¹Department of Biomedical Sciences and of Morphological and Functional Images, Unit of Nuclear Medicine, ²Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Messina, Messina; ³Unit of Endocrinology, Hospital of Scilla, Reggio Calabria, Calabria; ⁴Department of Pathology, University of Messina; Italy

OBJECTIVE: Thyroid hemiagenesis is a rare congenital disorder characterized by the absence of a lobe and/or of isthmus. Studies on the association between thyroid hemiagenesis, Graves’ disease and differentiated thyroid cancer are rare.
CASE PRESENTATION: We describe the medical and surgical history of a patient in whom a molecular evaluation was performed. A 36-year-old man presented with symptoms and signs of hyperthyroidism of a few months’ duration. Hyperthyroidism was confirmed biochemically and anti-TSH-receptor antibodies were positive. Thyroid ultrasonography showed no left lobe and demonstrated a diffused enlargement of the right lobe; an ipoechoic, non-homogenous nodule 15 millimeters in size was identified in the middle part of the lobe. A ^99mTc-pertechnetate thyroid scintigraphy (111 MBq) confirmed thyroid hemiagenesis due to the absence of the left lobe. Treatment with methimazole (30mg/day) was started. As the patient’s hyperthyroidism improved, he underwent fine-needle needle aspiration cytology (FNAC) of the right nodule. Cytology was suspicious for malignancy (THY4) and the patient was referred for surgery. Histopathological findings revealed a papillary thyroid carcinoma. The molecular analysis did not show PAX8 or TSHR mutations in the thyroid tissue nor mutations of BRAF, H-RAS, N-RAS or K-RAS genes in the tumor.
CONCLUSION: Though thus far studies on the association of thyroid hemiagenesis, Graves’ disease and differentiated thyroid cancer are extremely rare, the possibility of the development of thyroid cancer must be taken into account in patients affected by thyroid hemiagenesis and the nodular variant of Graves’ disease.

Differentiated thyroid cancer, Graves’ disease, Radioiodine treatment, Thyroid hemiagenesis

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INTRODUCTION

Thyroid hemiagenesis is a rare congenital anomaly in which one lobe and/or isthmus fail to develop. This condition was described for the first time by Handfield-Jones in 1866.

The etiology of thyroid hemiagenesis is unknown, with postulations of failure of descent from the foramen cecum to the trachea,¹ defects in lobulation² or genetic mechanisms.^3-5 Many genes have been identified as important contributors to proliferation and migration of thyroid cells precursors, acting during embryogenesis (NKX2-1, PAX8, FOXE1, NKX2-5, TSHR). However, mutations in such genes playing a role in thyroid morphogenesis have been reported in only a small minority of patients. In particular, a heterozygous mutation of the PAX8 gene has been proposed as being responsible for some familial cases.⁶ However, Castanet et al,⁷ having found no PAX-8 mutations in 22 patients with hemiagenesis, proposed other mutations (i.e. TTF-1, FOXE-1, TTF-2). It is likely that sporadic cases of hemiagenesis are caused by epigenetic factors rather than by mutations in thyroid transcription factors or genes involved in thyroid development.

Thyroid hemiagenesis is often discovered incidentally,^2,8 its incidence ranging from 0.025% to 0.16%.³ Searching in the literature from 1970 and up to the present day, we have noticed how the association of thyroid hemiagenesis and differentiated thyroid cancer is rare,⁴ while it is relatively common with Graves’ disease (GD).

To date, only one female patient has been described in whom all three conditions were present.⁵ Herein we report, for the first time, a male patient with thyroid hemiagenesis associated with GD and differentiated thyroid cancer and review the pertinent literature.

CASE PRESENTATION

Patient findings

A 36-year-old-man was referred to our outpatient clinic in July 2013 because of fatigue, palpitations, tremor, insomnia, sweating and weight loss of a few months’ duration. Physical examination revealed warm, moist skin and hyper-reflexia; moreover, a diffuse enlargement of the right thyroid lobe was observed, while the left lobe was not-detected. His heart rate was 98 beats/minute and his mean blood pressure was 145/70 mmHg.

No photophobia and/or eyelid retraction were present on ophthalmological examination. Funduscopic and visual field examinations were within the normal range.

The serum TSH was 0.012 mU/l (normal range 0.270–4.2) and the serum free triiodothyronine (FT3) and free thyroxine (FT4) levels were elevated (FT3: 22.6 pg/ml, range 2.2–4.2; FT4: 34.4 pmol/L; normal range 9.0–16.0). Serum anti-TSH-receptor antibodies (TRAb) were markedly increased (20 IU/L; range 0-1.5), whereas anti-thyroglobulin antibodies (Tg-Ab) and anti-peroxidase antibodies (TPO-Ab) were absent.

