Search tips
Search criteria 


Logo of actotoritalLink to Publisher's site
Acta Otorhinolaryngol Ital. 2009 December; 29(6): 296–304.
PMCID: PMC2868203

Language: English | Italian

Occult thyroid carcinoma

Carcinoma tiroideo occulto


Some medical definitions remain the same for many years, others change due to the progress in the diagnostic tools, which are able to distinguish markers and symptoms until then undetectable. Occult thyroid carcinoma is a general term indicating clinically different situations, whereas the incidentally detected papillary thyroid microcarcinoma is the most important from the clinical point of view. It is fundamental, for therapeutic management, to determine biological parameters which would define a small group of papillary thyroid microcarcinomas with aggressive biological behaviour. The most promising genetic and molecular markers for papillary thyroid carcinoma risk stratification are discussed in this review. Preoperative evaluation of these markers, obtained through analysis of ultrasonography-guided fine needle biopsy specimens of papillary thyroid microcarcinoma, could be very valuable in guiding treatment of this type of cancer.

Keywords: Thyroid, Occult carcinoma, Papillary microcarcinoma, Molecular markers, Therapeutic strategy


Alcune definizione mediche restano invaiate nel tempo, mentre altre si modificano seguendo i progressi che consentono in campo diagnostico di definire markers e sintomi fino a quel momento non valutabili. Il carcinoma occulto della tiroide è un termine generico che indica differenti situazioni cliniche, mentre il microcarcinoma papillifero della tiroide diagnosticato incidentalmente resta l’entità clinica maggiormente significativa. È fondamentale ai fini della programmazione terapeutica la possibilità di identificare dei parametri biologici in grado di differenziare i microcarcinomi papilliferi sulla base della loro aggressività. In questa review sono stati rivisti i markers genetici e molecolari del microcarcinoma papillifero della tiroide più significativi ai fini di una loro possibile stratificazione. La valutazione pre-operatoria di questi markers, ottenuti attraverso l’analisi di agobiopsie ecoguidate di microcarcinomi papilliferi, potrebbe essere utile per la pianificazione terapeutica di questo tipo di carcinoma.


Papillary and follicular malignancies are well differentiated carcinomas of the thyroid gland and are among the most curable cancers 1. Patients can be identified by using well-established prognostic parameters and therapy can follow a variety of published and regularly renewed guidelines. Treatment of thyroid cancer employs a three-tiered approach comprising surgery, iodine radiometabolic treatment and long-term thyroid-stimulating hormone suppression by exogenous administration of thyroid hormone 2. The overall survival rate, at 10 years, for middle-aged adults with thyroid carcinomas, is about 80-95% 1. This review focuses on one subcategory of differentiated thyroid carcinomas. “Occult thyroid carcinoma” is a general term including clinically different situations.


In the literature, there are different definitions of the term: “Occult Thyroid Carcinoma”. The Merriam-Webster dictionary, in the current on-line version, explains “Occult carcinoma” as “not manifest or detectable by clinical methods alone”, and also as “not present in macroscopic amounts” 3. The McGraw-Hill Concise Dictionary of Modern Medicine (2002) defines “occult primary malignancy” as “unknown primary malignancy that is symptomless, which first manifests itself as metastases or secondary paraneoplastic phenomena” 4. In 1997, Moosa and Mazzaferri defined “Occult thyroid carcinoma” as an “impalpable thyroid carcinoma that is generally smaller than 1.0 cm” 5. A more precise definition of size is used by Stedman’s Medical Dictionary (2006), where “occult papillary carcinoma of the thyroid” is described as microcarcinoma of the thyroid or microscopic papillary carcinoma of the thyroid, usually well encapsulated and measuring less than 5 mm in diameter 6. A combination is used in the WHO (World Health Organization) classification system, where papillary thyroid microcarcinoma (PTMC) is defined as “papillary carcinoma measuring 1.0 cm or less in maximal diameter while other clinico-pathological features, such as metastasis to regional lymph nodes and/or distant organs as well as extrathyroid extension, are not considered” 7. Shaha is using a broader definition of PTMC: “Traditionally, microcarcinoma was considered to be less than 1 or 1.5 cm” 8.

From the previous paragraph, it is clear that the term occult thyroid carcinoma and papillary microcarcinoma could be considered synonyms in the majority of clinical situations. Nevertheless, there are some mismatching situations. For a better understanding, we can divide the term “occult thyroid carcinoma” into four different categories. The first group comprises patients with thyroid carcinoma or microcarcinoma incidentally found in the thyroid gland after total thyroidectomy for benign disease 911 or at autopsy 1219. In the second group there are patients with incidentally detected PTMC on imaging studies, mainly ultrasonography, and evaluated by fine needle aspiration biopsy (FNAB). The third group are patients with clinically apparent metastases of thyroid carcinoma, where the primary tumour is not detectable before surgery and microscopic tumour – microcarcinoma is found in the final histological specimen. The fourth group covers patients with thyroid cancer localized in ectopic thyroid tissue with clinical symptoms or with apparent metastases.

