Thyroid nodule pathophysiology
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Thyroid nodules may arise from different cells in the thyroid parenchyma. The pathogenesis of developing a thyroid nodule may differ based on the type of the nodule, and whether it is malignant or benign. Basically thyroid nodules may develop secondary to hyperplasia, mutations and resultant carcinoma, excess colloid accumulation, or frominflammation of thyroid tissue. Genetic mutation is considered as one of the most important mechanisms of developing thyroid nodules, especially neoplastic thyroid nodules. Most of these mutations occur as somatic mutations, while some may exhibit familial inheritance. The most important variety of familial thyroid cancers are caused by genetic mutations, and are called familial non-medullary thyroid cancer (FNMTC). Other important genes related to thyroid nodule formation include, N&H ras, RET, Gsp, C-MET, TRK, EGF / EGF-R, and P53.
A summary of thyroid nodule pathophysiology is presented in the slides below: 
- Thyroid nodules may arise from different cells in thyroid parenchyma. The pathogenesis of developing a thyroid nodule may differ based on the type of the nodule, and whether it is malignant or benign.
- Basically thyroid nodules may develop secondary to hyperplasia, mutations and resultant carcinoma, excess colloid accumulation, or frominflammation of thyroid tissue.
(a) Hyperplastic nodules
- Hyperplastic nodule pathogenesis seems to start with an increase in thyroid proliferation, which lead to thyroid hyperplasia.
- Rapid thyroid proliferation mainly occur in response to certain stimulants.
- Stimulants mainly act through TSH mediated activity and production. Following the hyperplasia development phase, a new phase may begin, leading to a neoplasia.
1. TSH role in thyroid nodule formation
- Growth signals in thyroid tissue start by a stimulant, that attaches to the thyroid receptors. The following signals can be transmitted through 3 distinct pathways:
- The most important pathway for thyroid growth is the activation of adenylate cyclase/protein kinase A system. Activation of phospholipase C and phospholipase A2 have only a minor effect on thyroid growth.
- TSH acts as a stimulant by binding to the TSH receptor and leads to activation of both the adenylate cyclase and phospholipase C pathways. As mentioned, the phospholipase C pathway has minor effects, and most of the TSH effect on cell growth is generated by adenylate cyclase pathway. The signal generated by the adenylate cyclase cAMP-dependent pathway is then transduced in the nucleus where transcription factors–upon phosphorylation–induce the expression of cAMP-inducible genes. It has been established that TSH has a main mitogenic role, through cAMP, Gs proteins and protein kinase A, which activates the metabolic cascade leading to the stimulation of growth.
- However, to produce hyperplasia, overproduction of cAMP must be continuous, as it occurs in mutations constitutive of the genes which regulate cAMP production.
- Constitutive cAMP overproduction has been demonstrated to be due to point mutation of the TSH receptor or Gs protein.
- Constitutive cAMP overproduction not only stimulates growth but also function.
- Hyperplastic thyroid nodule pathogenesis can be divided into 2 phases:
2. Thyroid overgrowth stimulants:
Thyroid normally has a low proliferative activity, although it can start proliferation rapidly in response to certain stimulants. Stimulants mainly act through TSH mediated activity and production. The following stimulants appear to have the most important role in pathogenesis of hyperplastic nodules:
- Iodine deficiency:
- Effects directly or indirectly
- The most potent stimulator replication of the cells of thyroid gland
- Mechanism of action:
- Acts as an initiator for TSH rise
- May enhance the effect of other chemicals that induce a rise in TSH by inducing the promotor overactivity
- The most important reason of high prevalence of thyroid hyperplasia and nodules in iodine-deficient areas
- Industrial chemicals:
- Complex anions and inorganic atoms (iodine, lithium, CLO4–, TcO4–, BF4–)
- Thiocyanate (SCN–)
- Goitrin, isolated in plants of the genus Brassica
- Aniline derivatives (sulfonamides, tolbutamide, sulfaguanidine, sulfamethoxazole, etc.)
- Phenol derivatives and polyhydroxyphenols
- TPO inhibitors
- Also act on thyroid metabolism by interacting with the nuclear receptor for thyroid hormones
- Antithyroid drugs:
- Thionamides that are used in the treatment of hyperthyroidism
- May be the reason of high prevalence of thyroid hyperplasia and nodules in iodine-sufficient areas
- Thyroid stromal cells interact with thyroid follicular cells by cytokines. Inappropriate cytokine activities also seem to be related to TSH overproduction and thyroid hyperplastic nodule formation. The most important cytokines that may lead to differentiation or inhibition of thyroid growth are:
3. Hyperplasia development phase:
- Thyroid cells produce the angiogenic vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) sensitive to TSH stimulation.
