Minimally Invasive Follicular Thyroid Carcinoma Developed in Dyshormonogenetic Multinodular Goiter Due to Thyroid Peroxidase Gene Mutation

Abstract

Background:

The occurrence of thyroid carcinoma in patients with congenital hypothyroidism (CH) caused by dyshormonogenesis is very rare, and has only been reported in one patient harboring mutations in the thyroid peroxidase (TPO) gene.

Patient Findings:

We report on a 29-year follow-up of two consanguineous siblings with CH due to total iodide organification defect who also had sensorineural hearing loss. Molecular analysis revealed a novel biallelic mutation of the TPO gene in which phenylalanine substitutes serine at codon 292 (c.875C>T, p.S292F) in exon 8. Despite early initiation, adequate doses of levothyroxine treatment and consequently normal thyrotropin (TSH) levels, the proposita developed a huge multinodular goiter (MNG) and underwent total thyroidectomy due to tracheal compression. Pathological examination revealed a unifocal follicular thyroid carcinoma without vascular invasion in the left lobe of the thyroid gland.

Summary:

Our finding of follicular thyroid carcinoma arising from dyshormonogenetic MNG in a patient without elevated serum TSH levels indicates that genetic and environmental factors other than TSH level might be involved in the development of thyroid carcinoma in dyshormonogenetic MNG.

Conclusions:

Despite the rare occurrence of thyroid carcinoma in dyshormonogenetic MNG, we recommend long-term follow-up and regular neck ultrasound imaging to prevent delayed diagnosis of thyroid carcinoma.

Introduction

C ongenital hypothyroidism (CH) occurs in about 1 in 2000 live births (1,2). Most cases are sporadic and associated with abnormal thyroid gland development and migration (thyroid dysgenesis); 15%–20% of the cases with CH are caused by inherited defects in different steps of hormone synthesis (3). Genes associated with dyshormonogenesis include those for thyroglobulin (TG), sodium iodide symporter (NIS), pendrin (PDS), thyroid dual oxidase 2 (DUOX2) and its maturation factor (DUOXA2), dehalogenase (DEHAL1), and thyroperoxidase (TPO) (3,4).

TPO mutations are the most common cause of an enzymatic thyroid synthesis defect, responsible for more than 50% of the CH cases due to dyshormonogenesis (5). The clinical characteristics include CH and goiter, in some cases attaining huge sizes. Rapid and elevated radioactive iodine uptake (RAIU) with significant discharge of thyroidal radioiodine after perchlorate administration is consistent with an iodide organification defect (IOD) (6). The TPO gene is located on the short arm of chromosome 2 (2p25) and comprises 17 exons. It covers ∼150 kb of genomic DNA. TPO is a membrane-bound glycoprotein located at the apical membrane of the thyroid follicular cells that catalyzes both iodination and coupling of iodotyrosine residues within the TG molecule, leading to the synthesis of thyroid hormone. TPO defects are inherited in an autosomal recessive manner (5). To date, more than 50 different mutations of the TPO gene have been described (MIM #606765). Goiter may be present at birth or develop with time. We described the presence of three different TPO mutations in 22 patients living in the same geographical area, in the northern region of Israel: 44% of the patients developed multinodular goiter (MNG) over the years, with both hot and cold nodules demonstrated by ^99mTC scan (7). Among them, four patients underwent thyroidectomy due to pressure symptoms and follicular hyperplasia in fine-needle aspiration. However, pathological findings excluded thyroid carcinoma (7). Occurrence of thyroid carcinoma has been reported in about 1%–4% of patients with MNG (8), but the precise rate of thyroid carcinoma arising from dyshormonogenetic MNG is not known. In 1981, 17 such cases were reported but without confirmed genetic analysis (9). Over the last two decades, with the advent of commonly available molecular analyses, 11 cases with confirmed mutations have been reported: 9 with TG mutations (10 –12), 1 with PDS mutation (13), and 1 case in an infant with a monoallelic TPO mutation (14). Herein we describe a 29-year follow-up of two siblings with the TPO mutation S292F, resulting in substitution of serine with phenylalanine in position 292 of exon 8 (c.875C>T, p.S292F). The proposita manifested with goitrous CH that progressed over the years to a huge MNG harboring follicular thyroid carcinoma.

