Thyroid nodule pathophysiology: Difference between revisions

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==Overview==
==Overview==
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
Thyroid nodules may arise from different [[Cells (biology)|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 from[[inflammation]] of [[Thyroid gland|thyroid tissue]]. [[Genetic mutation]] is considered as one of the most important mechanisms of developing thyroid nodules, especially [[Thyroid Cancer|neoplastic thyroid nodules]]. Most of these [[mutations]] occur as [[Somatic mutation|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 / [[EGFR|EGF-R]], and [[P53 gene|P53]].  
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==
==Pathogenesis==
A summary of [[Thyroid Gland|thyroid]] nodule pathophysiology is presented in the slides below:
{{#widget:ThyroidNodulePatho}}
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Metab. |volume=80 |issue=4 |pages=1144–7 |year=1995 |pmid=7714083 |doi=10.1210/jcem.80.4.7714083 |url=}}</ref><ref name="pmid1356609">{{cite journal |vauthors=Gaskin D, Parai SK, Parai MR |title=Hashimoto's thyroiditis with medullary carcinoma |journal=Can J Surg |volume=35 |issue=5 |pages=528–30 |year=1992 |pmid=1356609 |doi= |url=}}</ref><ref name="pmid7988459">{{cite journal |vauthors=Gerber H, Huber G, Peter HJ, Kämpf J, Lemarchand-Beraud T, Fragu P, Stocker R |title=Transformation of normal thyroids into colloid goiters in rats and mice by diphenylthiohydantoin |journal=Endocrinology |volume=135 |issue=6 |pages=2688–99 |year=1994 |pmid=7988459 |doi=10.1210/endo.135.6.7988459 |url=}}</ref><ref name="pmid21190442">{{cite journal |vauthors=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 |title=A large multicenter correlation study of thyroid nodule cytopathology and histopathology |journal=Thyroid |volume=21 |issue=3 |pages=243–51 |year=2011 |pmid=21190442 |pmc=3698689 |doi=10.1089/thy.2010.0243 |url=}}</ref><ref name="pmid9429860">{{cite journal |vauthors=Gharib H |title=Changing concepts in the diagnosis and management of thyroid nodules |journal=Endocrinol. Metab. Clin. North Am. |volume=26 |issue=4 |pages=777–800 |year=1997 |pmid=9429860 |doi= |url=}}</ref><ref name="pmid9020075">{{cite journal |vauthors=Giordano C, Stassi G, De Maria R, Todaro M, Richiusa P, Papoff G, Ruberti G, Bagnasco M, Testi R, Galluzzo A |title=Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis |journal=Science |volume=275 |issue=5302 |pages=960–3 |year=1997 |pmid=9020075 |doi= |url=}}</ref><ref name="pmid2196027">{{cite journal |vauthors=de los Santos ET, Keyhani-Rofagha S, Cunningham JJ, Mazzaferri EL |title=Cystic thyroid nodules. The dilemma of malignant lesions |journal=Arch. Intern. Med. |volume=150 |issue=7 |pages=1422–7 |year=1990 |pmid=2196027 |doi= |url=}}</ref><ref name="pmid1987443">{{cite journal |vauthors=Greenspan FS |title=The problem of the nodular goiter |journal=Med. Clin. North Am. |volume=75 |issue=1 |pages=195–209 |year=1991 |pmid=1987443 |doi= |url=}}</ref><ref name="pmid1632470">{{cite journal |vauthors=Isaacson PG, Androulakis-Papachristou A, Diss TC, Pan L, Wright DH |title=Follicular colonization in thyroid lymphoma |journal=Am. J. Pathol. |volume=141 |issue=1 |pages=43–52 |year=1992 |pmid=1632470 |pmc=1886561 |doi= |url=}}</ref><ref name="pmid1726932">{{cite journal |vauthors=Ledent C, Parmentier M, Maenhaut C, Taton M, Pirson I, Lamy F, Roger P, Dumont JE |title=The TSH cyclic AMP cascade in the control of thyroid cell proliferation: the story of a concept |journal=Thyroidology |volume=3 |issue=3 |pages=97–101 |year=1991 |pmid=1726932 |doi= |url=}}</ref><ref name="pmid1371462">{{cite journal |vauthors=Ledent C, Dumont JE, Vassart G, Parmentier M |title=Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism |journal=EMBO J. |volume=11 |issue=2 |pages=537–42 |year=1992 |pmid=1371462 |pmc=556484 |doi= |url=}}</ref><ref name="pmid7036066">{{cite journal |vauthors=Livolsi VA, Merino MJ |title=Histopathologic differential diagnosis of the thyroid |journal=Pathol Annu |volume=16 |issue=Pt 2 |pages=357–406 |year=1981 |pmid=7036066 |doi= |url=}}</ref><ref name="pmid9274519">{{cite journal |vauthors=Ludgate M, Jasani B |title=Apoptosis in autoimmune and non-autoimmune thyroid disease |journal=J. Pathol. |volume=182 |issue=2 |pages=123–4 |year=1997 |pmid=9274519 |doi=10.1002/(SICI)1096-9896(199706)182:2<123::AID-PATH832>3.0.CO;2-F |url=}}</ref><ref name="pmid3484533">{{cite journal |vauthors=Maceri DR, Sullivan MJ, McClatchney KD |title=Autoimmune thyroiditis: pathophysiology and relationship to thyroid cancer |journal=Laryngoscope |volume=96 |issue=1 |pages=82–6 |year=1986 |pmid=3484533 |doi= |url=}}</ref><ref name="pmid1570743">{{cite journal |vauthors=Moriuchi A, Yokoyama S, Kashima K, Andoh T, Nakayama I, Noguchi S |title=Localized primary amyloid tumor of the thyroid developing in the course of Hashimoto's thyroiditis |journal=Acta Pathol. Jpn. |volume=42 |issue=3 |pages=210–6 |year=1992 |pmid=1570743 |doi= |url=}}</ref><ref name="pmid8242306">{{cite journal |vauthors=McKee RF, Krukowski ZH, Matheson NA |title=Thyroid neoplasia coexistent with chronic lymphocytic thyroiditis |journal=Br J Surg |volume=80 |issue=10 |pages=1303–4 |year=1993 |pmid=8242306 |doi= |url=}}</ref><ref name="pmid3605864">{{cite journal |vauthors=Ott RA, McCall AR, McHenry C, Jarosz H, Armin A, Lawrence AM, Paloyan E |title=The incidence of thyroid carcinoma in Hashimoto's thyroiditis |journal=Am Surg |volume=53 |issue=8 |pages=442–5 |year=1987 |pmid=3605864 |doi= |url=}}</ref><ref name="pmid3285378">{{cite journal |vauthors=Paynter OE, Burin GJ, Jaeger RB, Gregorio CA |title=Goitrogens and thyroid follicular cell neoplasia: evidence for a threshold process |journal=Regul. Toxicol. Pharmacol. |volume=8 |issue=1 |pages=102–19 |year=1988 |pmid=3285378 |doi= |url=}}</ref><ref name="pmid8626858">{{cite journal |vauthors=Berndorfer U, Wilms H, Herzog V |title=Multimerization of thyroglobulin (TG) during extracellular storage: isolation of highly cross-linked TG from human thyroids |journal=J. Clin. Endocrinol. Metab. |volume=81 |issue=5 |pages=1918–26 |year=1996 |pmid=8626858 |doi=10.1210/jcem.81.5.8626858 |url=}}</ref><ref name="pmid1036742">{{cite journal |vauthors=Bialas P, Marks S, Dekker A, Field JB |title=Hashimoto's thyroiditis presenting as a solitary functioning thyroid nodule |journal=J. Clin. Endocrinol. Metab. |volume=43 |issue=6 |pages=1365–9 |year=1976 |pmid=1036742 |doi=10.1210/jcem-43-6-1365 |url=}}</ref>
* Thyroid nodules may arise from different [[Cell (biology)|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 from[[inflammation]] of [[Thyroid gland|thyroid tissue]].