Thyroid ultrasonography (US) did not show the left lobe and demonstrated a diffused enlargement of the right lobe, associated with hypoechogenicity and an increased thyroid blood flow. An ipoechoic, non-homogenous nodule (15 millimeters in size), with nodular microcalcifications and high intranodular blood flow by color-Doppler, was identified in the middle part of the lobe. The isthmus was not observed. A 99mTc-pertechnetate thyroyd scintigraphy (111 MBq), performed a few days later, confirmed thyroid hemiagenesis due to the absence of the left lobe. In the right lobe, the 99mTc-pertecnetate uptake was non-homogeneous and a cold nodule was detected in the middle part (Figure 1). No other family members were affected by thyroid hemiagenesis.

Figure 1

All findings were consistent with GD, nodular variant, in a patient affected by left thyroid lobe hemiagenesis and treatment with methimazole [MMI (20 mg/day)] was started. After several weeks, we observed a progressive improvement of symptoms and signs of thyrotoxicosis, as well as normalization of FT3 and FT4 values. Some weeks later, the patient underwent fine-needle aspiration cytology (FNAC) of the nodule located in the right lobe. Cytology was suspicious for malignancy (THY4) and the patient underwent surgery. Histopathological findings were conclusive for papillary thyroid carcinoma (PTC) associated with diffused hyperplasia and hypertrophy of follicular cells, without lymph-node metastases (pT1aN0Mx) (Figure 2).

Figure 2

After surgery, the patient was maintained on levothyroxine (L-T4) suppressive therapy, with serum TSH values <0.2 mUI/L and serum levels of FT3 and FT4 within the normal range. Serum levels of thyroglobulin (hTg) were undetectable (<0.15 ng/ml) and Tg-Ab were absent.

Three months later, neck US showed a right thyroid remnant but did not reveal any findings suspicious for neoplastic/metastatic disease in the lymph nodes. The patient underwent radioiodine treatment (RaIT) with ablative activity of 131I (2220 MBq) on levothyroxine therapy and after recombinant human TSH (rhTSH) stimulation (0.9 mg daily for two consecutive days administered by intra-muscular injections). The post-therapy whole body scan, performed 5 days later, showed an intense and well defined radioiodine uptake located in the right thyroid bed, consistent with thyroid remnant tissue At the time of the RaIT, serum peak level of TSH and hTg were 117 mU/l and 31 ng/ml, respectively. In the absence of Tg-Ab (<4 UI/ml), hTg levels were consistent with the persistence of the thyroid remnant only.

Twelve months later, basal and stimulated serum levels of hTg (after rhTSH-stimulation) were undetectable and Tg-Ab were absent. Neck US was negative for thyroid remnant tissue and/or loco-regional metastases. Thus, the patient was declared “disease free”.

Molecular studies

The surgical thyroid specimens were analyzed for mutations of the PAX8 gene, since PAX8 is considered the main regulator of thyroid morphogenesis. The TSH receptor (TSHR) gene was also studied. Moreover, the tumour nodule was examined for activating mutations of H-RAS, N-RAS, K-RAS and BRAF genes by direct sequencing.

Extraction of somatic DNA from the surgical specimens was performed with the Nucleospin Tissue Kit (Macherey-Nagel, Germany), according to the manufacturer’s instructions.

The DNA samples were used for directly sequencing exon 15 of the BRAF gene, exons 1 and 2 of the H-RAS, K-RAS and N-RAS genes, exons 1-10 of the TSHR gene and exons 3-12 of the PAX8 gene. Direct sequencing of polymerase chain reaction (PCR) products was performed using the Big Dye Terminator v1.1 cycle sequencing kit (Applied Biosystems, Foster City, CA) and an automatic ABI310 sequencer (Applied Biosystems). The employed primers are shown in Table 1. All the above exons were amplified by PCR as follows: initial denaturation for 5 min (94˚C), followed by 30 cycles of 30 sec at 94˚C, 30 sec at the appropriate annealing temperature and 30 sec at 72˚C, followed by a final 5-min elongation at 72˚C. The annealing temperature was 53° C for N-RAS exon 2; 55˚C for BRAF exon 15, H-RAS and K-RAS exon 1, TSHR exons 1-8, PAX8 exon 4; 57° C for H-RAS exon 2, N-RAS exon 1 and PAX8 exon 3; 58° C for K-RAS exon 2 and PAX8 exons 7 and 8; 59˚C for TSHR exons 9 and 10, and for PAX8 exon 11; 61° for PAX8 exons 5 and 9; 62 °C for PAX8 exon 10; 63 °C for PAX8 exon 12. The PCR products were purified using the Nucleospin Extract II kit (Macherey-Nagel, Germany).