Thyroid gland embryology

The primordial thyroid gland is the first identifiable, approximately on the 24th day of gestation, beginning as an endodermal invagination, a proliferation of endodermal epithelial cells on the median surface of the developing pharyngeal floor. The thyroid gland originates between the first and second pharyngeal (branchial) pouches. The area is known as the foramen caecum and lies where the midline intersects the sulcus terminalis, which divides the tongue into anterior two thirds (oral part) and posterior one third (pharyngeal part). The thyroid diverticulum begins its descent through the tongue carrying with it the thyroglossal duct and, during the fifth and sixth weeks, the path of descent carries the developing gland anterior to the hyoid bone and the larynx. At the same time, the gland becomes bi-lobed, medially connecting with the isthmus and the superior part of the thyroglossal duct degenerates. During the seventh week, the descent of the thyroid continues and it reaches its final position, level under the cricoid cartilage anteriorly to the trachea. The distal part of the thyroglossal duct degenerates, but may remain as a pyramidal lobe 20. Thyroid hormones start to be secreted during the twelfth week of development. Para-folicular cells originate in the neural crest region and infiltrate the ultimobranchial body which arises from the fifth pharyngeal pouch. Ultimobranchial body then fuses with the thyroid beyond the anterior part of the neck during the process of descent and the cells disseminate into the thyroid and differentiate into calcitonin-producing C cells 21.

Thyroid carcinoma in ectopic thyroid tissue

Failure of migration can result in ectopic thyroid tissue being differentiated anywhere along the thyroglossal tract. It has been found in a variety of sites ranging from the base of the tongue to the neck, and has also been found in the trachea, oesophagus 22, mediastinum 23 and associated with the heart’s descent 24 25. The majority of ectopias are manifested as simple thyroglossal duct cysts in conjunction with a normally developed thyroid gland 26. The most frequent remnant is the caudal part of the track-pyramidal lobe, present in 30-50% of patients 21 24.

Complete arrest of the descent of the developing thyroid, resulting in the presence of thyroid tissue at the tongue base, is known as lingual thyroid. Carcinoma arising in a lingual thyroid is very unusual 26 and, in contrast to other localizations, the follicular type is predominantly reported. Less differentiated (medullary) or undifferentiated (anaplastic) carcinomas in the lingual thyroid have not been reported in the literature. The explanation for medullary carcinoma can be found in embryology. The C-cells migrate independently and fuse with the thyroid after its complete descent from the foramen caecum. Clinical symptoms occur mainly on account of a mass effect and include dysphonia, dyspnoea, dysphagia or a foreign body sensation, rarely hemoptysis. Due to the fact that lingual thyroid carcinoma is an extremely rare entity, there is no general consensus regarding the most appropriate therapeutic strategy in the literature. Surgery is the treatment of choice, usually peroral resection, which could be combined with an external approach – lateral pharyngotomy or transhyoid incision. A neck dissection would only be indicated if metastatic nodules are noted. If there are positive margins, or more advanced disease is present, adjuvant radiometabolic treatment should be given 26.

Persistence of the thyroglossal duct with cyst formation is the most common congenital cervical abnormality. It may be located anywhere from the thyroid cartilage up to the base of the tongue, but approximately 50% of these cystic masses are located at, or just below, the level of the hyoid bone. The incidence of carcinoma arising in the thyroglossal duct cyst is reported to be about 1.3% in the adult population, with papillary thyroid carcinoma (PTC) comprising the majority of cases 27. Also mixed papillary-follicular, squamous cell carcinoma or Hürthle cell carcinoma may be found 28. Choice of therapy must be based upon the patient’s age and the size and extent of the tumour. The treatment of choice for thyroglossal duct cyst with microscopic focus of papillary carcinoma (TDCC), without cyst wall invasion, is surgical excision via a Sistrunk procedure 29, first described in 1920 30. The key elements are removal of the central portion of the hyoid bone and excision of any proximal thyroglossal duct. In other situations, removal of all thyroid tissue, followed by radiometabolic treatment should be performed 28 31. Nevertheless, opinions differ as to whether thyroidectomy and neck dissection should be performed since carcinoma is found in approximately 25-40% of thyroid glands and about 10% metastasize to cervical lymph nodes 32. Moreover, Hartl et al. 33 recently reported a high rate of multi-focality and lymph node metastases. They found foci of carcinoma in thyroid lobes in 56% of patients and 75% had lymph node metastases, in both central and lateral compartments 33. However, overall prognosis is favourable for the majority of patients 31 32.

In very rare circumstances, thyroid tissue may be found below the diaphragm. It could be associated with the gastro-intestinal tract 20, but more often it is described as a struma ovarii. Struma ovarii is a monodermal highly specialized ovarian teratoma, which is composed predominantly of biologically active thyroid tissue (more than 50% of thyroid tissue in tumour mass) 34 35. It was described for the first time in 1889 36. This thyroid tissue is derived from an ovarian germ cell tumour 20 and exhibits the same histological, physiological and pharmacological features as cervical thyroid tissue. Only 3-5% of these cases are classified as malignant. Although the most prevalent histological type is follicular carcinoma, papillary, mixed follicular-papillary or a follicular variant of papillary carcinoma have also been reported. Metastatic disease is extremely rare. Metastases are predominantly found in the peritoneum, mesentery and omentum. Primary carcinoma of the thyroid must be excluded. The therapeutic schema is not well defined, metastases can accumulate radioiodine, and thus, total thyroidectomy is usually part of a complex surgical therapeutic approach followed by radioiodine ablation and thyroid-stimulating hormone (TSH) suppression. Furthermore, thyroglobulin levels can be monitored as a tumour marker for recurrence.

Occult thyroid carcinoma

Some medical definitions remain unchanged for many years, others are changed due to the progress in the diagnostic tools, which are able to distinguish markers and symptoms, until then undetectable. The term “Occult thyroid carcinoma” was used, for the first time, in the middle of the last century 37. It defined thyroid cancer, with or without local metastases, which was identified after final histology 38. This situation has radically changed in the last 10-15 years, since when ultrasonography (US) has become a routine investigation in the care of patients with thyroid diseases and is now a gold standard both in the diagnostic process and follow-up. US allows detection of very small nodules (up to 3 mm) and US guided FNAB can be, with high sensitivity, helpful in defining the biological behaviour of the nodule 3941.