=== Common causes ===
=== (a) Hyperplastic nodules ===
* [[Hyperplasia|Hyperplastic]] nodule [[pathogenesis]] seems to start with an increase in [[Thyroid Gland|thyroid]] [[proliferation]], which lead to [[Thyroid Gland|thyroid]] [[hyperplasia]].
* Rapid [[Proliferation|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]].


==== Hyperplastic nodules ====
==== 1. TSH role in thyroid nodule formation ====
* The proliferative activity of the thyroid is very low.
* Growth signals in [[Thyroid Gland|thyroid tissue]] start by a stimulant, that attaches to the [[Thyroid Gland|thyroid]] receptors. The following signals can be transmitted through 3 distinct pathways:
** [[Adenylate cyclase]]/[[Protein kinase A|protein kinase A system]]
** [[Phospholipase C|Phospholipase C pathways]]
** [[Phospholipase A2|Phospholipase A2 system]] ([[intracellular]] metabolism of [[prostaglandins]])


* The thyroid however shows the ability to proliferate rapidly in response to appropriate stimuli. 
* The most important pathway for [[Thyroid Gland|thyroid]] growth is the activation of [[adenylate cyclase]]/[[Protein kinase A|protein kinase A system]]. Activation of [[Phospholipase c|phospholipase C]] and [[phospholipase A2]] have only a minor effect on [[Thyroid Gland|thyroid]] growth.
** iodine deficiency directly or indirectly is the principal potent stimulator of the replicative potential of the gland. 
* [[TSH]] acts as a stimulant by binding to the [[Thyrotropin receptor|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 (biology)|cell]] growth is generated by [[adenylate cyclase]] pathway. The signal generated by the [[adenylate cyclase]] [[CAMP-dependent protein kinase|cAMP-dependent]] pathway is then [[Transduction|transduced]] in the [[nucleus]] where [[transcription factors]]–upon [[phosphorylation]]–induce the expression of [[Cyclic adenosine monophosphate|cAMP]]-inducible [[genes]]. It has been established that [[TSH]] has a main [[mitogenic]] role, through [[cAMP]], Gs [[proteins]] and [[Protein kinase A|protein kinase A,]] which activates the metabolic cascade leading to the stimulation of growth. 
** industrial chemicals, diet, goitrogens, antithyroid drugs
* However, to produce [[hyperplasia]], overproduction of [[cAMP]] must be continuous, as it occurs in [[mutations]] constitutive of the [[genes]] which regulate [[cAMP]] production.
** DDT, polychlorinated byphenyls and tobacco have been implicated in goitrogenesis. 
* Constitutive [[Cyclic adenosine monophosphate|cAMP]] overproduction has been demonstrated to be due to [[Point mutations|point mutation]] of the [[Thyrotropin receptor|TSH receptor]] or [[G proteins|Gs protein]]. 
* Mechanism of action:
* Constitutive [[Cyclic adenosine monophosphate|cAMP]] overproduction not only stimulates growth but also function.
** Acting as an initiators but need the promoter action of other chemicals that induce a rise in TSH.
* [[Hyperplastic]] thyroid nodule [[pathogenesis]] can be divided into 2 phases:
** May be related to high prevalence of thyroid hyperplasia and nodules are found in iodine-sufficient areas
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.  
==== 2. Thyroid overgrowth stimulants: ====
[[Thyroid Gland|Thyroid]] normally has a low [[Proliferation|proliferative]] activity, although it can start [[proliferation]] rapidly in response to certain stimulants. Stimulants mainly act through [[Thyroid-stimulating hormone|TSH]] mediated activity and production. The following stimulants appear to have the most important role in [[pathogenesis]] of [[hyperplastic]] nodules:<ref name="pmid2921306">{{cite journal |vauthors=Gaitan E, Lindsay RH, Reichert RD, Ingbar SH, Cooksey RC, Legan J, Meydrech EF, Hill J, Kubota K |title=Antithyroid and goitrogenic effects of millet: role of C-glycosylflavones |journal=J. Clin. Endocrinol. Metab. |volume=68 |issue=4 |pages=707–14 |year=1989 |pmid=2921306 |doi=10.1210/jcem-68-4-707 |url=}}</ref><ref name="pmid1696490">{{cite journal |vauthors=Gaitan E |title=Goitrogens in food and water |journal=Annu. Rev. Nutr. |volume=10 |issue= |pages=21–39 |year=1990 |pmid=1696490 |doi=10.1146/annurev.nu.10.070190.000321 |url=}}</ref>
* [[Iodine]] deficiency:
** Effects directly or indirectly 
** The most potent stimulator replication of the [[Cell (biology)|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 Gland|thyroid]] hyperplasia and nodules in [[iodine]]-deficient areas
* Industrial chemicals:
** [[DDT]]
** [[Polychlorinated biphenyl|Polychlorinated biphenyls]]
** [[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]]:
*** [[Thyroid peroxidase|TPO]] inhibitors
*** Also act on [[Thyroid Gland|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 Gland|thyroid]] [[hyperplasia]] and nodules in [[iodine]]-sufficient areas 