Patient 1

The proband, a 29-year-old woman of Arab-Muslim origin, was born to parents who were first-degree cousins. She was admitted at the age of 3 weeks due to prolonged jaundice, hoarse cry, goiter, and constipation. Primary CH was identified by neonatal screening (thyrotropin [TSH] 183 mIU/L, normal range <10 mIU/L; total thyroxine [TT₄] 1.5 μg/dL, normal range >7 μg/dL). Laboratory tests confirmed the diagnosis of CH (TSH 75 mIU/L; TT₄ 9.6 μg/dL; total triiodothyronine [TT₃] 38 ng/dL) and levothyroxine (l-T₄) therapy was initiated. On follow-up, slightly delayed psychomotor development was observed. At 3 years of age, one month after l-T₄ withdrawal, a ^99mTC thyroid scintigraphy revealed homogeneous hypertrophy of the thyroid gland with an enlarged left lobe. At the age of 4 years, she underwent RAIU and perchlorate test, showing 43% ¹³¹I uptake after 2 hours of iodine ingestion with a discharge of 90% 2 hours after administration of 200 mg perchlorate. This result was consistent with total IOD (TIOD). At the age of 10 years, bilateral hearing loss was found and repeated audiometric tests performed until the age of 22 years revealed stable moderate-to-severe bilateral sensorineural hearing loss. The combination of congenital goiter, familial deafness, and familial CH raised the possibility of Pendred syndrome as the etiology for the dyshormonogenesis in this family. However, sequencing of the PDS gene revealed no mutation. Furthermore, brain computed tomography (CT) excluded the typical inner ear anomalies found in Pendred syndrome. Further molecular analysis for the etiology of familial deafness included a study of the seven most common mutations of connexin 26 and 30 genes that are responsible for most cases of deafness in our population: this test was negative. Sequencing of the TPO gene revealed a novel homozygous missense mutation in exon 8 (c.875C>T, p.S292F) (7). Long-term follow-up demonstrated good compliance with a euthyroid state (Table 1). An enlarged thyroid gland was palpable at the age of 6 years. A repeat ^99mTC scan revealed an enlarged left thyroid lobe with small nonhomogeneous areas of uptake. Serum TG levels were significantly elevated (TG 1851 ng/mL, normal range 0–55 ng/mL), consistent with an enlargement of the thyroid. Neck CT demonstrated an enlarged nodular thyroid gland, wrapped around the trachea, with the largest nodule being 4.5 cm in diameter. Left thyroidectomy and partial right lobe resection were performed. The operation was complicated by left vocal cord paralysis. Pathological findings revealed a minimally invasive follicular carcinoma with no invasion into the blood vessels (Fig. 1). The surgical margins were free of tumor. Total thyroidectomy was not possible due to the risk of paralyzing the second vocal cord. An ablation dose of 30 mCi ¹³¹I was given. Currently, the patient, aged 29 years, is on l-T₄ suppressive therapy with a TG level of 62 ng/mL. No signs of recurrence have been demonstrated by neck ultrasonographic imaging.

FIG. 1.

(A) Histological aspect of the thyroid tumor. At low magnification, neoplastic tissue presents beyond the capsule of the tumor (hematoxylin–eosin staining, 200× magnification). (B) At a higher magnification, follicular carcinoma demonstrating capsular invasion. The tumor bud has completely invaded the thick fibrous capsule (hematoxylin–eosin staining, 400× magnification).

Table 1.

Summary of Thyroid Function and Size in the Index Case Before Thyroidectomy

Age ^a	TSH (mIU/L)	TT₄ (μg/dL)	FT₄ (ng/dL)	TT₃ (ng/dL)	l-T4 (μg/kg per day)	Thyroid examination
30 days	183	1.5			16.6	Enlarged
5 months	4.2	10.4		183	8.6	NA
1.2 years	11.7	8.8			7.5	NA
1.8 years	1.2	11.4	1.67	175	6.5	NA
2.5 years	1	13.5	1.7	154	3.8	Mildly enlarged
3 years	42	0.8	0.08		Without treatment	NA
4 years	1.75	12.1			4.8	NA
4.8 years	1.2	13	2.2	163	4.3	NA
5.4 years	4.2	12.9	1.7		3.8	NA
6.4 years	17	9.7	1.38	159	4.0	Diffuse goiter
7.5 years	0.8	11	1.7	153	3.4	NA
8.2 years	2.4	10	1	141	3.2	NA
9 years	3.8		1.4	162	2.6	Diffuse goiter
10 years	1.7		1.7	125	3.0	Diffuse goiter
11 years	2.4		1.32	150	3.2	Diffuse goiter
12 years	2.9		0.94		3	Diffuse goiter
3.2 years	0.88		1.17		2.3	MNG
14 years	0.7		1	150	2.1	MNG
15 years	7.2		0.67		2.7	MNG
16 years	0.5		1.55	193	2.8	MNG
17 years	<0.01		1.6		2.5	MNG
18 years	<0.03		1.8	141	2.2	MNG
19 years	0.04		1.43	112	2.1	MNG
20 years	0.22		1.37		2.1	MNG
21 years	<0.03		1.9	200	2.1	MNG
22 years	0.1		1.5	121	2.1	MNG
23 years	0.12		1.7	177	2.1	MNG
24 years	0.33		1.7		2.1	MNG
25 years	2.03		1.5		2.1	MNG
26 years	0.82		NA		2.1	MNG
Normal range	0.5–4.67		0.7–1.85	45–137

