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
Common causes
[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 maily occur in response to certain stimulants. Following the hyperplasia development phase, a new phase may begin, leading to a neoplasia. 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. 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 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 growth of thyroid gland 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, which binds to specific receptors on endothelial cells and induces neovascularization by sprouting of new capillaries. In turn, endothelial cells produce growth factors that increase thyroid hyperplasia. Sprouting of new capillaries is accompanied by the production of proteolytic enzymes, which facilitate the expansion in 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.
In thyroid cells there are three distinct pathways for signal transduction: 1) receptor/adenylate cyclase/protein kinase A system; 2) receptor/phospholipase C pathways; and 3) receptor/phospholipase A2 system (intracellular metabolism of prostaglandins).
TSH activates both the adenylate cyclase and phospholipase C pathways.
Activation of phosholipase C and phospholipase A2 have only a minor or absent effect on thyroid growth.
The signal generated by the cAMP-dependent pathways is then transduced into the nucleus where transcription factors–upon phosphorylation–induce the expression of cAMP-inducible genes [97]. In figure 3 the pathway of signal transduction from the plasma membrane to the promoter elements in the nucleus is schematized. It has been definitely established that TSH has a main mitogenic role, through cAMP, Gs proteins (G-protein heterotrimeric α-, β- and γ-subunits coded by the gsp gene which, binding to GTP, relays the TSH signal from its receptor to adenyl cyclase) 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 [70] or Gs protein
Constitutive cAMP overproduction not only stimulates growth but also function.
Neoplastoc nodules
Neoplastic nodules development may involve the activation of oncogenes, as the underlying event leading to uncontrolled cell growth. Activated oncogenes have been identified in thyroid malignancies and also in adenoma and hyperplasia. The most important oncogens related to thyroid neoplasia development are mentioned in the table below.[34][35][36][37][38][39]
Colloid nodules
These nodules are produced as a defect of intraluminal thyroglobulin reabsorption.
By the process of macro- (pseudopods) and micro-pinocytosis (microvilli), the colloid is reabsorbed into the follicular cells, forming colloid droplets, whereas newly synthesized thyroglobulin is compacted into exocytotic vesicles and secreted into the colloid. An imbalance of such equilibrium produces a colloid appearance.
the combined actions of TSH and iodine excess produces a colloid goitre
iodine has been found to inhibit the protease activity of thyroid lysosomes [82], thereby inhibiting endocytosis buit for this effect large doses of iodine (Lugol solution) is needed
iodine reduces the expression of the TSH receptor on the surface of thyroid cells and hence colloid reabsorption
Maybe in colloid nodules the mechanism of stocking thyroglobulin into ‘globules’ is lost, part of the thyroglobulin is no longer osmotically inert and consequently an enormous enlargement of the follicles and flattening of the epithelium takes place, giving the histological appearance of ‘colloid follicle’.
Cystic nodules
- True cysts
- Pseudo cysts
hyperplasia of thyroid nodules proceed towards necrosis, colliquation and ultimately to pseudocyst formation
necrosis is due to a relative insufficiency of blood supply, which is inadequate for the growth of the replicating neoplasia [60, 94] or is due to an imbalance between angiogenesis and cell growth where replicating cells do not outgrow but gradually compress neovascularization, leading to cell damage, necrosis and colliquation
autoimmunity might participate in the formation of the serum-like cyst
An increased concentration of VEGF/VPF has been found in the fluid of thyroid cysts, particularly in the fluid of rapidly enlarging or recurrent cysts. This finding suggests that VEGF/VPF stimulates vascular permeability and promotes accumulation of fluid.
Cysts may also be considered as the end result of apoptosis
Thyroiditic nodule
Nodular lymphocytic thyroiditis includes two different entities: lymphocyte thyroiditis growing as a nodule in a hyperplastic or normal gland; and lymphocytic thyroiditis associated with other nodular thyroid diseases.
In Hashimoto thyroiditis, by scintigraphy solitary or dominant cold nodules are common
by cytology and ultrasonography thyroiditic nodules are easily diagnosed
- Carcinogenics:
- 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).
Less common causes
- Piogenic infection
- Tuberculosis
- de Quervain’s thyroiditis
- Fibrosing (Riedel’s) thyroiditis,
- Parasites
- Dyshormonogenesis
- Amyloidosis
- Plasma cell granuloma
- Histiocytosis X
Genetics
- Some diseases are genetic, and have particular inheritance patterns, and express different phenotypes
- The effect that genetics may have on the pathophysiology of a disease can be described in this section
- familial nonmedullary thyroid cancer (FNMTC):
- rare
- related to non-medullary tumors
- Inheritance: autosomal dominant with incomplete penetrance and variable expressivity
- earlier age of thyroid cancer onset
- more benign thyroid nodules
- Associated with multifocal disease
- Associated with a higher rate of locoregional recurrence
| Principal oncogenes and growth factors involved in thyroid carcinogenesis | Gene mechanism | Mutation effect | Neoplasia |
|---|---|---|---|
| N&H ras | ras-constitutively bound to GAP (GTPase-activating protein) | Activation of adenylate cyclase and calcium channels |
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| RET (Receptor for glial-derived neurotrophic GF) |
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|
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| gsp | Ribosylated GS-α at arginine 201 | Impairing of GTPase activity | Hot adenomas |
| c-MET (α and β subunit) | Increased receptors for HGF/SF | Enhancement of receptor kinase activity | Ca. papillary (aggressive) |
| TRK | Receptor for NGF | Mitogen activated TK cascade | Ca. papillary |
| EGF / EGF-R | Lack of activation of p21/Waf l gene expression | Loss of regulation at the critical G1 to S phase | Ca. anaplastic |
| p53 | Lack of activation of p21/Waf l gene expression | Loss of regulation at the critical G1 to S phase | Ca. anaplastic
Papillary Follicular |
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
- Gross pathology refers to macroscopic or larger scale manifestations of disease in organs, tissues and body cavities. The term is commonly used by pathologist to refer to diagnostically useful findings made during the gross examination portion of surgical specimen processing or an autopsy.
- This section is a good place to include pictures. Search for copyleft images on The Pathology Wiki [1] and Ask Dr. Wiki [2].
Microscopic pathology
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19888858
| Cytology classification | Referred to | FNA | Surgical biopsy | May be seen in: | FNA cytology | |
|---|---|---|---|---|---|---|
| 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) | + | common, especially in nodular goiters. |
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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 | + | Medullary cancer |
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| Anaplastic thyroid cancer | +
Large needle biopsy if needed |
Anaplastic thyroid cancer |
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Microscopic Pathology
- Microscopic pathology is the disease process as it occurs at the microscopic level.
- This section is a good place to include pictures. Search for copyleft images on The Pathology Wiki [3] and Ask Dr. Wiki [4].
- Both polyclonal and monoclonal nodules appear similar on fine needle aspiration (FNA) (macrofollicular) and are benign 8426623
- Thus, the diagnosis of follicular cancer in situ does not exist, 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.