Activation of phosholipase C and phospholipase A2 have only a minor or absent effect on thyroid growth.
* [[Thyroid]] [[stromal cells]] interact with [[thyroid]] follicular [[Cells (biology)|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 Gland|thyroid]] growth are:
** [[TGF beta|TGFβ]]
** [[Interferon|IFNγ]]
** [[Interleukin 6|IL-6]]
** [[Somatostatin]]


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
===== 3. Hyperplasia development phase: =====
* [[Thyroid Gland|Thyroid]] [[Cells (biology)|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 [[Blood vessel|vessel]] production.  
* In response, [[endothelial cells]] produce [[growth factors]] that increase [[thyroid]] [[cell]] [[proliferation]] and lead to [[Thyroid Gland|thyroid]] [[hyperplasia]].
* [[Neovascularization]] in [[Thyroid Gland|thyroid]] matrix is accompanied by the production of [[Proteolytic enzyme|proteolytic enzymes]], which facilitate the expansion of [[Thyroid Gland|thyroid]] tissue into the [[extracellular matrix]].


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
===== 4. Neoplasia development phase: =====
* Each follicle is composed of different clones of [[Cell (biology)|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 disease|neoplastic]] follicle shows a [[monoclonal]] pattern, suggesting that [[cancer]] arises from a single [[cell]]. 


Constitutive cAMP overproduction not only stimulates growth but also function.
* Activation of [[oncogenes]] is considered the underlying event leading to uncontrolled [[cell]] growth.  


Thyroid overgrowth stimulants:
=== (b) Neoplastic nodules ===
* [[Neoplastic disease|Neoplastic]] nodules development mainly involve the activation of [[Proto oncogenes|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 (biology)|cells]] ([[polyclonal]]). During nodule formation, cells replicate in a coordinated fashion simultanously, so each follicle of the nodule shares the same heterogenity with other [[Cell (biology)|cells]].
* [[Hyperplasia|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.<ref name="pmid19209125">{{cite journal |vauthors=Taccaliti A, Boscaro M |title=Genetic mutations in thyroid carcinoma |journal=Minerva Endocrinol. |volume=34 |issue=1 |pages=11–28 |year=2009 |pmid=19209125 |doi= |url=}}</ref><ref name="pmid10834397">{{cite journal |vauthors=Vecchio G, Santoro M |title=Oncogenes and thyroid cancer |journal=Clin. Chem. Lab. Med. |volume=38 |issue=2 |pages=113–6 |year=2000 |pmid=10834397 |doi=10.1515/CCLM.2000.017 |url=}}</ref><ref name="pmid7629379">{{cite journal |vauthors=Fusco A, Santoro M, Grieco M, Carlomagno F, Dathan N, Fabien N, Berlingieri MT, Li Z, De Franciscis V, Salvatore D |title=RET/PTC activation in human thyroid carcinomas |journal=J. Endocrinol. Invest. |volume=18 |issue=2 |pages=127–9 |year=1995 |pmid=7629379 |doi=10.1007/BF03349720 |url=}}</ref><ref name="pmid8806699">{{cite journal |vauthors=Fugazzola L, Pierotti MA, Vigano E, Pacini F, Vorontsova TV, Bongarzone I |title=Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer |journal=Oncogene |volume=13 |issue=5 |pages=1093–7 |year=1996 |pmid=8806699 |doi= |url=}}</ref><ref name="pmid8918855">{{cite journal |vauthors=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 |title=The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis |journal=JAMA |volume=276 |issue=19 |pages=1575–9 |year=1996 |pmid=8918855 |doi= |url=}}</ref><ref name="pmid1468509">{{cite journal |vauthors=Goretzki PE, Simon D, Röher HD |title=G-protein mutations in thyroid tumors |journal=Exp. Clin. Endocrinol. |volume=100 |issue=1-2 |pages=14–6 |year=1992 |pmid=1468509 |doi=10.1055/s-0029-1211167 |url=}}</ref>