Incidentally detected thyroid carcinoma

The first papers reporting thyroid cancer, usually found at autopsy date back to the middle of the last century. The patients did not have any clinical symptoms during their lives 13. The same methodology has been updated since then in several autopsy studies across the world 12 1419 4250 and autopsy prevalence of thyroid carcinoma (or microcarcinoma) has been reported ranging from 0.01% in USA 16 to 35.6% in Finland 15. This enormous difference might be explained by genetic factors, environmental factors and methods used for histological examination.

Probably the most important factor is genetic predisposition, which is supported by the fact that the prevalence in the Japanese population exposed to the radiation during the bomb attack on Hiroshima and Nagasaki (11.3-28.4%) 12 14 16 and in the Japanese population staying in Hawaii, without the radiation exposure (24%) 16 19, is similar. In the literature, several critical genetic alterations, associated with development of specific thyroid tumour types, have been described. The three types of genetic alteration in the Mitogen-activated Protein Kinase (MAPK) pathway, including RET rearrangement and Ras and BRAF mutation, are present in approximately 70% of PTCs 51. The MAPK pathway is activated by signals from a variety of cell surface receptors and growth factors 52. All of them are sufficient to trigger PTC tumourigenesis, but from numerous clinico-pathological and molecular studies, it is obvious that BRAF mutation plays a fundamental role in progression, invasiveness and recurrence of PTC. BRAF mutation is also associated with overexpression of the Vascular Endothelial Growth Factor (VEGF) 53, which is a strong angiogenic protumour molecule that plays a critical role in human cancer progression and invasion 54. The explanation for this proangiogenic BRAF – VEGF association is in the unique molecular mechanism, when BRAF mutation promotes VEGF overexpression and inhibition of Tissue Inhibitor of Metalloproteinases-3 (TIMP3) 51. TIMP3 is the tumour inhibitor, which suppresses tumour growth, angiogenesis, invasion and metastasis by preventing the interstitial matrix destruction promoted by matrix metalloproteinase 3 (MMP-3) 55. Moreover, BRAF mutation, in the primary PTC, is associated with loss of radioiodine avidity in the recurrent tumour 56.

Recently, Gudmundsson et al. 57 published the results of a genome-wide association study, which involved more than 37,000 individuals of European descent and reported that a common variation on 9q22.33 and 14q13.3 predisposes to thyroid cancer. Individuals who are homozygous for both variants have an estimated risk of thyroid cancer 5.7-fold greater than non-carriers.

Iodine intake is mentioned as an important environmental factor. A wide range of variants has been found in different parts of the world. In areas with sufficient iodine intake, the incidence of thyroid cancer is higher and a predominance of papillary carcinoma has been mentioned. Iodine-dependent areas represent an increased prevalence of goitre and thyroid nodules and follicular and anaplastic cancers would be more prevalent 58. On the other hand, in 2005, Kovacs et al. 43 published results of a study, where consecutive series of autopsies were performed in Hungary in two areas with different iodine uptake 59. They concluded, that the prevalence of microcarcinomas was not related to iodine intake, because from 222 thyroids examined in an iodine deficient group and from 221 thyroids in an iodine sufficient group, the prevalence was only 4.74%, with respect to 4.52% 43.

The next important and, in extreme situations, the most important factor, is exposure to radiation. The thyroid gland is highly sensitive to radiation-induced oncogenesis and both types of radiation, external or internal (delivered from radioiodine), are the most prominent factors in the development of thyroid cancer 60. The most vulnerable is the thyroid gland in children, which was clearly documented in Belarus, in connection with the Chernobyl accident. The incidence of thyroid cancer, in children, was less than 1 per million, per year, before the accident, but after the accident increased, in certain areas, to 100 cases per million per year. Surprisingly, in the Chernobyl region, a big difference was found in children, exposed to radiation in the age group younger than 3 years and those exposed before birth (in utero), born after the accident. Fifteen years after the accident, in the first group, 33 cases of thyroid cancer were found (out of 9472 children), compared to no cases in the group exposed in utero (out of 12129 children) 61.

Within the context of radiation, it is necessary to mention that there is an increased risk in patients with a history of benign thyroid disease (thyroid nodules, Grave´s disease, hyperthyroidism) and external radiation to the neck area and, indeed, very young oncologic patients, after radiation therapy 11 6265.

Methods used for histological examination of the thyroid glands differed in the studies 12 1419 4250. While formalin fixation and 3 mm slices of the gland were used in all studies, only some Authors examined all slides microscopically. Others embedded only macroscopically suspected. Meta-analysis 43 of the prevalence of thyroid microcarcinomas (or occult thyroid carcinoma) found 13.19% of the microcarcinomas in the first group and 10.20% in the second. Moreover, Sampson et al. 42 published a study focusing on more than 140 papillary microcarcinomas less than 1 mm in maximum dimension. Thus the prevalence of papillary microcarcinoma in autopsies, if sectioned thinly enough, could be even higher than data published to date.

Papillary thyroid carcinoma versus microcarcinoma

The incidence of thyroid cancer is increasing, while the incidence of many head and neck cancers is decreasing 66 67. But, as epidemiological studies and stable overall mortality for this type of cancer have revealed, it is predominantly due to the increased detection of small cancers – microcarcinomas, which is the result of the use of precise imaging studies – magnetic resonance imaging (MRI) and, US 66. The more frequent detection of occult thyroid carcinoma is the main reason for changes in the ratio in the prevalence of papillary and follicular thyroid carcinoma in Western countries and in Japan. In both regions, the percentage of papillary thyroid carcinoma is increasing, from 78. 4% thirty years ago 68 to 93%, registered by the Japanese Society of Thyroid Surgeons (JSTS), in 2004. A similar situation has been reported in Western countries, where, in 2002, papillary carcinoma comprised 85.3% 69 70. The second reason for the increasing prevalence of papillary thyroid carcinoma, mentioned by Ito & Miyouchi 69, could be the previous classification of the follicular variant of papillary carcinoma as a follicular carcinoma.