The full-length TSHR and PAX8 sequence and the RAS and the BRAF sequences present in the GenBank database were used for mutagenesis analysis.

However, no genetic alterations were found either in the tumour or in the surrounding thyroid tissue.

DISCUSSION

Thyroid hemiagenesis is a rare developmental anomaly, with a female predominance (F:M ratio 3:1),⁹ the most common feature being absence of the left lobe (L:R ratio 4:1).¹ The presence or absence of the isthmus is variable (50% of cases).⁹ Currently, the prevalence of thyroid hemiagenesis is estimated to be from 0.025% to 0.16%, according to the literature,⁹ and it seems to be higher in iodine-deficient areas.¹⁰ However, a true incidence of thyroid hemiagenesis is very difficult to verify, since the absence of a lobe and/or isthmus is often clinically irrelevant and the diagnosis is frequently incidental in the setting of accompanying thyroid disorders.

We have searched the literature which includes approximately 350 cases described to date. In the majority of patients (195/350 or 56%), the hemiagenesis was associated with another thyroid disease, hypothyroidism and/or Hashimoto thyroiditis being the most common. The associations, however, include a wide range of thyroid diseases: euthyroid multinodular goiter,¹ Hashimoto thyroiditis,¹ congenital hypothyroidism,³ hypothyroidism,¹⁰ hyperthyroidism (due to GD or nodular toxic goiter), differentiated thyroid cancer,^10,11 accessory lingual thyroid¹ and thyroglossal duct cyst.¹

Only 40 patients (33 F and 7 M, mean age 37.2 ± 14.2, range 7-63 years) with thyroid hemiagenesis and GD have been reported in the literature to date (Table 2). With the exception of a case in which data were missing, the thyroid hemiagenesis was on the left in 29 patients (74.4%) and on the right in 9 (23.1%), while isolated isthmus absence was present only in one patient (2.5%). All patients with right hemiagenesis were women, while 7 men (24.1%) and 22 women (75.9%) had a left hemiagenesis. The only patient with isolated isthmus agenesis was a woman. Thus, 82.5% of patients with association of hemiagenesis and GD were women, they were younger than the men (p=0.20) and the hemiagenesis was prevalently on the left lobe (76.3%).

Searching for the association between thyroid hemiagenesis and cancer, we found 15 patients (14 females and 1 male, mean age 48.57±15.9, range 14 to 74 years)^{2,4,5,8,10-20} (Table 3). Thyroid hemiagenesis was on the left in 8 cases (7 F and 1 M, mean age 50.5±17.1, range 14-69) and on the right in 6 (all women; mean age 47.8±16.5, range 30-74), while only one woman presented isolated isthmus absence. Among these patients, 12 (80%; 11 females aged 30-70 yr and 1 54-yr-old male) were affected by PTC, a woman had a follicular thyroid cancer (FTC) and another woman a medullary thyroid carcinoma (MTC), while the coexistence of PTC and FTC was observed in a third woman. Once again, the above mentioned conditions were significantly prevalent in the female gender.

Limiting the research to patients with GD, hemiagenesis and thyroid cancer, only one case was reported in the literature.⁵ Ammaturo et al described a 39-year-old woman with GD, left hemiagenesis and papillary thyroid cancer. As in our patient, the diagnosis of thyroid hemiagenesis was incidentally obtained via instrumental thyroid studies performed to better define a hyperthyroid state. No molecular studies were performed in this patient.

In conclusion, we describe the first case of a male patient affected by thyroid hemiagenesis, GD and differentiated thyroid cancer. To date, only one female patient has previously been reported in the literature. In our patient we failed to identify any gene mutation. Although this condition is extremely rare, the possibility of developing a thyroid cancer must be taken into account in patients affected by thyroid hemiagenesis and the nodular variant of GD.

CONFLICT OF INTEREST

There is no potential conflict of interest and the authors have nothing to disclose.

FUNDING

This work was not supported by any grant.