Effectors of thyroid growth: external effectors are hormones, immunoglobulins and nutrients. Cells of the stromal apparatus (endothelium, lymphocytes, fibroblasts, monocytes/macrophages) cross-talk with follicular cells by the cytokines. A group of cytokines is produced by and acts on the thyroid cell itself. Most cytokines stimulate growth directly or through TSH. TGFβ, IFNγ, IL-6 and somatostatin exert an action of differentiation or inhibition of growth.
* 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
*** [[Thiourea]]
*** [[Methimazole]]
*** Ethylenethiourea (ETU)
*** [[Thiouracil]]
*** [[Propylthiouracil]]
** Aminotriazole: [[Herbicide]]
** Acetylaminofluorene (AAF)
** Use: [[Insecticide]]
** Oxydianiline (ODA)
** Use: Azo-Dye
** [[Methylene]] [[Benzenamine, 3-(trifluoromethyl)-|benzenamine]]
** Use: Dye intermediate
** [[Nitrosamine|Nitrosamines]]
** [[Nitrosourea|Nitrosoureas]] (NMU), (NBU), (ENU)
** Use: derivatives (BCNU, CCNU, MeCCNU) are drugs against [[Tumor|tumors]]
** [[Streptozocin]] (naturally occurring [[nitrosourea]]) is used in the treatment of islet-cell [[carcinoma]] of the [[pancreas]]


Hyperplasia development phase:
==== Papillary thyroid carcinoma ====
* The most important [[pathogenic]] factor involved in developing [[papillary thyroid cancer]] is an [[intracellular]] signaling pathway called [[Mitogen-activated protein kinase|MAPK]] pathyway ([[Mitogen-activated protein kinase|Mitogen-activated protein kinases]]), also known as ERK pathway ([[Extracellular signal-regulated kinases|extracellular signal-regulated kinase]]). After [[antigen]] binding to [[tyrosine]] receptors, [[Mitogen-activated protein kinase|MAPK]] is translocated into the [[Cell nucleus|nucleus]]. Receptor activation leads to [[cell division]], after [[phosphorylation]] by MEK (a [[serine]]/[[threonine]] [[kinase]]).
* Other steps leading to [[Mitogen-activated protein kinase|MAPK]] [[phosphorylation]] include [[phosphorylation]] of [[RAS]] which activates [[BRAF]], a [[serine]]/[[threonine]] [[kinase]] followed by MEK and [[Mitogen-activated protein kinase|MAPK]] [[phosphorylation]].
* In [[Papillary thyroid cancer|papillary thyroid carcinoma]], a [[somatic mutation]] may lead to activation of this linear signaling cascade.
* As a result, there will be increased [[Transcription (genetics)|transcription]] of [[nuclear]] [[proteins]], which lead to un-regulated activity and reproduction of [[cancerous]] [[Cells (biology)|cells]]. This implies that any single alteration is sufficient to play an early role in tumorigenesis.<ref name="pmid11390647">{{cite journal |vauthors=Melillo RM, Santoro M, Ong SH, Billaud M, Fusco A, Hadari YR, Schlessinger J, Lax I |title=Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade |journal=Mol. Cell. Biol. |volume=21 |issue=13 |pages=4177–87 |year=2001 |pmid=11390647 |pmc=87079 |doi=10.1128/MCB.21.13.4177-4187.2001 |url=}}</ref><ref name="pmid16946010">{{cite journal |vauthors=Ciampi R, Nikiforov YE |title=RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis |journal=Endocrinology |volume=148 |issue=3 |pages=936–41 |year=2007 |pmid=16946010 |doi=10.1210/en.2006-0921 |url=}}</ref>
'''Abbrevaitions:'''


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.
'''ERK:''' [[extracellular signal-regulated kinase]]; '''MAPK:''' [[mitogen-activated protein kinase]]


Neoplasia development phase:
=== (c) Colloid and cystic nodules ===


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. 
==== 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]] ([[Pseudopod|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. 


activated oncogenes are considered the underlying event leading to uncontrolled cell growth.
==== 2. Iodine related nodules pathogenesis: ====
[[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 Gland|thyroid]] [[Lysosome|lysosomes]] thereby inhibiting [[endocytosis]]
* [[Exocytosis]] inhibition: [[Iodine]] reduces the expression of the [[TSH receptor]] on the surface of [[Thyroid Gland|thyroid]] cells thereby inhibiting and decreasing colloid reabsorption
* [[Iodine]] excess in combination with [[Thyroid-stimulating hormone|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]].  


==== Colloid nodule ====
==== 3. Cystic thyroid nodules ====
These nodules are produced as a defect of intraluminal thyroglobulin reabsorption. 
Cystic thyroid nodules may be classified into the following types:
* [[Necrosis|Necrotic]] cystic nodules:
** May be due to a relative deficiency of [[blood]] supply:
*** Inadequate [[blood]] supply for [[neoplastic]] growth
*** Imbalance between [[angiogenesis]] and [[Cell (biology)|cell]] growth
*** Compression of new [[Blood vessel|vessels]] due to mass effect, leading to [[Cell (biology)|cell]] damage and [[necrosis]]
** [[Hyperplasia|Hyperplastic]] thyroid nodules may proceed towards [[necrosis]], colliquation, and [[pseudocyst]] formation
* [[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 [[Vascular endothelial growth factor|VEGF]]/VPF inside the cystic area
** [[VEGF]]/VPF lead to stimulation of [[vascular permeability]] and promoting the accumulation of [[fluids]] in the cysts
** [[Vascular endothelial growth factor|VEGF]]/VPF are particularly found in the cystic fluid of rapidly enlarging or recurrent cysts