The prevalence of incidentally detected PTMC found at autopsy and from clinical studies was 100-1000-fold higher than the incidence of clinical cancer 43 69. This finding strongly suggests that most papillary microcarcinomas remain latent and do not become clinically apparent. Therefore, there is considerable doubt as to whether all PTMC should be treated surgically, immediately after diagnosis, although it is also true that PTMC is frequently multicentric and metastasizes to the lymph nodes 69. PTMC is not a uniform category. Fundamental, for future clinical work, is to determine the clinical and especially the molecular parameters which would define a small group of PTMC with an aggressive biological behaviour 71.

Roti et al. 9 attempted to identify clinical characteristics differentiating incidental PTMC and suspected clinical carcinoma. There were no clinical differences, except for the size of the tumour. None of the patients with a cancer < 8 mm had distant metastases 9 72.

One of the most interesting molecular markers for determining the biological behaviour of the papillary microcarcinoma could be Cyclin D1, the overexpression of which has been associated with 93.3% of clinical PTC, but only 12.5% of asymptomatic PTMC (p = 0.0001) 73. Also Khoo et al. 74 found that Cyclin D1 protein is greatly overexpressed in metastasizing PTMC (90.9%), but only in 8% of nonmetastasizing PTMCs (p < 0.001). These Authors did not find any increase in the Cyclin D1 gene. They concluded that Cyclin D1 overexpression was associated with metastasizing PTMC and Cyclin D1 immunohistochemistry might be a valuable tool in predicting the metastatic potential 74.

Activation of the signalling pathways (Wnt / b-catenin) through Cyclin D1 up-regulation, at an early stage of thyroid carcinogenesis, may promote tumour growth and metastatic potential in PTMC. Cyclin D1 expression was significantly associated with tumour size, aggressive growth and metastases to lymph nodes 75 76.

Ito et al. 77 demonstrated that increased expression of Cyclin D1 protein is associated with overexpression of other cell proliferating markers, such as pRb (retinoblastoma gene product) and Ki-67 as well as with decreased expression of p27 (p27 is a tumour suppressor protein and acts as an inhibitor of Cyclin Dependent Kinases 2 (Cdk2) activity, it is also required early in the cell cycle for the assembly of Cyclin D1/Cdk4 complexes) in patients with clinically apparent metastasis of PTMC compared to patients without metastases or patients with occult metastases.

Cyclin D1 protein overexpression was frequently demonstrated in clinically apparent well differentiated papillary carcinoma 78, but is also associated with more aggressive types of thyroid carcinomas (tall cell variant, anaplastic, etc.) 79 and with tumours of patients under 40 years of age 80.

Protein S100A4 has been mentioned with regard to the metastatic potential of papillary microcarcinoma. Its positivity, in immunohistochemistry, was significantly associated with macrometastasis and lateral node metastases 81 82. S100A4 is member of the S100 calcium-binding proteins that regulate intracellular processes such as cell growth, motility, cell cycle, transcription and differentiation. Its capacity to promote invasion and metastasis of many human malignancies has also been identified 8387.

As already pointed out, genetic alterations associated with MAPK pathway are frequently detected in PTC. Although the overall prevalence of BRAF mutation in PTC is relatively high (approximately 45% on average), the prevalence in PTMC is much lower, as documented in studies from many parts of the world 8891. The only exception are studies from Korea, in which an unusually high prevalence of BRAF has been reported in both PTC (80-90%) 9294 and PTMC (65%) 95. A relatively low prevalence of BRAF, in PTMC, seems to be feasible for a new risk stratification of PTMC. BRAF mutation detected by means of FNAB 94 96 could be the parameter of choice for the selection of patients for the appropriate extent of surgical and medical treatments 97.

Therapeutic strategy

Incidentally detected PTMC is clinically the most important subcategory of the term “Occult thyroid carcinoma”. The incidence of PTMC is increasing because of the routine use of imaging methods, in combination with FNAB. The majority of these patients do extremely well with appropriate limited surgery and close follow-up 98. The impact of medical and surgical interventions on the survival of patients with PTMC was evaluated by Lin et al. 99. Overall actuarial survival rates, at 10 and 15 years, were 96.6% and 96.3%, respectively. Increasing age was the only statistically important predictor for disease-specific survival (p = 0.001). Neither the type of surgery (total thyroidectomy, near-total/subtotal thyroidectomy or lobectomy), nor the radiometabolic treatment has any impact on excellent prognosis of patients with PTMC. The Authors conclude, that patients lacking evidence of metastatic disease may undergo lobectomy alone 99. The concept of limited surgery is supported also by many other Authors 2 99 100. Bilimoria et al. 100 analysed almost 40,000 patients from the National Cancer Data Base with papillary thyroid carcinoma and concluded that the treatment of choice for patients with a tumour less than 1 cm is thyroid lobectomy 100.

Some Authors are of the opinion, that surgery, even if limited, may not be the first step of treatment 69. Ito et al. 101 selected low-risk patients with PTMC and, during 5 years’ follow-up, only 6.7% of these patients were confirmed as showing an increase in size at US compared to baseline findings. None developed additional distant metastasis or died of thyroid carcinoma. The Authors conclude that surgical treatment after the appearance of carcinoma progression is not late 101.