- The vascular growth factor induces neovascularization by binding to specific receptors on endothelial cells and stimulating new vessel production.
- In response, endothelial cells produce growth factors that increase thyroid cell proliferation and lead to thyroid hyperplasia.
- Neovascularization in thyroid matrix is accompanied by the production of proteolytic enzymes, which facilitate the expansion of thyroid tissue into the extracellular matrix.
4. Neoplasia development phase:
- Each follicle is composed of different clones of cells (polyclonal), but during nodule formation they replicate in a simultaneous and coordinated manner, so each follicle of the nodule reproduces the same heterogeneity of the mother follicle.
- When a neoplasm arises in the nodule, then the neoplastic follicle shows a monoclonal pattern, suggesting that cancer arises from a single cell.
(b) Neoplastic nodules
- Neoplastic nodules development mainly involve the activation of proto-oncogenes as the underlying event leading to uncontrolled cell growth.
- Proto-oncogene activation is associated with thyroid adenoma, hyperplasia, and malignancies.
- Thyroid gland is made up of different follicles, and each follicle is composed of different clones of cells (polyclonal). During nodule formation, cells replicate in a coordinated fashion simultanously, so each follicle of the nodule shares the same heterogenity with other cells.
- Hyperplastic thyroid nodules are considered a risk factor for the development of neoplasia, as these cells may express neoplastic potential during their rapid proliferation phase.
- During neoplasm formation in the nodule, the neoplastic follicle mostly shows a monoclonal pattern. These findings may indicate that neoplasia arises from a single cell genetic mutation. The most important oncogenes related to thyroid neoplasia development are mentioned in the genetic table below.
- Environmental factors can play an important role in triggering the oncogene mutation. The most important carcinogens involved in the pathogenesis of neoplastic thyroid nodules are:
- Thioamide compounds
- Ethylenethiourea (ETU)
- Aminotriazole: Herbicide
- Acetylaminofluorene (AAF)
- Use: Insecticide
- Oxydianiline (ODA)
- Use: Azo-Dye
- Methylene benzenamine
- Use: Dye intermediate
- Nitrosoureas (NMU), (NBU), (ENU)
- Use: derivatives (BCNU, CCNU, MeCCNU) are drugs against tumors
- Streptozocin (naturally occurring nitrosourea) is used in the treatment of islet-cell carcinoma of the pancreas
- Thioamide compounds
Papillary thyroid carcinoma
- The most important pathogenic factor involved in developing papillary thyroid cancer is an intracellular signaling pathway called MAPK pathyway (Mitogen-activated protein kinases), also known as ERK pathway (extracellular signal-regulated kinase). After antigen binding to tyrosine receptors, MAPK is translocated into the nucleus. Receptor activation leads to cell division, after phosphorylation by MEK (a serine/threonine kinase).
- Other steps leading to MAPK phosphorylation include phosphorylation of RAS which activates BRAF, a serine/threonine kinase followed by MEK and MAPK phosphorylation.
- In papillary thyroid carcinoma, a somatic mutation may lead to activation of this linear signaling cascade.
- As a result, there will be increased transcription of nuclear proteins, which lead to un-regulated activity and reproduction of cancerous cells. This implies that any single alteration is sufficient to play an early role in tumorigenesis.
ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase
(c) Colloid and cystic nodules
1. Colloid nodules
- The colloid nodules consist of colloid droplets and thyroglobulin vesicles.
- Thyroid gland keeps a balance between colloid and thyroglobulin production by regulating the secretion of thyroglobulin into colloid and reabsorption of colloid into thyroid follicular cells. This regulation is maintained by macro-pinocytosis (pseudopods) and micro-pinocytosis (microvilli).
- Any imbalance between secretion and reabsorption of thyroglobulin leads to a disruption of the equilibrium, and produces a colloid appeared thyroid nodule. These nodules may also be produced as a defect of intraluminal thyroglobulin reabsorption.