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.
=== (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 examination|physical exam]], and are detected during [[thyroid]] [[scintigraphy]]. The most important thyroiditic diseases that may present as [[lymphocytic]] nodular [[thyroid]] are:
* Local [[infections]]:
** [[Pyogenic infection]]
**[[Tuberculosis]]
**[[Parasites]]
* [[De Quervain's thyroiditis|Subacute de Quervain’s]] thyroiditis
* [[Riedel's thyroiditis|Fibrosing (Riedel’s) thyroiditis]]
* [[Plasma cell]] [[granuloma]]
* [[Plasmacytoma]]
* Primary [[amyloid]] [[tumor]] and [[amyloidosis]]
* [[Thymoma]]
* [[Primary thyroid lymphoma]]
** Thyroiditic nodule due to [[Diffuse large B cell lymphoma|diffuse B-cell]] infiltration into [[lymphoma]] presented areas
* [[Histiocytosis X]]
* [[Medullary carcinoma of the thyroid|Medullary carcinoma]]
* [[Papillary carcinoma of the thyroid|Papillary carcinoma]]
** Thyroiditic nodule may be due to an [[immune response]] to some abnormal [[Thyroid Gland|thyroid]] antigen expressed in the [[tumor]]


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
* Go''oitrogenics:''
** Complex anions and inorganic atoms (iodine, lithium, CLO4–, TcO4–, BF4–), thiocyanate (SCN–)
** Thionamides that are used in the treatment of hyperthyroidism
** Goitrin, isolated in plants of the genus ''brassica''
** Aniline derivatives (sulfonamides, tolbutamide, sulfaguanidine, sulfamethoxazole, etc.)
** Phenol derivatives and polyhydroxyphenols
** Flavonoids act on thyroid metabolism by interacting with the nuclear receptor for thyroid hormones. Flavonoids such as vitaxin and others are inhibitors of TPO
** pesticides, environmental toxins such as isomers of DDD and DDT, polychlorinated biphenyls
* 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==
==Genetics==
*Some diseases are genetic, and have particular inheritance patterns, and express different phenotypes.
[[Genetic mutation]] is considered as one of the most important mechanisms of developing thyroid nodules, especially [[Thyroid Cancer|neoplastic thyroid nodules]]. Most of these [[mutations]] occur as [[Somatic mutation|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:
*The effect that genetics may have on the pathophysiology of a disease can be described in this section.
* Rare group of [[Cancer|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


* familial nonmedullary thyroid cancer (FNMTC):
==== The most important genetic mutations associated with thyroid neoplasia development ====
** 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
{| class="wikitable"
{| class="wikitable"
!Principal oncogenes and growth factors involved in thyroid carcinogenesis.
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Oncogenes and growth factors
!Gene mechanism
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Gene mechanism
!Mutation effect
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Mutation effect
!Neoplasia
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Neoplasia
|-
|-
|''N&H ras''
!''N&H [[Ras oncogene|ras]]''
|ras-constitutively bound to GAP (GTPase-activating protein)
|Activation of adenylate cyclase and calcium channels
|
|
* Adenoma
* [[Ras oncogene|Ras]]-constitutively bound to [[GTPase activating protein|GTPase-activating protein]] (GAP)
* Ca. papillary
|
* Follicular
* Activation of [[adenylate cyclase]] and [[calcium]] channels
* Anaplastic
|
* [[Adenomas]]
* [[Papillary carcinoma of the thyroid|Papillary carcinoma]]
* [[Follicular carcinoma of the Thyroid|Follicular carcinoma]]
* [[Anaplastic carcinoma of the thyroid|Anaplastic carcinoma]]
|-
|-
|RET (Receptor for glial-derived neurotrophic GF)
![[RET proto-oncogene|RET]]
|
|
* Fusion proteins with constitutive TK activities
* Encodes a receptor for glial-derived neurotrophic GF
* Dimerization of RET TKR
* Fusion proteins with constitutive thyrosine [[kinase]] activities
* Dimerization of RET thyrosine kinase receptors (TRK)
|
|
* Mitogenic through constitutive activation of TKR
* [[Mitogenic]] through constitutive activation of TKR
* Increased auto-phosphorylation and alteration of substrate specificity
* Increased auto-[[phosphorylation]] and alteration of substrate specificity
|
|
* Ca. papillary
* [[Papillary carcinoma of the thyroid|Papillary carcinoma]]
* MEN 2A
* [[MEN 2a|MEN 2A]]
* FMTC
* FMTC
* MEN 2B
* [[MEN 2B]]
|-
|-
|gsp
!Gsp
|Ribosylated GS-α at arginine 201
|
|Impairing of GTPase activity
* Ribosylated GS-α at [[arginine]] 201
|Hot adenomas
|
* Impairing of [[GTPase]] activity
|
* Hot adenomas
|-
|-
|c-MET (α and β subunit)
![[C-MET]] (α and β subunit)
|Increased receptors for HGF/SF
|
|Enhancement of receptor kinase activity
* Increased receptors for HGF/SF
|Ca. papillary (aggressive)
|
* Enhancement of receptor [[kinase]] activity
|
* [[Papillary carcinoma of the thyroid|Papillary carcinoma]]
|-
|-
|TRK
![[TRK]]
|Receptor for NGF
|
|Mitogen activated TK cascade
* Receptor for [[nerve]] [[growth factor]]
|Ca. papillary
|
* Mitogen activated TK cascade
|
* [[Papillary carcinoma of the thyroid|Papillary carcinoma]]
|-
|-
|EGF / EGF-R
!EGF / [[EGFR|EGF-R]]
|Lack of activation of p21/Waf l gene expression
|
|Loss of regulation at the critical G1 to S phase
* Competence factor in [[cell cycle]]
|Ca. anaplastic
|
* Transition through [[G0 phase|G0-G1 phase]]
|
* [[Anaplastic carcinoma of the thyroid|Anaplastic carcinoma]]
|-
|-
|p53
![[P53 (protein)|P53]]
|Lack of activation of p21/Waf l gene expression
|
|Loss of regulation at the critical G1 to S phase
* Lack of activation of p21/Waf l [[gene]] expression
|Ca. anaplastic
|
Papillary
* Loss of regulation at the critical [[G1 phase|G1]] to [[S phase]]
 