REFERENCE

1. Karabay N, Comlekci A, Canda MS, Bayraktar F, Degirmenci B, 2003 Thyroid Hemiagenesis with Multinodular Goiter: A Case Report and Review of the Literature. Endocr J 50: 409-413.
2. Greening WP, Sarker SK, Osborne MP, 1980 Hemiagenesis of the thyroid gland. Br J Surg 67: 445-448.
3. Tonacchera M, Banco ME, Montanelli L, et al, 2007 Genetic analysis of the PAX8 gene in children with congenital hypothyroidism and dysgenetic or eutopic thyroid glands: identification of a novel sequence variant. Clin Endocrinol (Oxf) 67: 34-40.
4. Shaha AR, Gujarati R, 1997 Thyroid hemiagenesis. J Surg Oncol 65: 137-140.
5. Ammaturo C, Cerrato C, Duraccio S, et al, 2007 Thyroid hemiagenesis associated with Flajani’s disease and papillary carcinoma. A case report. Chir Ital 59: 263-267.
6. Szczepanek-Parulska E, Szaflarski W, Piątek K, et al, 2013 Alternative 3’ acceptor site in the exon 2 of human PAX8 gene resulting in the expression of unknown mRNA variant found in thyroid hemiagenesis and some types of cancers. Acta Biochim Pol 60: 573-578.
7. Castanet M, Leenhardt L, Léger J, et al, 2005 Thyroid hemiagenesis is a rare variant of thyroid dysgenesis with a familial component but without Pax8 mutations in a cohort of 22 cases. Pediatr Res 57: 908-913.
8. Pizzini AM, Papi G, Corrado S, Carani C, Roti E, 2005 Thyroid hemiagenesis and incidentally discovered papillary thyroid cancer: Case report and review of the literature. J Endocrinol Invest 28: 66-71.
9. Melnick JC, Stemkowski PE, 1981 Thyroid hemiagenesis (hockey stick sign): a review of the world literature and a report of four cases. J Clin Endocrinol Metab 52: 247-251.
10. Mikosch P, Gallowitsch HJ, Kresnık E, Molnar M, Gomez I, Lind P, 1999 Thyroid hemiagenesis in an endemic goiter area diagnosed by ultrasonography: Report of sixteen patients. Thyroid 9: 1075-1084.
11. McHenry CR, Walfish PG, Rosen IB, Lawrence AM, Paloyan E, 1995 Congenital thyroid hemiagenesis. Am Surg 61: 634-639.
12. Lee YS, Yun JS, Jeong JJ, Nam KH, Chung WY, Park CS, 2008 Thyroid hemiagenesis associated with thyroid adenomatous hyperplasia and papillary thyroid carcinoma. Thyroid 18: 381-382.
13. Hamburger JI, Hamburger SW, 1970 Thyroidal hemiagenesis. Report of a case and commnets on clinical ramifications. Arch Surg 100: 319-320.
14. Harada T, Nishikawa Y, Ito K, 1972 Aplasia of one thyroid lobe. Am J Surg 124: 617-619.
15. Khatri VP, Espinosa MH, Harada WA, 1992 Papillary adenocarcinoma in thyroid hemiagenesis. Head Neck 14: 312-315.
16. Huang SM, Chen HD, Wen TY, Kun MS, 2002 Right thyroid hemiagenesis associated with papillary thyroid cancer and an ectopic prelaryngeal thyroid: a case report. J Formos Med Assoc 101: 368-371.
17. Berni Canani F, Dall’Olio D, Chiarini V, Casadei GP, Papini E, 2008 Papillary carcinoma of a thyroglossal duct cyst in a patient with thyroid hemiagenesis: effectiveness of conservative surgical treatment. Endocr Pract 14: 465-469.
18. Karatağ GY, Albayrak ZK, Önay HK, Karatağ O, Peker Ö, 2013 Coexistence of thyroid hemiagenesis, nodular goitre and papillary carcinoma. Kulak Burun Bogaz Ihtis Derg 23: 115-118.
19. Vayisoglu Y, Ozcan C, Gen R, Eti CM, Sut H, Gorur K, 2013 Thyroid isthmus agenesis associated with thyroid papillary carcinoroid isthmus agenesis associated with thyroid papillary carcinoma. J Craniofac Surg 24: 428-429.
20. Wang J, Gao MM, Song C, 2014 Thyroid hemiagenesis associated with medullary or papillary carcinoma: Two cases report. Head Neck 36: 106-111.

Address for correspondence:
Alfredo Campennì, MD, PhD, Unità di Medicina Nucleare, Dipartimento di Scienze Biomediche e delle Immagini Morfologiche e Funzionali, Padiglione E, Policlinico Universitario “G. Martino”, v. Consolare Valeria, 98125 Messina, Italy; Tel.: +39 090 2217156; Fax: +39 090 2212843, E-mail: acampenni@unime.it

Received: 17-05-2015, Accepted: 19-05-2015