Iodine excess can lead to colloid nodules in thyroid gland, leading to a colloid goitre:
- Endocytosis inhibition: High dosage of iodine may lead to inhibition of the protease activity of thyroid lysosomes thereby inhibiting endocytosis
- Exocytosis inhibition: Iodine reduces the expression of the TSH receptor on the surface of thyroid cells thereby inhibiting and decreasing colloid reabsorption
- Iodine excess in combination with TSH over activity may lead to colloid goitre
Another mechanism that may lead to colloid goitre formation is loss of thyroglobulin packaging ability, that may lead to an enormous enlargement of the follicles and flattening of the epithelium.
3. Cystic thyroid nodules
Cystic thyroid nodules may be classified into the following types:
- Necrotic cystic nodules:
- May be due to a relative deficiency of blood supply:
- Inadequate blood supply for neoplastic growth
- Imbalance between angiogenesis and cell growth
- Compression of new vessels due to mass effect, leading to cell damage and necrosis
- Hyperplastic thyroid nodules may proceed towards necrosis, colliquation, and pseudocyst formation
- May be due to a relative deficiency of blood supply:
- Serum-like cystic nodules:
- May be related to autoimmunity
- Apoptotic cystic nodules:
- Cysts that may be related to normal cellular apoptosis or neoplastic/infected cellular apoptosis
- Vascular growth factor related cystic nodules:
- Cyst formation may be the result of an increased concentration of VEGF/VPF inside the cystic area
- VEGF/VPF lead to stimulation of vascular permeability and promoting the accumulation of fluids in the cysts
- VEGF/VPF are particularly found in the cystic fluid of rapidly enlarging or recurrent cysts
(d) Thyroiditic nodule
Nodular lymphocytic thyroiditis almost always present in combination with other thyroiditic diseases. They can also present as a part of infection. It has been shown that the ability of super-antigens (SAgs) to activate the immune system may play a role in the course of autoimmune disorders. In most of these cases, the mechanism of nodular lesion is the same as the mechanism of the main disease, implying that the thyroid nodule is a part of normal disease pattern. Many of these nodules are not identifiable based on physical exam, and are detected during thyroid scintigraphy. The most important thyroiditic diseases that may present as lymphocytic nodular thyroid are:
- Local infections:
- Subacute de Quervain’s thyroiditis
- Fibrosing (Riedel’s) thyroiditis
- Plasma cell granuloma
- Primary amyloid tumor and amyloidosis
- Primary thyroid lymphoma
- Thyroiditic nodule due to diffuse B-cell infiltration into lymphoma presented areas
- Histiocytosis X
- Medullary carcinoma
- Papillary carcinoma
- Thyroiditic nodule may be due to an immune response to some abnormal thyroid antigen expressed in the tumor
Genetic mutation is considered as one of the most important mechanisms of developing thyroid nodules, especially neoplastic thyroid nodules. Most of these mutations occur as somatic mutations, while some may occur in a familial order. The most important category of familial thyroid cancers are due to genetic mutations, and are called familial non-medullary thyroid cancer (FNMTC), with the following features:
- Rare group of cancers
- Related to other non-medullary tumors
- Inheritance: Autosomal dominant with incomplete penetrance and variable expressivity
- Affected patients in an earlier age
- Associated with:
- More benign thyroid nodules
- Multifocal disease
- A higher rate of locoregional recurrence
The most important genetic mutations associated with thyroid neoplasia development
|Oncogenes and growth factors||Gene mechanism||Mutation effect||Neoplasia|
|C-MET (α and β subunit)||
|EGF / EGF-R||
Preoperative serum TSH is an independent risk factor for predicting malignancy in a thyroid nodule, and is associated with:
- Higher differentiated thyroid cancer stage
- Gross extrathyroidal extension
- Neck node metastases
- On gross pathology, cystic lesions, multiple or a single nodule, and encapsulated lesions are the most important and prevalent characteristic findings of thyroid nodules.
- On gross pathology, follicular thyroid adenoma may present as a big lesion with thick capsule.
