adenomas. These showed a microfollicular pattern of growth, delimitated by a complete fibrous capsule (Table 1). These adenomas were found in patient 2 (a nodule in the lower portion of the left lobe of 30 x 35 x 40 mm) and in patient 7 (a nodule in the right lobe of 30 x 50 x 78 mm). In two patients (5, 6) focal lymphocytic infiltration was present.

Genetic analysis

Direct sequencing of exons 9 and 10 of the TSHr gene revealed the presence of a mutation in 14 of 20 hyperfunctioning areas scattered throughout the nine multinodular goiters (Table 2). In four patients (2, 4, 8, 9) the two hyperfunctioning areas contained in the same goiter harbored different TSHr mutations. Two different TSHr mutations were also present in two of four hyperfunctioning areas of patient 6. In the remaining four patients (1, 3, 5, 7) a TSHr mutation was detected in only one of the two hyperfunctioning areas.

All the mutations identified were heterozygotic and somatic. Only wild-type TSHr sequences were found in normal thyroid tissue surrounding the hyperfunctioning areas or in cold thyroid nodules. No Gs mutation was identified in hyperfunctioning nodules. All the mutations identified had been described previously and were found to be gain-of-function mutations producing a stimulation of cAMP and or IP3 production (4, 5, 6).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In this study, we show that in patients with toxic or functionally autonomous multinodular goiter the majority of nonadenomatous hyperfunctioning areas identified at thyroid scintiscan and scattered throughout the thyroid gland harbor an activating TSHr mutation. Activating TSHr mutations have already been described in toxic thyroid adenomas by several studies (4, 5, 6, 14, 15, 16, 17, 18, 19, 20), their frequency greatly varying in different studies (21), and in single or multiple well-defined hyperfunctioning nodules contained in multinodular goiters (7, 8, 9). We report here the results of the genetic analysis performed in thyroid glands from nine patients with toxic or functionally autonomous multinodular goiter, which showed an irregular patchy pattern of radioiodine uptake at thyroid scintiscan. In these goiters hot scintigraphic areas were often not superimposable onto the nodular lesions found on physical or ultrasonographic examination. Fourteen of the 20 hyperfunctioning areas detected at the scintiscan contained an activating TSHr mutation, and in the same goiter different TSHr mutations were found in different hyperfunctioning areas. Most hyperfunctioning areas corresponded to aggregates of micromacrofollicular structures not defined by a capsule. Only two nodules could be classified true adenomas (22), showing a typical microfollicular pattern of growth and circumscribed by a complete capsule. These results suggest a prevalent role of activating TSHr mutations in the genesis of nonadenomatous hyperfunctioning areas of toxic or functionally autonomous multinodular goiter.

Toxic nodular goiter is relatively rare in iodine-sufficient regions, whereas it is the most common form of hyperthyroidism in iodine-deficient areas (2, 3), where aged patients with long-standing nontoxic goiter experience a progressive increase in size and number of thyroid nodules. Within this process, thyroid function may progress from a fully TSH-dependent condition to autonomy (i.e. independent from TSH regulation), and then to overt thyrotoxicosis (3). According to current pathogenetic models, in populations exposed to iodine deficiency toxic or functionally autonomous multinodular goiter results from chronic TSH stimulation that leads to thyroid cell proliferation and progressive accumulation of new follicles with heterogeneous ability of iodine turnover and hormone synthesis (1, 23, 24, 25). It was proposed that autonomous growth could be a new stable trait of cells generated during goitrogenesis or could represent the rapid expansion of naturally occurring cell strains with an intrinsically short replication rate (24, 25). The observation reported here that TSHr mutations are frequently found even in nonadenomatous hot areas of human toxic multinodular goiters suggests that this may be one of the genetic alterations giving to mutated thyroid cells an increased ability of producing thyroid hormone. Because cAMP is an important mediator of growth pathway in the thyreocite (10, 11), constitutively active TSHr mutations might be responsible for an increased replication rate of thyroid cells.

A question is why TSHr-activating mutations are so frequent in the glands of patients with toxic multinodular goiter in geographical areas of iodine deficiency. A recent study by Gabriel et al. (12) failed to find TSHr mutations both in toxic adenomas and in multiple autonomous nodules contained in toxic multinodular goiters, despite the complete sequencing of the entire exon 10 of the TSHr gene. These results are in agreement with those of Takeshita et al. (26), who reported a low frequency of TSHr mutations in toxic adenoma in the Japanese population. At difference with these studies, all done in areas of iodine sufficiency, a high frequency of TSHr mutations in toxic thyroid adenomas was described in Italy (4), Germany (18), and Belgium (19), all countries characterized by a borderline-low iodine intake (27). These data, together with the observation that toxic nodular goiter is much more frequent in areas of iodine deficiency (28), suggest that toxic adenoma and toxic multinodular goiter might recognize different pathogenetic mechanisms according to iodine intake. We suggest that iodine deficiency and/or chronic TSH stimulation might play a role in the clinical expression of gain-of-function mutations of the TSHr gene, because both increase the thyroid cell replication rate, thus increasing the probability of mutations (11). A further mechanism could be an enhanced mutagenic load due to an increased TSH-dependent formation of intracellular H₂O₂ and then O₂-derived free radicals through the activation of the PIP₂ PLC Ca⁺⁺ pathway (11). The higher mutagenic load and the higher proliferation rate in thyroids exposed to iodine deficiency could also account for a higher incidence of mutations in genes involved in pathways different from the TSHr/cAMP pathway, but still implicated in thyroid cell growth (10, 11). These mechanisms have to be elucidated to explain the increased occurrence of nonfuctioning thyroid nodules that often coexist with hyperfunctioning nodules or nonadenomatous hyperfunctioning areas in glands of patients with toxic multinodular goiter (29).

Received December 2, 1999.

Revised February 5, 2000.

Accepted March 7, 2000.

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