|
Follicular
* [[Anaplastic carcinoma of the thyroid|Anaplastic carcinoma]]
* [[Papillary carcinoma of the thyroid|Papillary carcinoma]]
* [[Follicular carcinoma of the Thyroid|Follicular carcinoma]]
|}
|}


==Associated Conditions==
==Associated Conditions==
*Preoperative serum TSH is an independent risk factor for predicting malignancy in a thyroid nodule, and is associated with: 18160464 23731273
Preoperative [[TSH|serum TSH]] is an independent [[risk factor]] for predicting malignancy in a thyroid nodule, and is associated with:<ref name="pmid18160464">{{cite journal |vauthors=Haymart MR, Repplinger DJ, Leverson GE, Elson DF, Sippel RS, Jaume JC, Chen H |title=Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage |journal=J. Clin. Endocrinol. Metab. |volume=93 |issue=3 |pages=809–14 |year=2008 |pmid=18160464 |pmc=2266959 |doi=10.1210/jc.2007-2215 |url=}}</ref><ref name="pmid23731273">{{cite journal |vauthors=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 |title=Prognosis of differentiated thyroid cancer in relation to serum thyrotropin and thyroglobulin antibody status at time of diagnosis |journal=Thyroid |volume=24 |issue=1 |pages=35–42 |year=2014 |pmid=23731273 |pmc=3887423 |doi=10.1089/thy.2013.0062 |url=}}</ref>
**Higher differentiated thyroid cancer stage
*Higher differentiated [[thyroid cancer]] stage
**Gross extrathyroidal extension
*Gross extrathyroidal extension
**Neck node metastases
*[[Neck]] [[Lymph node|node]] [[metastases]]
 
==Gross Pathology==
==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.
* On [[gross pathology]], cystic lesions, multiple or a single nodule, and encapsulated lesions are the most important and prevalent characteristic findings of thyroid nodules.
*This section is a good place to include pictures. Search for copyleft images on The Pathology Wiki [http://pathinfo.wikia.coom/wiki/Pathology_Resident_Wiki <nowiki>[1]</nowiki>] and Ask Dr. Wiki [http://askdrwiki.com/mediawiki/index.php?title=Category:Pathology <nowiki>[2]</nowiki>].
* On [[gross pathology]], [[follicular thyroid adenoma]] may present as a big lesion with thick capsule.
Microscopic pathology


4071393
== Microscopic Pathology ==
 
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<ref name="pmid4071393">{{cite journal |vauthors=Walfish PG, Strawbridge HT, Rosen IB |title=Management implications from routine needle biopsy of hyperfunctioning thyroid nodules |journal=Surgery |volume=98 |issue=6 |pages=1179–88 |year=1985 |pmid=4071393 |doi= |url=}}</ref><ref name="pmid19888858">{{cite journal |vauthors=Cibas ES, Ali SZ |title=The Bethesda System for Reporting Thyroid Cytopathology |journal=Thyroid |volume=19 |issue=11 |pages=1159–65 |year=2009 |pmid=19888858 |doi=10.1089/thy.2009.0274 |url=}}</ref><ref name="pmid27078145">{{cite journal |vauthors=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 |title=Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors |journal=JAMA Oncol |volume=2 |issue=8 |pages=1023–9 |year=2016 |pmid=27078145 |pmc=5539411 |doi=10.1001/jamaoncol.2016.0386 |url=}}</ref><ref name="pmid19888858">{{cite journal |vauthors=Cibas ES, Ali SZ |title=The Bethesda System for Reporting Thyroid Cytopathology |journal=Thyroid |volume=19 |issue=11 |pages=1159–65 |year=2009 |pmid=19888858 |doi=10.1089/thy.2009.0274 |url=}}</ref>
19888858
 