On the other hand, PTMC is often multifocal; the range of multiple non-contiguous tumour foci is between 18 and 87%, depending upon the technique used for the pathological analysis 102. The genetic studies, which compared the specific patterns of monoclonal X-chromosome inactivation 102 and distribution of BRAF mutation 103 demonstrated that the individual tumour foci often arise as independent tumours and, indeed, that they can grow and spread.


PTMC is not a uniform category. Fundamental for future clinical purposes is to determine clinical and especially molecular parameters which would define small groups of PTMC with aggressive biological behaviour. The clinical classification systems for high-risk papillary carcinoma patients, such as the UICC/AJCC TNM staging system 7, or AMES 104, or AGES 105, or MACIS 106, were proposed to stratify the risk based on different clinical parameters, but these are not helpful for PTMC. The most promising genetic and molecular markers for PTMC risk stratification have been discussed in this review. Preoperative information regarding BRAF mutation status, overexpression of protein S100A4 or Cyclin D1, obtained by analysis of FNAB specimens of PTMC, could be extremely valuable in determining the choice of therapeutic management of this cancer. It could help to assess the extent of initial surgical treatment and the need for radioiodine ablation. In some cases, patients for whom only follow-up was indicated, could be defined thanks to these genetic and molecular markers.


This work was supported by the Ministry of Education, Youth and Sports of The Czech Republic (project NPV II no. 2B06106).



papillary thyroid microcarcinoma
papillary thyroid carcinoma
World Health Organization
fine-needle aspiration biopsy
Union Internacional Contra la Cancrum or International Union Against Cancer
American Joint Committee on Cancer
age, metastases, extent and size
age, grade, extent, and size
metastases, age, completeness of excision, invasiveness, size
thyroglossal duct cyst papillary carcinoma
mitogen-activated protein kinase
vascular endothelial growth factor
retinoblastoma gene product
magnetic resonance imaging


1. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med 1998;338:297-306. [PubMed]
2. Udelsman R. Is total thyroidectomy the procedure of choice for papillary thyroid cancer? Nat Clin Pract Oncol 2008;5:184-5. [PubMed]
3. Merriam-Webster on-line dictionary – 2009 (accessed at
4. Segen J. Concise Dictionary of Modern Medicine. New York: McGraw-Hill; 2002.
5. Moosa M, Mazzaferri EL. Occult thyroid carcinoma. Cancer J 1997;10:180-8.
6. Stedman’s Medical Dictionary. Philadelphia, PA: Lippincott Williams & Wilkins; 2006 (accessed at
7. Sobin LH, Wittekind C. TNM Classification of malignant tumours. 6th edn. New York: Wiley-Liss; 2002.
8. Shaha AR. TNM classification of thyroid carcinoma. World J Surg 2007;31:879-87. [PubMed]
9. Roti E, Rossi R, Trasforini G, Bertelli F, Ambrosio MR, Busutti L, et al. Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients. J Clin Endocrinol Metab 2006;91:2171-8. [PubMed]
10. Fink A, Tomlinson G, Freeman JL, Rosen IB, Asa SL. Occult micropapillary carcinoma associated with benign follicular thyroid disease and unrelated thyroid neoplasms. Mod Pathol 1996;9:816-20. [PubMed]
11. Behar R, Arganini M, Wu TC, McCormick M, Straus FH, DeGroot LJ, et al. Graves’ disease and thyroid cancer. Surgery 1986;100:1121-7. [PubMed]
12. Yamamoto Y, Maeda T, Izumi K, Otsuka H. Occult papillary carcinoma of the thyroid. A study of 408 autopsy cases. Cancer 1990;65:1173-9. [PubMed]
13. Vanderlaan W. The occurrence of carcinoma of the thyroid gland in autopsy material. N Engl J Med 1947;237:221-2. [PubMed]
14. Sampson RJ, Woolner LB, Bahn RC, Kurland LT. Occult thyroid carcinoma in Olmsted County, Minnesota: prevalence at autopsy compared with that in Hiroshima and Nagasaki, Japan. Cancer 1974;34:2072-6. [PubMed]
15. Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study. Cancer 1985;56:531-8. [PubMed]
16. Fukunaga FH, Yatani R. Geographic pathology of occult thyroid carcinomas. Cancer 1975;36:1095-9. [PubMed]
17. Bondeson L, Ljungberg O. Occult thyroid carcinoma at autopsy in Malmo, Sweden. Cancer 1981;47:319-23. [PubMed]
18. Bondeson L, Ljungberg O. Occult papillary thyroid carcinoma in the young and the aged. Cancer 1984;53:1790-2. [PubMed]
19. Fukunaga FH, Lockett LJ. Thyroid carcinoma in the Japanese in Hawaii. Arch Pathol 1971;92:6-13. [PubMed]
20. Stewart W, Rizzolo L. Embryology and surgical anatomy of the thyroid and parathyroid glands. In: Oertli D, Udelsman R, editors. Surgery of the thyroid and parathyroid glands. Berlin-Heidelberg: Springer; 2007. p. 13-20.
21. Embryology of the thyroid and parathyroids. Medscape, 2007 (accessed at
22. Noyek AM, Friedberg J. Thyroglossal duct and ectopic thyroid disorders. Otolaryngol Clin North Am 1981;14:187-201. [PubMed]
23. Arriaga MA, Myers EN. Ectopic thyroid in the retroesophageal superior mediastinum. Otolaryngol Head Neck Surg 1988;99:338-40. [PubMed]
24. Bailey B, Johnson J, Newlands S. Head and neck surgery - Otolaryngology. 4th edn. Philadelphia: Lippincott Williams and Wilkins; 2006.
25. Pollice L, Caruso G. Struma cordis. Ectopic thyroid goiter in the right ventricle. Arch Pathol Lab Med 1986;110:452-3. [PubMed]
26. Massine RE, Durning SJ, Koroscil TM. Lingual thyroid carcinoma: a case report and review of the literature. Thyroid 2001;11:1191-6. [PubMed]
27. Ibrahim NB, Milewski PJ, Gillett R, Temple JG. Benign thyroid inclusions within cervical lymph nodes: an alarming incidental finding. Aust N Z J Surg 1981;51:188-9. [PubMed]
28. Kennedy TL, Whitaker M, Wadih G. Thyroglossal duct carcinoma: a rational approach to management. Laryngoscope 1998;108:1154-8. [PubMed]
29. Doshi SV, Cruz RM, Hilsinger RL, Jr. Thyroglossal duct carcinoma: a large case series. Ann Otol Rhinol Laryngol 2001;110:734-8. [PubMed]
30. Sistrunk WE. The surgical treatment of cysts of the thyroglossal tract. Ann Surg 1920;71:121-2. [PubMed]
31. Patel SG, Escrig M, Shaha AR, Singh B, Shah JP. Management of well-differentiated thyroid carcinoma presenting within a thyroglossal duct cyst. J Surg Oncol 2002;79:134-9 (discussion 40-1). [PubMed]
32. Mazzaferri EL. Thyroid cancer in thyroglossal duct remnants: a diagnostic and therapeutic dilemma. Thyroid 2004;14:335-6. [PubMed]
33. Hartl DM, Al Ghuzlan A, Chami L, Leboulleux S, Schlumberger M, Travagli JP. High rate of multifocality and occult lymph node metastases in papillary thyroid carcinoma arising in thyroglossal duct cysts. Ann Surg Oncol 2009;16:2595-601. [PubMed]
34. McGill JF, Sturgeon C, Angelos P. Metastatic struma ovarii treated with total thyroidectomy and radioiodine ablation. Endocr Pract 2009;15:167-73. [PubMed]
35. McDougall IR. Metastatic struma ovarii: the burden of truth. Clin Nucl Med 2006;31:321-4. [PubMed]
36. Böttlin R. Ueber Zahnentwicklelung in Dermoidcystem des Ovariums. Virchows Arch Pathol Anat 1889;115:493.
37. Klinck GH, Winship T. Occult sclerosing carcinoma of the thyroid. Cancer 1955;8:701-6. [PubMed]
38. Woolner LB, Lemmon ML, Beahrs OH, Black BM, Keating FR, Jr. Occult papillary carcinoma of the thyroid gland: a study of 140 cases observed in a 30-year period. J Clin Endocrinol Metab 1960;20:89-105. [PubMed]
39. Kim DW, Lee EJ, Kim SH, Kim TH, Lee SH, Kim DH, et al. Ultrasound-guided fine-needle aspiration biopsy of thyroid nodules: comparison in efficacy according to nodule size. Thyroid 2009;19:27-31. [PubMed]
40. Ito Y, Amino N, Yokozawa T, Ota H, Ohshita M, Murata N, et al. Ultrasonographic evaluation of thyroid nodules in 900 patients: comparison among ultrasonographic, cytological, and histological findings. Thyroid 2007;17:1269-76. [PubMed]
41. Utiger RD. The multiplicity of thyroid nodules and carcinomas. N Engl J Med 2005;352:2376-8. [PubMed]
42. Sampson RJ, Key CR, Buncher CR, Iijima S. Smallest forms of papillary carcinoma of the thyroid. A study of 141 microcarcinomas less than 0.1 cm in greatest dimension. Arch Pathol 1971;91:334-9. [PubMed]