Diagnostic speciemen feature: the presence of at least six follicular cell groups, each containing 10–15 cells derived from at least two aspirates of a nodule
|Cytology classification||Also referred to as:||Efficient diagnosis||May be seen in:||FNA cytology|
|Follicular lesions||Benign (macrofollicular)||
|Follicular lesion of undetermined significance (FLUS)||+||
|Atypia of undetermined significance (AUS)|
||+||Epithelioid giant cells
|Anaplastic thyroid cancer||+||
- Both polyclonal and monoclonal nodules appear similar on fine needle aspiration (FNA) (macrofollicular) and are benign
- The diagnosis of follicular cancer can not be made based on FNA, because vascular or capsular invasion is required to make the diagnosis of follicular cancer. 8420446
Neoplastic thyroid nodules subclassification microscopic pathology:
|Follicular thyroid lesions||Minimally invasive follicular carcinoma|
|Widely invasive follicular carcinoma|
|Encapsulated follicular variant of papillary thyroid cancer|
|Infiltrative variant of papillary thyroid cancer|
|Papillary thyroid cancer||Tall cell variant||
|Hürthle or oxyphilic variant||
|Clear cell variant||
|Diffuse sclerosing variant||
|Cribriform morular variant||
- ↑ Aozasa K, Inoue A, Katagiri S, Matsuzuka F, Katayama S, Yonezawa T (1986). "Plasmacytoma and follicular lymphoma in a case of Hashimoto's thyroiditis". Histopathology. 10 (7): 735–40. PMID 3755697.
- ↑ Bastomsky CH (1977). "Enhanced thyroxine metabolism and high uptake goiters in rats after a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin". Endocrinology. 101 (1): 292–6. doi:10.1210/endo-101-1-292. PMID 862558.
- ↑ Brix K, Lemansky P, Herzog V (1996). "Evidence for extracellularly acting cathepsins mediating thyroid hormone liberation in thyroid epithelial cells". Endocrinology. 137 (5): 1963–74. doi:10.1210/endo.137.5.8612537. PMID 8612537.
- ↑ Burch HB (1995). "Evaluation and management of the solid thyroid nodule". Endocrinol. Metab. Clin. North Am. 24 (4): 663–710. PMID 8608777.
- ↑ Coclet J, Foureau F, Ketelbant P, Galand P, Dumont JE (1989). "Cell population kinetics in dog and human adult thyroid". Clin. Endocrinol. (Oxf). 31 (6): 655–65. PMID 2627756.
- ↑ 6.0 6.1 de los Santos ET, Keyhani-Rofagha S, Cunningham JJ, Mazzaferri EL (1990). "Cystic thyroid nodules. The dilemma of malignant lesions". Arch. Intern. Med. 150 (7): 1422–7. PMID 2196027.
- ↑ Di Carlo A, Mariano A, Pisano G, Parmeggiani U, Beguinot L, Macchia V (1990). "Epidermal growth factor receptor and thyrotropin response in human thyroid tissues". J. Endocrinol. Invest. 13 (4): 293–9. doi:10.1007/BF03349565. PMID 2164546.
- ↑ Dumont JE, Maenhaut C, Pirson I, Baptist M, Roger PP (1991). "Growth factors controlling the thyroid gland". Baillieres Clin. Endocrinol. Metab. 5 (4): 727–54. PMID 1661579.
- ↑ Duprez L, Parma J, Van Sande J, Allgeier A, Leclère J, Schvartz C, Delisle MJ, Decoulx M, Orgiazzi J, Dumont J (1994). "Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism". Nat. Genet. 7 (3): 396–401. doi:10.1038/ng0794-396. PMID 7920658.
- ↑ Ericsson UB, Lindgärde F (1991). "Effects of cigarette smoking on thyroid function and the prevalence of goitre, thyrotoxicosis and autoimmune thyroiditis". J. Intern. Med. 229 (1): 67–71. PMID 1995765.
- ↑ Farid NR, Shi Y, Zou M (1994). "Molecular basis of thyroid cancer". Endocr. Rev. 15 (2): 202–32. doi:10.1210/edrv-15-2-202. PMID 8026388.
- ↑ Liekens S, De Clercq E, Neyts J (2001). "Angiogenesis: regulators and clinical applications". Biochem. Pharmacol. 61 (3): 253–70. PMID 11172729.
- ↑ Gaitan E, Cooksey RC, Legan J, Lindsay RH (1995). "Antithyroid effects in vivo and in vitro of vitexin: a C-glucosylflavone in millet". J. Clin. Endocrinol. Metab. 80 (4): 1144–7. doi:10.1210/jcem.80.4.7714083. PMID 7714083.
- ↑ Gaskin D, Parai SK, Parai MR (1992). "Hashimoto's thyroiditis with medullary carcinoma". Can J Surg. 35 (5): 528–30. PMID 1356609.
- ↑ Gerber H, Huber G, Peter HJ, Kämpf J, Lemarchand-Beraud T, Fragu P, Stocker R (1994). "Transformation of normal thyroids into colloid goiters in rats and mice by diphenylthiohydantoin". Endocrinology. 135 (6): 2688–99. doi:10.1210/endo.135.6.7988459. PMID 7988459.