27078145
 
19888858
{| class="wikitable"
{| class="wikitable"
! colspan="2" |Cytology classification
! colspan="2" rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |[[Cytology]] classification
!Referred to
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Also referred to as:
!FNA
! colspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |Efficient diagnosis
!Surgical biopsy
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |May be seen in:
!May be seen in:
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" + |FNA cytology
!FNA cytology
|-
! align="center" style="background:#4479BA; color: #FFFFFF;" + |<small>FNA</small>
! align="center" style="background:#4479BA; color: #FFFFFF;" + |<small><small><small>Surgical biopsy</small></small></small>
|-
|-
| rowspan="5" |Follicular lesions 
! rowspan="5" |Follicular lesions 
|Benign (macrofollicular)
![[Benign]] (macrofollicular)
|
|
* Adenomatoid adenoma
* Adenomatoid [[adenoma]]
* Hyperplastic adenoma
* [[Hyperplastic]] [[adenoma]]
* Colloid adenoma
* Colloid [[adenoma]]
| +
| +
|
|
|
|
*Normal thyroid tissue
*Normal [[Thyroid Gland|thyroid]] [[Tissue (biology)|tissue]]
*Sporadic nodular goiter
*Sporadic nodular [[goiter]]
*Monoclonal macrofollicular tumors
*[[Monoclonal]] macrofollicular tumors
*Hyperplastic nodules
*[[Hyperplasia|Hyperplastic]] nodules
*Colloid adenomas (most common)
*Colloid adenomas (most common)
|
|
*May have areas of cystic degeneration with cellular debris and hemosiderin-laden macrophages
*May have areas of cystic degeneration with cellular debris and [[hemosiderin]]-laden [[macrophages]]
*Cellular characteristics:
*[[Cellular]] characteristics:
**Small and flat
**Small and flat
**Uniform in size
**Uniform in size
Line 232: Line 292:
**Follicle size may vary, with a few microfollicles interspersed among the macrofollicles, especially if the sample was obtained from an area close to the capsule of the lesion
**Follicle size may vary, with a few microfollicles interspersed among the macrofollicles, especially if the sample was obtained from an area close to the capsule of the lesion
*Colloid:
*Colloid:
**May smear across the slide or occasionally aggregated into droplets due to disruption of follicles during FNA
**May smear across the slide or occasionally aggregated into droplets due to disruption of follicles during [[FNA]]
**Stains blue on a Papanicolaou stain
**Stains blue on a [[Papanicolaou smear|Papanicolaou]] stain
**May be abundant in the background of macrofollicular lesions
**May be abundant in the background of macrofollicular lesions
|-
|-
|Follicular neoplasm/microfollicular 
![[Follicular neoplasm of thyroid|Follicular neoplasm]]/microfollicular 
|
|
* Cellular adenoma
* [[Cellular]] [[adenoma]]
* Indeterminate adenoma
* Indeterminate [[adenoma]]
* Trabecular adenoma
* Trabecular [[adenoma]]
|
|
| +
| +
|
|
* Follicular adenomas
* Follicular [[adenomas]]
* Follicular carcinomas
* Follicular [[carcinomas]]
* Follicular variant of papillary cancer
* Follicular variant of [[Papillary carcinoma of the thyroid|papillary cancer]]
* Occasionally from autonomously functioning thyroid nodules
* Occasionally from autonomously functioning thyroid nodules
|
|
Line 257: Line 317:
* Follicular carcinoma:
* Follicular carcinoma:
** Focal microscopic invasion
** Focal microscopic invasion
* Cellular or trabecular adenomas:
* [[Cellular]] or trabecular adenomas:
** Lesions with less definite or no follicle formation
** Lesions with less definite or no follicle formation
** May show vascular or capsule invasion
** May show vascular or capsule invasion
|-
|-
|Follicular lesion of undetermined significance (FLUS)
!Follicular lesion of undetermined significance (FLUS)
| rowspan="2" |
| rowspan="2" |
| rowspan="2" | +
| rowspan="2" | +
| rowspan="2" |
| rowspan="2" |
| rowspan="2" |common, especially in nodular goiters.
| rowspan="2" |
* Commonly, especially in nodular [[goiters]]
| rowspan="2" |
| rowspan="2" |
* FLUS:
* FLUS:
** the lesion has approximately equal number of macrofollicular fragments and microfollicles
** The lesion has approximately equal number of macrofollicular fragments and microfollicles
* AUS:
* AUS:
** cells with mild nuclear atypia
** [[Cells (biology)|Cells]] with mild [[nuclear]] atypia
* Mostly due to compromised speciemens:
* Mostly due to compromised speciemens:
** Poor fixation or obscuring blood (FLUS)
** Poor fixation or obscuring [[blood]] (FLUS)
|-
|-
|Atypia of undetermined significance (AUS)
!Atypia of undetermined significance (AUS)
|-
|-
|Hürthle cells 
![[Hurthle cells|Hürthle cells]] 
|
|
* Oncocytes
* Oncocytes
* Askanazy cells
* Askanazy cells
* Oxyphil cells
* [[Oxyphil cell|Oxyphil cells]]
| +
| +
|
|
|
|
* Focal Hürthle-cell change:
* Focal [[Hurthle cell carcinoma|Hürthle-cell]] change:
** Degenerating macrofollicular lesions
** Degenerating macrofollicular lesions
** Hashimoto's thyroiditis
** [[Hashimoto's thyroiditis]]
|
|
* Large polyclonal cells
* Large [[polyclonal]] [[Cells (biology)|cells]]
* Oxyphil cytoplasm
* [[Oxyphil cell|Oxyphil]] [[cytoplasm]]
* Considered benign if there is no evidence of vascular or capsular invasion
* Considered [[benign]] if there is no evidence of [[vascular]] or capsular invasion
* Considered malignant if invasion is present
* Considered [[malignant]] if invasion is present
** Hürthle-cell cancer
** [[Hurthle cell carcinoma|Hürthle-cell]] [[cancer]]
** Follicular cancer
** [[Follicular cancer of the thyroid|Follicular cancer]]
** Oxyphil cell type cancer
** [[Oxyphil cell]] type [[cancer]]
|-
|-
| colspan="2" |Papillary cancer
! colspan="2" |[[Papillary thyroid cancer|Papillary cancer]]
|
|
* The follicular variant of papillary cancer
* The follicular variant of papillary cancer
|
|
| +
| +
|Epithelioid giant cells  
|[[Epithelioid]] [[giant cells]]
*Papillary cancer
*[[Papillary thyroid cancer|Papillary cancer]]
*Degenerating areas of macrofollicular nodules
*Degenerating areas of macrofollicular nodules
*Subacute granulomatous thyroiditis  
*[[Subacute granulomatous thyroiditis]]
Psammoma bodies
[[Psammoma body|Psammoma bodies]]
* Papillary carcinoma
* [[Papillary carcinoma of the thyroid|Papillary carcinoma]]
* Benign thyroid lesions
* [[Benign]] [[Thyroid Gland|thyroid]] lesions
|
|
*Large cells and nuclei 
*Large [[Cells (biology)|cells]] and [[nuclei]] 
*Ground glass appearance of cytoplasm 
*Ground glass appearance of [[cytoplasm]] 
*Nuclei appearance:
*[[Nuclei]] appearance:
**Clefts 
**Clefts 
**Grooves 
**Grooves 
**Holes 
**Holes 
**Intranuclear cytoplasmic inclusions = Orphan Annie eyes 
**Intranuclear [[cytoplasmic]] inclusions = Orphan Annie eye
**Small nucleoli 
**Small [[nucleoli]] 
*Psammoma bodies
*Psammoma bodies
**Small laminated calcifications
**Small laminated calcifications
*Sticky colloid  
*Sticky colloid  
**Colloid "stick" to debris and cell clusters, instead of smearing across the slide
**Colloid "stick" to debris and cell clusters, instead of smearing across the slide
*Epithelioid giant cells  
*[[Epithelioid]] [[giant cells]]
**Can also be seen in:
**Can also be seen in:
***Degenerating areas of macrofollicular nodules
***Degenerating areas of macrofollicular nodules
***Subacute granulomatous thyroiditis  
***[[Subacute granulomatous thyroiditis]]
|-
|-
| colspan="2" |Medullary cancer 
! colspan="3" |[[Medullary carcinoma of thyroid|Medullary cancer]] 
|
|
| +
|
|
| +
* Medullary cancer
|Medullary cancer
|
|
*Spindle-shaped cells
*Spindle-shaped cells
*Frequently pleomorphic cells without follicle development
*Frequently [[pleomorphic]] [[Cells (biology)|cells]] without follicle development
*Supporting stroma may frequently stains for amyloid
*Supporting [[stroma]] may frequently stains for [[amyloid]]
*Red cytoplasmic granules
*Red [[cytoplasmic]] granules
*Eccentrically placed nuclei
*Eccentrically placed [[nuclei]]
*Slightly granular Cytoplasm that may be configured as a tear drop or cytoplasmic tail  
*Slightly granular [[cytoplasm]] that may be configured as a tear drop or [[cytoplasmic]] tail  
|-
|-
| colspan="2" |Anaplastic thyroid cancer
! colspan="3" |[[Anaplastic thyroid cancer]]
| +
|
|
| +
Large needle biopsy if needed
|
|
|Anaplastic thyroid cancer
* [[Anaplastic thyroid cancer]]
|
|
* Spindle cells
* [[Spindle cells]]
* Pleomorphic giant cell
* Pleomorphic [[giant cell]]
* Squamoid
* Squamoid
* Mitosis
* [[Mitosis]]
** Numerous mitotic figures
** Numerous [[mitotic]] figures
** Atypical mitoses
** Atypical [[mitoses]]
* Extensive necrosis.
* Extensive [[necrosis]]
|}
 