43. Kovacs GL, Gonda G, Vadasz G, Ludmany E, Uhrin K, Gorombey Z, et al. Epidemiology of thyroid microcarcinoma found in autopsy series conducted in areas of different iodine intake. Thyroid 2005;15:152-7. [PubMed]
44. Bisi H, Fernandes VS, de Camargo RY, Koch L, Abdo AH, de Brito T. The prevalence of unsuspected thyroid pathology in 300 sequential autopsies, with special reference to the incidental carcinoma. Cancer 1989;64:1888-93. [PubMed]
45. de Matos PS, Ferreira AP, Ward LS. Prevalence of papillary microcarcinoma of the thyroid in Brazilian autopsy and surgical series. Endocr Pathol 2006;17:165-73. [PubMed]
46. Ottino A, Pianzola HM, Castelletto RH. Occult papillary thyroid carcinoma at autopsy in La Plata, Argentina. Cancer 1989;64:547-51. [PubMed]
47. Sampson RJ, Oka H, Key CR, Buncher CR, Iijima S. Metastases from occult thyroid carcinoma. An autopsy study from Hiroshima and Nagasaki, Japan. Cancer 1970;25:803-11. [PubMed]
48. Sampson RJ, Key CR, Buncher CR, Oka H, Iijima S. Papillary carcinoma of the thyroid gland. Sizes of 525 tumors found at autopsy in Hiroshima and Nagasaki. Cancer 1970;25:1391-3. [PubMed]
49. Solares CA, Penalonzo MA, Xu M, Orellana E. Occult papillary thyroid carcinoma in postmortem species: prevalence at autopsy. Am J Otolaryngol 2005;26:87-90. [PubMed]
50. Thorvaldsson SE, Tulinius H, Bjornsson J, Bjarnason O. Latent thyroid carcinoma in Iceland at autopsy. Pathol Res Pract 1992;188:747-50. [PubMed]
51. Xing M. BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev 2007;28:742-62. [PubMed]
52. DeLellis RA. Pathology and genetics of thyroid carcinoma. J Surg Oncol 2006;94:662-9. [PubMed]
53. Jo YS, Li S, Song JH, Kwon KH, Lee JC, Rha SY, et al. Influence of the BRAF V600E mutation on expression of vascular endothelial growth factor in papillary thyroid cancer. J Clin Endocrinol Metab 2006;91:3667-70. [PubMed]
54. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249-57. [PubMed]
55. Anand-Apte B, Bao L, Smith R, Iwata K, Olsen BR, Zetter B, et al. A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochem Cell Biol 1996;74:853-62. [PubMed]
56. Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 2005;90:6373-9. [PubMed]
57. Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasson JG, Sigurdsson A, Bergthorsson JT, et al. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet 2009;41:460-4. [PubMed]
58. Szpak S, Zeman M, Handkiewicz-Junak D, Kochanska-Dziurowicz A, Kurzeja E, Stanjek A, et al. Geographic differences in iodine supply in the Silesia terrain in relation to thyroid cancer risk. Wiad Lek 2001;54(Suppl 1):169-75. [PubMed]
59. Szabolcs I, Podoba J, Feldkamp J, Dohan O, Farkas I, Sajgo M, et al. Comparative screening for thyroid disorders in old age in areas of iodine deficiency, long-term iodine prophylaxis and abundant iodine intake. Clin Endocrinol (Oxf) 1997;47:87-92. [PubMed]
60. Nagataki S, Nystrom E. Epidemiology and primary prevention of thyroid cancer. Thyroid 2002;12:889-96. [PubMed]
61. Shibata Y, Yamashita S, Masyakin VB, Panasyuk GD, Nagataki S. 15 years after Chernobyl: new evidence of thyroid cancer. Lancet 2001;358:1965-6. [PubMed]
62. Goldman MB, Monson RR, Maloof F. Cancer mortality in women with thyroid disease. Cancer Res 1990;50:2283-9. [PubMed]
63. Franceschi S, Preston-Martin S, Dal Maso L, Negri E, La Vecchia C, Mack WJ, et al. A pooled analysis of case-control studies of thyroid cancer. IV. Benign thyroid diseases. Cancer Causes Control 1999;10:583-95. [PubMed]
64. Pettorini BL, Narducci A, de Carlo A, Abet F, Caldarelli M, Massimi L, et al. Thyroid neoplasm after central nervous system irradiation for medulloblastoma in childhood: report of two cases. Childs Nerv Syst 2009;25:631-4. [PubMed]
65. Seaberg RM, Eski S, Freeman JL. Influence of previous radiation exposure on pathologic features and clinical outcome in patients with thyroid cancer. Arch Otolaryngol Head Neck Surg 2009;135:355-9. [PubMed]
66. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 2006;295:2164-7. [PubMed]
67. Davies L, Welch HG. Epidemiology of head and neck cancer in the United States. Otolaryngol Head Neck Surg 2006;135:451-7. [PubMed]
68. Ezaki H, Ebihara S, Fujimoto Y, Iida F, Ito K, Kuma K, et al. Analysis of thyroid carcinoma based on material registered in Japan during 1977-1986 with special reference to predominance of papillary type. Cancer 1992;70:808-14. [PubMed]
69. Ito Y, Miyauchi A. Prognostic factors and therapeutic strategies for differentiated carcinomas of the thyroid. Endocr J 2009;56:177-92. [PubMed]
70. Parkin DM, Muir CS. Cancer incidence in five continents. Comparability and quality of data. IARC Sci Publ 1992:45-173. [PubMed]
71. Ito Y, Miyauchi A. Appropriate treatment for asymptomatic papillary microcarcinoma of the thyroid. Expert Opin Pharmacother 2007;8:3205-15. [PubMed]
72. Roti E, degli Uberti EC, Bondanelli M, Braverman LE. Thyroid papillary microcarcinoma: a descriptive and meta-analysis study. Eur J Endocrinol 2008;159:659-73. [PubMed]
73. Kovacs GL, Stelkovics E, Krenacs L, Gonda G, Goth M, Kovacs L, et al. Low level of cyclin D1 protein expression in thyroid microcarcinomas from an autopsy series. Endocrine 2005;26:41-4. [PubMed]
74. Khoo ML, Ezzat S, Freeman JL, Asa SL. Cyclin D1 protein expression predicts metastatic behavior in thyroid papillary microcarcinomas but is not associated with gene amplification. J Clin Endocrinol Metab 2002;87:1810-3. [PubMed]
75. Lantsov D, Meirmanov S, Nakashima M, Kondo H, Saenko V, Naruke Y, et al. Cyclin D1 overexpression in thyroid papillary microcarcinoma: its association with tumour size and aberrant beta-catenin expression. Histopathology 2005;47:248-56. [PubMed]
