Thyroid nodule pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
[Pathogen name] is usually transmitted via the [transmission route] route to the human host. Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell. On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. [Disease name] is transmitted in [mode of genetic transmission] pattern. [Disease/malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells]. Development of [disease name] is the result from multiple genetic mutations. Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3]. The progression to [disease name] usually involves the [molecular pathway]. The pathophysiology of [disease name] depends on the histological subtype.
Pathogenesis
[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][6][19][20][21][22][23][24][25][26][27][28][29][30][31]
Hyperplastic nodules
Hyperplastic nodule pathogenesis seems to start with an increase in thyroid proliferation, which lead to thyroid hyperplasia. Rapid thyroid prolifertion 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.
TSH role in thyroid nodule formation
Growth signals in thyroid tissue start their pathways by an stimulant, that attaches to the thyroid receptors. The following signals can be transmitted through 3 distinct pathways:
- Adenylate cyclase/protein kinase A system
- Phospholipase C pathways
- Phospholipase A2 system (intracellular metabolism of prostaglandins)
The most important and effective 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 or absent effect on thyroid growth.
TSH acts as an stimulant by binding to the receptor and activating both the adenylate cyclase and phospholipase C pathways. As mentioned, the phospholipase C pathways 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 pathways is then transduced into the nucleus where transcription factors–upon phosphorylation–induce the expression of cAMP-inducible genes. It has been definitely 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 devided into 2 phases:
1. 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 look like to have the most important role in pathogenesis of hyperplastic nodules:[32][33]
- Iodine deficiency:
- Effects directly or indirectly
- The most important potent stimulator of the replicative potential of the gland
- Mechanism of action:
- Acting 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:
- DDT
- Polychlorinated byphenyls
- Pesticides
- Goitrogens:
- 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
- Flavonoids:
- 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
- Tobacco:
- 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 can exert an action of differentiation or inhibition of thyroid growth are:
- TGFβ
- IFNγ
- IL-6
- Somatostatin
2. 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 thyropid proliferaion 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.
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.
activated oncogenes are considered the underlying event leading to uncontrolled cell growth.
Neoplastoc nodules
Neoplastic nodules development mainly involve the activation of proto-oncogenes as the underlying event leading to uncontrolled cell growth. Proto-oncogens activation are associated with thyroid adenoma, hyperplasia, and malignancies. Thyroid gland is made of different follicles, and each follicle is composed of different clones of cells (polyclonal). During nodule formation, cells replicate in a coordinated way simultanously, so each follicle of the nodule share the same heterogenity with other cells. Hyperplastic thyroid nodules are considered as risk factor for neoplasia development, as these cells may express neoplasia 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 oncogens related to thyroid neoplasia development are mentioned in the genetic table below.[34][35][36][37][38][39]
Environmental factors can play an important role in triggering the oncogen mutation. The most important carcinogens involved in the pathogenesis of neoplastic thyroid nodules are:
- Thionamid compounds: thiourea, methimazole, ethylenethiourea (ETU), thiouracil, propylthiouracil
- Aminotriazole: herbicide
- Acetylaminofluorene (AAF). Use: insecticide
- Oxydianiline (ODA). Use: Azo-Dye
- Methylene benzenamine. Use: Dye intermediate
- Nitrosamines
- 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)
Papillary thyroid carcinoma
Schematic representation of the MAPK signaling cascade in papillary thyroid carcinoma. MAPK, also known as ERK, translocates to the nucleus and promotes cell division when it is phosphorylated by MEK, a serine/threonine kinase. Constitutive activation of this process is tumorigenic. MAPK phosphorylation is a relatively distal step in a sequential phosphorylation cascade that can begin with the activation of a tyrosine kinase, is followed by phosphorylation of RAS which activates BRAF, a serine/threonine kinase followed by MEK and MAPK phosphorylation. In papillary thyroid carcinoma, somatic genetic alterations at three of these steps activate this linear signaling cascade. A gene rearrangement creating a chimeric RET or TRK activates the initial tyrosine kinase step. Activating point mutations of either RAS or BRAF constitutively activates these proteins. The tyrosine kinase, RAS, and BRAF genetic alterations are usually mutually exclusive, suggesting that any single alteration is sufficient to play an early role in tumorigenesis [1,2].
ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase.
thyrosin kinase RAS BRAF MEK MAPK nucleus tumorogenesis
- Melillo RM, Castillone D, Guarino V, et al. The ret/ptc-ras-braf linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest 2005; 115:1068.