- ↑ Wang CC, Friedman L, Kennedy GC, Wang H, Kebebew E, Steward DL, Zeiger MA, Westra WH, Wang Y, Khanafshar E, Fellegara G, Rosai J, Livolsi V, Lanman RB (2011). "A large multicenter correlation study of thyroid nodule cytopathology and histopathology". Thyroid. 21 (3): 243–51. doi:10.1089/thy.2010.0243. PMC 3698689. PMID 21190442.
- ↑ Gharib H (1997). "Changing concepts in the diagnosis and management of thyroid nodules". Endocrinol. Metab. Clin. North Am. 26 (4): 777–800. PMID 9429860.
- ↑ Giordano C, Stassi G, De Maria R, Todaro M, Richiusa P, Papoff G, Ruberti G, Bagnasco M, Testi R, Galluzzo A (1997). "Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis". Science. 275 (5302): 960–3. PMID 9020075.
- ↑ Greenspan FS (1991). "The problem of the nodular goiter". Med. Clin. North Am. 75 (1): 195–209. PMID 1987443.
- ↑ Isaacson PG, Androulakis-Papachristou A, Diss TC, Pan L, Wright DH (1992). "Follicular colonization in thyroid lymphoma". Am. J. Pathol. 141 (1): 43–52. PMC 1886561. PMID 1632470.
- ↑ Ledent C, Parmentier M, Maenhaut C, Taton M, Pirson I, Lamy F, Roger P, Dumont JE (1991). "The TSH cyclic AMP cascade in the control of thyroid cell proliferation: the story of a concept". Thyroidology. 3 (3): 97–101. PMID 1726932.
- ↑ Ledent C, Dumont JE, Vassart G, Parmentier M (1992). "Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism". EMBO J. 11 (2): 537–42. PMC 556484. PMID 1371462.
- ↑ Livolsi VA, Merino MJ (1981). "Histopathologic differential diagnosis of the thyroid". Pathol Annu. 16 (Pt 2): 357–406. PMID 7036066.
- ↑ Ludgate M, Jasani B (1997). "Apoptosis in autoimmune and non-autoimmune thyroid disease". J. Pathol. 182 (2): 123–4. doi:10.1002/(SICI)1096-9896(199706)182:2<123::AID-PATH832>3.0.CO;2-F. PMID 9274519.
- ↑ Maceri DR, Sullivan MJ, McClatchney KD (1986). "Autoimmune thyroiditis: pathophysiology and relationship to thyroid cancer". Laryngoscope. 96 (1): 82–6. PMID 3484533.
- ↑ Moriuchi A, Yokoyama S, Kashima K, Andoh T, Nakayama I, Noguchi S (1992). "Localized primary amyloid tumor of the thyroid developing in the course of Hashimoto's thyroiditis". Acta Pathol. Jpn. 42 (3): 210–6. PMID 1570743.
- ↑ McKee RF, Krukowski ZH, Matheson NA (1993). "Thyroid neoplasia coexistent with chronic lymphocytic thyroiditis". Br J Surg. 80 (10): 1303–4. PMID 8242306.
- ↑ Ott RA, McCall AR, McHenry C, Jarosz H, Armin A, Lawrence AM, Paloyan E (1987). "The incidence of thyroid carcinoma in Hashimoto's thyroiditis". Am Surg. 53 (8): 442–5. PMID 3605864.
- ↑ Paynter OE, Burin GJ, Jaeger RB, Gregorio CA (1988). "Goitrogens and thyroid follicular cell neoplasia: evidence for a threshold process". Regul. Toxicol. Pharmacol. 8 (1): 102–19. PMID 3285378.
- ↑ Berndorfer U, Wilms H, Herzog V (1996). "Multimerization of thyroglobulin (TG) during extracellular storage: isolation of highly cross-linked TG from human thyroids". J. Clin. Endocrinol. Metab. 81 (5): 1918–26. doi:10.1210/jcem.81.5.8626858. PMID 8626858.
- ↑ Bialas P, Marks S, Dekker A, Field JB (1976). "Hashimoto's thyroiditis presenting as a solitary functioning thyroid nodule". J. Clin. Endocrinol. Metab. 43 (6): 1365–9. doi:10.1210/jcem-43-6-1365. PMID 1036742.