76. Londero SC, Godballe C, Krogdahl A, Bastholt L, Specht L, Sorensen CH, et al. Papillary microcarcinoma of the thyroid gland: is the immunohistochemical expression of cyclin D1 or galectin-3 in primary tumour an indicator of metastatic disease? Acta Oncol 2008;47:451-7. [PubMed]
77. Ito Y, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, et al. Papillary microcarcinomas of the thyroid with preoperatively detectable lymph node metastasis show significantly higher aggressive characteristics on immunohistochemical examination. Oncology 2005;68:87-96. [PubMed]
78. Goto A, Sakamoto A, Machinami R. An immunohistochemical analysis of cyclin D1, p53, and p21waf1/cip1 proteins in tumors originating from the follicular epithelium of the thyroid gland. Pathol Res Pract 2001;197:217-22. [PubMed]
79. Wang S, Lloyd RV, Hutzler MJ, Safran MS, Patwardhan NA, Khan A. The role of cell cycle regulatory protein, cyclin D1, in the progression of thyroid cancer. Mod Pathol 2000;13:882-7. [PubMed]
80. Basolo F, Caligo MA, Pinchera A, Fedeli F, Baldanzi A, Miccoli P, et al. Cyclin D1 overexpression in thyroid carcinomas: relation with clinico-pathological parameters, retinoblastoma gene product, and Ki67 labeling index. Thyroid 2000;10:741-6. [PubMed]
81. Min HS, Choe G, Kim SW, Park YJ, Park do J, Youn YK, et al. S100A4 expression is associated with lymph node metastasis in papillary microcarcinoma of the thyroid. Mod Pathol 2008;21:748-55. [PubMed]
82. Zou M, Al-Baradie RS, Al-Hindi H, Farid NR, Shi Y. S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma. Br J Cancer 2005;93:1277-84. [PMC free article] [PubMed]
83. Barraclough R. Calcium-binding protein S100A4 in health and disease. Biochim Biophys Acta 1998;1448:190-9. [PubMed]
84. Lee WY, Su WC, Lin PW, Guo HR, Chang TW, Chen HH. Expression of S100A4 and Met: potential predictors for metastasis and survival in early-stage breast cancer. Oncology 2004;66:429-38. [PubMed]
85. Sherbet GV. Metastasis promoter S100A4 is a potentially valuable molecular target for cancer therapy. Cancer Lett 2009;280:15-30. [PubMed]
86. Oslejskova L, Grigorian M, Hulejova H, Vencovsky J, Pavelka K, Klingelhofer J, et al. Metastasis-inducing S100A4 protein is associated with the disease activity of rheumatoid arthritis. Rheumatology (Oxf) 2009;48:1590-4. [PubMed]
87. Schneider M, Hansen JL, Sheikh SP. S100A4: a common mediator of epithelial-mesenchymal transition, fibrosis and regeneration in diseases? J Mol Med 2008;86:507-22. [PubMed]
88. Rodolico V, Cabibi D, Pizzolanti G, Richiusa P, Gebbia N, Martorana A, et al. BRAF V600E mutation and p27 kip1 expression in papillary carcinomas of the thyroid < or = 1 cm and their paired lymph node metastases. Cancer 2007;110:1218-26. [PubMed]
89. Lupi C, Giannini R, Ugolini C, Proietti A, Berti P, Minuto M, et al. Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab 2007;92:4085-90. [PubMed]
90. Sedliarou I, Saenko V, Lantsov D, Rogounovitch T, Namba H, Abrosimov A, et al. The BRAFT1796A transversion is a prevalent mutational event in human thyroid microcarcinoma. Int J Oncol 2004;25:1729-35. [PubMed]
91. Ugolini C, Giannini R, Lupi C, Salvatore G, Miccoli P, Proietti A, et al. Presence of BRAF V600E in very early stages of papillary thyroid carcinoma. Thyroid 2007;17:381-8. [PubMed]
92. Kim TY, Kim WB, Rhee YS, Song JY, Kim JM, Gong G, et al. The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin Endocrinol (Oxf) 2006;65:364-8. [PubMed]
93. Kim KH, Kang DW, Kim SH, Seong IO, Kang DY. Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med J 2004;45:818-21. [PubMed]
94. Chung KW, Yang SK, Lee GK, Kim EY, Kwon S, Lee SH, et al. Detection of BRAFV600E mutation on fine needle aspiration specimens of thyroid nodule refines cyto-pathology diagnosis, especially in BRAF600E mutation-prevalent area. Clin Endocrinol (Oxf) 2006;65:660-6. [PubMed]
95. Park YJ, Kim YA, Lee YJ, Kim SH, Park SY, Kim KW, et al. Papillary microcarcimoma in comparison with larger papillary thyroid carcinoma in BRAF(V600E) mutation, clinicopathological features, and immunohistochemical findings. Head Neck 2010;32:48-5. [PubMed]
96. Pizzolanti G, Russo L, Richiusa P, Bronte V, Nuara RB, Rodolico V, et al. Fine-needle aspiration molecular analysis for the diagnosis of papillary thyroid carcinoma through BRAF V600E mutation and RET/PTC rearrangement. Thyroid 2007;17:1109-15. [PubMed]
97. Xing M. BRAF mutation in papillary thyroid microcarcinoma: the promise of better risk management. Ann Surg Oncol 2009;16:801-3. [PMC free article] [PubMed]
98. Shaha AR, Tuttle RM, Shah JP. Papillary microcarcinoma of the thyroid. J Surg Oncol 2007;95:532-3. [PubMed]
99. Lin HW, Bhattacharyya N. Survival impact of treatment options for papillary microcarcinoma of the thyroid. Laryngoscope 2009;119:1983-7. [PubMed]
100. Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS, et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 2007;246:375-81 (discussion 81-4). [PubMed]
101. Ito Y, Uruno T, Nakano K, Takamura Y, Miya A, Kobayashi K, et al. An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid 2003;13:381-7. [PubMed]
102. Shattuck TM, Westra WH, Ladenson PW, Arnold A. Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma. N Engl J Med 2005;352:2406-12. [PubMed]
103. Giannini R, Ugolini C, Lupi C, Proietti A, Elisei R, Salvatore G, et al. The heterogeneous distribution of BRAF mutation supports the independent clonal origin of distinct tumor foci in multifocal papillary thyroid carcinoma. J Clin Endocrinol Metab 2007;92:3511-6. [PubMed]
104. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104:947-53. [PubMed]
105. Hay ID, Grant CS, Taylor WF, McConahey WM. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 1987;102:1088-95. [PubMed]
106. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114:1050-7 (discussion 7-8). [PubMed]

Articles from Acta Otorhinolaryngologica Italica are provided here courtesy of Pacini Editore