- Ciampi R, Nikiforov YE. Ret/ptc rearrangements and braf mutations in thyroid tumorigenesis. Endocrinology 2007; 148:936.
Colloid and cystic nodules
Colloid nodules
The colloid nodules consist of colloid droplets and thyroglobulin vesicles. Thyroid gland keeps a balance between colloid and thyroglobulin production by interacting between secretion of thyroglobulin into colloid and reabsorption of colloid into thyroid follicular cells. The mentioned interaction is processed by macro-pinocytosis (pseudopods) and micro-pinocytosis (microvilli). Any imbalance between secretion and reabsorption of thyroglobulin equilibrium 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. The mechanism is due to several idoine effects on thyroid cells:
- Endocytosis inhibition: High dosage of iodine may lead to inhibition of the protease activity of thyroid lysosomes, and thereby inhibiting endocytosis
- Exocytosis inhibition: Iodine reduces the expression of the TSH receptor on the surface of thyroid cells, and 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 due to loss of thyroglobulin packaging ability, that may lead to an enormous enlargement of the follicles and flattening of the epithelium. Therefore a colloid nodular goitre can be made.
Cystic thyroid nodules
Cystic thyroid nodules can be classified into the following types:
- Necrotic cystic nodules:
- May be due to a relative insufficiency of blood supply
- Inadequate blood supply for a neoplastic cells growth
- Imbalance between angiogenesis and cell growth
- Compression of new vessels due to lack of cellular outgrow, leading to cell damage, necrosis and colliquation
- Hyperplastic thyroid nodules may proceed towards necrosis, colliquation, and pseudocyst formation
- May be due to a relative insufficiency 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
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 thyroiditis diseases, the mechanism of nodular lesion is the same as the mechanism of the main disease, meaning 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 thryoid scintigraphy. The most important thyroiditic diseases that may present as lymphocytic nodular thyroid are:
- Local infections:
- Piogenic infection
- Tuberculosis
- Parasites
- Subacute de Quervain’s thyroiditis
- Fibrosing (Riedel’s) thyroiditis
- Plasmacell granuloma
- Plasmacytoma
- Primary amyloid tumor and amyloidosis
- Thymoma
- Primary thyroid lymphoma
- Thyroiditic nodule due to diffuse B-cell infiltration into lymphoma presented areas
- Histocytosis X
- Medullary carcinoma
- Papillary carcinoma
- Thyroiditic nodule may be due to an immune response to some abnormal thyroid antigen expressed in the tumor
Genetics
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 nonmedullary thyroid cancer FNMTC, with the following features:
- A rare group ofcancers
- Mostly related to non-medullary tumors
- Inheritance: autosomal dominant with incomplete penetrance and variable expressivity
- Affected patients have a earlier age of thyroid cancer onset
- 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 |
|---|---|---|---|
| N&H ras |
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| RET |
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| gsp |
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| c-MET (α and β subunit) |
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| TRK |
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| EGF / EGF-R |
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| p53 |
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Associated Conditions
- Preoperative serum TSH is an independent risk factor for predicting malignancy in a thyroid nodule, and is associated with: 18160464 23731273
- Higher differentiated thyroid cancer stage
- Gross extrathyroidal extension
- Neck node metastases
Gross Pathology
- On gross pathology, cystic lesions, multiple or a single nodule, and encapsulated lesions are themost important and prevalent characteristic findings of thyroid nodules.
- On gross pathology, follicular thyroid adenoma may present as a big lesion with thick capsule
Microscopic pathology
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| Cytology classification | Also referred to as: | Efficient diagnosis | May be seen in: | FNA cytology | ||
|---|---|---|---|---|---|---|
| FNA | Surgical biopsy | |||||
| Follicular lesions | Benign (macrofollicular) |
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+ |
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| Follicular neoplasm/microfollicular |
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+ |
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| Follicular lesion of undetermined significance (FLUS) | + |
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| Atypia of undetermined significance (AUS) | ||||||
| Hürthle cells |
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+ |
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| Papillary cancer |
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+ | Epithelioid giant cells
Psammoma bodies
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| Medullary cancer | + |
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| Anaplastic thyroid cancer | +
Large needle biopsy if needed |
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Microscopic Pathology
- Both polyclonal and monoclonal nodules appear similar on fine needle aspiration (FNA) (macrofollicular) and are benign 8426623
- 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
References
- ↑ 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.