Age at examination.

FT4, free thyroxine; l-T₄, levothyroxine; MNG, multinodular goiter; NA, not available; TSH, thyrotropin; TT₃, total triiodothyronine; TT₄, total thyroxine.

Patient 2

The younger 28-year-old brother of the index case was initially admitted at the age of 52 days because of prolonged jaundice and bilateral pneumonia. His thyroid gland was not palpable. Neonatal screening was consistent with primary CH (TSH 46.0 mU/L; TT₄ 0.7 μg/dL). l-T₄ was started immediately. A ^99mTC scan performed at the age of 3 years, one month after l-T₄ withdrawal, demonstrated a mildly enlarged thyroid gland. RAIU was 43% after 2 hours and declined to 7% 2 hours after perchlorate administration, confirming the diagnosis of a TIOD. Audiometric tests at the age of 9 and 16 years revealed moderate sensorineural hearing loss. No abnormalities of the inner ear were demonstrated on a brain CT. Ultrasonographic imaging of the neck at the age of 26 years revealed normal-size thyroid lobes with several small nodules in both lobes not suspicious for malignancy. Sequencing of the TPO gene revealed the same homozygous mutation (c.875C>T, p.S292F) found in the patient's sister.

Discussion

We describe the occurrence of noninvasive follicular thyroid carcinoma in a woman with goitrous CH due to a TPO mutation. This is the second reported case of a thyroid carcinoma in an affected patient with a TPO mutation.

In MNG, the prevalence of thyroid carcinoma has been estimated at 1%–4% (8). Vickery (9) reported 17 cases of thyroid carcinomas in dyshormonogenetic MNG, among them 4 cases with vascular invasion and 6 patients with hearing loss suggesting a diagnosis of Pendred syndrome. However, it should be noted that hearing impairment may result from late diagnosis and inadequate treatment of CH of other etiologies as well (15). Cooper et al. (16) were the first to describe congenital dyshormonogenetic goiter with malignancy and metastatic spread. An additional two reports of thyroid carcinoma in patients with Pended syndrome (17,18) and dyshormonogenetic goiter were described (19,20). Unfortunately molecular analysis was not available in any of those cases. However, over the last two decades, with the increasing availability of molecular analyses, 11 cases of thyroid carcinoma have been reported: 9 in patients with TG mutations (10 –12), 1 in a patient with a PDS mutation (13), and only 1 case with a TPO mutation (14) (Table 2). Both papillary and follicular carcinomas have been described. It has been postulated that long-standing elevated serum TSH levels is the main cause for the development of thyroid carcinoma arising from dyshormonogenetic MNG (21,22). TSH is a well-known growth factor for thyroid epithelial cells and can promote thyroid nodule formation and cancer progression (22,23). Nonsuppressed TSH appears to increase the risk of recurrence of thyroid carcinoma, supporting a crucial role for TSH in thyroid cell proliferation. Furthermore, constitutively activating TSH receptor mutations result in toxic adenoma and hyperfunctioning MNGs, and they have been found rarely in patients with hyperfunctioning thyroid carcinomas (24). Histological changes such as microfollicular nodules and cytological atypia can develop under prolonged TSH stimulation (16,25). However, the association between elevated TSH and the occurrence of thyroid cancer has not been conclusively established. In our cohort of 22 patients with TPO mutations, we observed a high rate of MNG but none showed malignant changes (7). In the present report, the fact that the index case was treated with l-T₄ from infancy with good compliance and no significant increase in TSH levels (Table 1) indicates that additional factors play a role in the development of huge MNG and the progression to thyroid follicular carcinoma.

Table 2.