- ↑ Gaitan E, Lindsay RH, Reichert RD, Ingbar SH, Cooksey RC, Legan J, Meydrech EF, Hill J, Kubota K (1989). "Antithyroid and goitrogenic effects of millet: role of C-glycosylflavones". J. Clin. Endocrinol. Metab. 68 (4): 707–14. doi:10.1210/jcem-68-4-707. PMID 2921306.
- ↑ Gaitan E (1990). "Goitrogens in food and water". Annu. Rev. Nutr. 10: 21–39. doi:10.1146/annurev.nu.10.070190.000321. PMID 1696490.
- ↑ Taccaliti A, Boscaro M (2009). "Genetic mutations in thyroid carcinoma". Minerva Endocrinol. 34 (1): 11–28. PMID 19209125.
- ↑ Vecchio G, Santoro M (2000). "Oncogenes and thyroid cancer". Clin. Chem. Lab. Med. 38 (2): 113–6. doi:10.1515/CCLM.2000.017. PMID 10834397.
- ↑ Fusco A, Santoro M, Grieco M, Carlomagno F, Dathan N, Fabien N, Berlingieri MT, Li Z, De Franciscis V, Salvatore D (1995). "RET/PTC activation in human thyroid carcinomas". J. Endocrinol. Invest. 18 (2): 127–9. doi:10.1007/BF03349720. PMID 7629379.
- ↑ Fugazzola L, Pierotti MA, Vigano E, Pacini F, Vorontsova TV, Bongarzone I (1996). "Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer". Oncogene. 13 (5): 1093–7. PMID 8806699.
- ↑ Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjöld M, Komminoth P, Hendy GN, Mulligan LM (1996). "The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis". JAMA. 276 (19): 1575–9. PMID 8918855.
- ↑ Goretzki PE, Simon D, Röher HD (1992). "G-protein mutations in thyroid tumors". Exp. Clin. Endocrinol. 100 (1–2): 14–6. doi:10.1055/s-0029-1211167. PMID 1468509.
- ↑ Melillo RM, Santoro M, Ong SH, Billaud M, Fusco A, Hadari YR, Schlessinger J, Lax I (2001). "Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade". Mol. Cell. Biol. 21 (13): 4177–87. doi:10.1128/MCB.21.13.4177-4187.2001. PMC 87079. PMID 11390647.
- ↑ Ciampi R, Nikiforov YE (2007). "RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis". Endocrinology. 148 (3): 936–41. doi:10.1210/en.2006-0921. PMID 16946010.
- ↑ Haymart MR, Repplinger DJ, Leverson GE, Elson DF, Sippel RS, Jaume JC, Chen H (2008). "Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage". J. Clin. Endocrinol. Metab. 93 (3): 809–14. doi:10.1210/jc.2007-2215. PMC 2266959. PMID 18160464.
- ↑ McLeod DS, Cooper DS, Ladenson PW, Ain KB, Brierley JD, Fein HG, Haugen BR, Jonklaas J, Magner J, Ross DS, Skarulis MC, Steward DL, Maxon HR, Sherman SI (2014). "Prognosis of differentiated thyroid cancer in relation to serum thyrotropin and thyroglobulin antibody status at time of diagnosis". Thyroid. 24 (1): 35–42. doi:10.1089/thy.2013.0062. PMC 3887423. PMID 23731273.
- ↑ Walfish PG, Strawbridge HT, Rosen IB (1985). "Management implications from routine needle biopsy of hyperfunctioning thyroid nodules". Surgery. 98 (6): 1179–88. PMID 4071393.
- ↑ 45.0 45.1 Cibas ES, Ali SZ (2009). "The Bethesda System for Reporting Thyroid Cytopathology". Thyroid. 19 (11): 1159–65. doi:10.1089/thy.2009.0274. PMID 19888858.
- ↑ Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LD, Barletta JA, Wenig BM, Al Ghuzlan A, Kakudo K, Giordano TJ, Alves VA, Khanafshar E, Asa SL, El-Naggar AK, Gooding WE, Hodak SP, Lloyd RV, Maytal G, Mete O, Nikiforova MN, Nosé V, Papotti M, Poller DN, Sadow PM, Tischler AS, Tuttle RM, Wall KB, LiVolsi VA, Randolph GW, Ghossein RA (2016). "Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors". JAMA Oncol. 2 (8): 1023–9. doi:10.1001/jamaoncol.2016.0386. PMC 5539411. PMID 27078145.