Summary of the Reported Cases of Thyroid Carcinoma in Dyshormonogenetic Goiter

Affected gene	Mutation type	Age ^a	Type of carcinoma	Uni-/multifocal	Gender	Goiter ^b	Reference
TPO	c.2421_2422insC (Hetero)	1 week	Follicular	Metastatic	F	Congenital	(14)
	c.875C>T, p.S292F (Homo)	years 27	Follicular	Unifocal	F	Congenital	This report
PDS	c.279delT, p.S93RfsX3 (Homo)	years 53	Follicular	Metastatic	F	Childhood	(13)
	IVS5_6+1G>A (Homo)	years 5	Follicular	Metastatic	M	1.5 years	(11)
	c.3790T>C, p.C1264R (Homo)	years 27	Papillary	Unifocal	F	NA	(12)
	c.3790T>C, p.C1264R (Homo)	years 12	Papillary	Multifocal	F	NA	(12)
	c.3790T>C, p.C1264R/c.7123G>M, p.G2375R	years 38	Papillary	Unifocal	M	NA	(12)
	c.unpublished, p.C1996S (Homo)	years 35	Follicular	Multifocal	F	NA	(12)
	c.unpublished, p.C1996S (Homo)	years 28	Papillary	Multifocal	F	NA	(12)
	c.3229T>C, p.C1077R (Homo)	years 17	Papillary	Multifocal	F	NA	(12)
	c.3229T>C, p.C1077R (Homo)	years 36	Papillary	Multifocal	F	NA	(12)
TG	c.6725G>A, p.R2242H (Homo)	21 years	Papillary	Multifocal, metastatic	F	Congenital	(10)

Age at operation.

Age at onset.

hetero, heterozygous; homo: homozygous; PDS, pendrin; TG, thyroglobulin; TPO, thyroid peroxidase.

Congenital goiter is a rare presentation of dyshormonogenesis and appears in only 10% of affected patients with TPO mutations (7). Indeed, the only case of thyroid carcinoma in a patient with TPO mutations occurred in an infant born with goitrous CH; this patient was found to have a metastatic follicular cancer already at birth (14). That report indicated that the thyroid carcinoma had existed in utero, arguing against the effect of long-standing elevated TSH as the main cause for the development of thyroid carcinoma. It maybe speculated that congenital goiter increases the risk of thyroid carcinoma development. Indeed, the brother of the proposita, who had the same TPO mutation and a normal-sized thyroid gland at birth, did not develop a thyroid tumor. However, some reports of thyroid carcinoma arising from dyshormonogenetic goiter have been described in patients without congenital goiter (11,13). The high concentrations of H₂O₂ produced in response to increased TSH levels might lead to DNA damage and could have mutagenic effects (26,27). Furthermore, organic iodocompounds have been shown to inhibit thyroid epithelial cell proliferation (23), and TPO mutations resulting in IOD might therefore increase the risk for MNG. The same mechanism may apply to Pendred syndrome, where iodide transport through the apical membrane is interrupted.

The development of a tumor depends on either stimulating factors or a lack of tumor-suppressor genes. Over the last two decades, significant progress has been made in understanding the genetic events in follicular cell–derived thyroid tumors. RET/PTC and PAX8-PPARγ chromosomal rearrangement and BRAF and RAS point mutations have been identified in more than 70% of papillary and follicular thyroid carcinomas (27). Activating point mutations of the RAS genes occur in follicular carcinomas and adenomas, poorly differentiated and anaplastic carcinomas, and some papillary carcinomas (28,29). Screening for PAX8-PPARγ chromosomal rearrangement and BRAF and RAS point mutations was negative in one patient with follicular carcinoma and a TG mutation (10), but positive for BRAF mutations in two others (12).

The mechanisms of thyroid cancer development in dyshormonogenesis remain to be elucidated. It might result from a combination of environmental factors, such as iodine deficiency and long-standing elevated TSH, which increase H₂O₂ concentration and activation or suppression of genes involved in thyroid cell proliferation. In this study, we present the second report of thyroid carcinoma in a patient with a TPO gene mutation. Although thyroid carcinoma is not common in dyshormonogenetic MNG, long-term follow-up by regular neck ultrasonographic imaging followed by fine-needle aspiration, if indicated, is recommended to avoid a delayed diagnosis of thyroid carcinoma in these cases.

Footnotes

Acknowledgment

The authors thank Camille Vainstein for professional language editing.

Disclosure Statement

The authors declare that no competing financial interests exist.

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