*Both [[polyclonal]] and [[monoclonal]] nodules appear similar on [[fine needle aspiration]] (FNA) (macrofollicular) and are [[benign]]
*The diagnosis of [[Follicular cancer of the thyroid|follicular cancer]] can not be made based on [[FNA]], because vascular or capsular invasion is required to make the diagnosis of [[Follicular cancer of the thyroid|follicular cancer]]. 8420446
 
 
==== Neoplastic thyroid nodules subclassification microscopic pathology: ====
{| class="wikitable"
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Neoplasm
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Subclass
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Features
!
|-
| rowspan="4" |Follicular [[Thyroid Gland|thyroid]] lesions
|Minimally invasive [[follicular carcinoma]]
|
* Only invasion of the capsule of the [[tumor]] without [[vascular]] invasion
|
|-
|Widely invasive [[follicular carcinoma]]
|
*Extensive invasion of the [[tumor]] capsule
*A multinodular [[tumor]] without a well-defined capsule invading the normal [[Thyroid Gland|thyroid]] surrounding the [[tumor]]
*Extensive [[vascular]] invasion (>4 foci of angioinvasion)
|
|-
|Encapsulated follicular variant of [[papillary thyroid cancer]]
| rowspan="2" |
* Minor [[vascular]] invasion (≤4 foci of angioinvasion within the [[tumor]] or capsule of the [[tumor]]) with or without capsular invasion
|
|-
|Infiltrative variant of [[papillary thyroid cancer]]
|
|-
| rowspan="8" |[[Papillary thyroid cancer]]
|Tall cell variant
|
* [[Tumor]] [[Cells (biology)|cells]] with [[eosinophilic]] [[cytoplasm]] that are twice as tall as they are wide
* The primary [[Tumor|tumors]] tend to be large 
* Often invasive, that many patients have both local and distant [[metastases]] at the time of diagnosis 
|
|-
|Insular varient
|
* Solid nests of tumor, often separated by fibrous bands, but the [[tumor cell]] nuclei have the same characteristics as do the [[nuclei]] of classical [[Papillary carcinoma of the thyroid|papillary cancers]]
|
|-
|Columnar variant
|
* Elongated cells with palisading [[nuclei]]
|
|-
|[[Hurthle cell carcinoma|Hürthle]] or [[Hurthle cell carcinoma|oxyphilic]] variant
|
* Cellular features of [[Hurthle cell carcinoma|Hürthle cell carcinomas]] but cells that are arranged in papillary formations.
|
|-
|Clear cell variant
|
* Clear cell view with clear [[cytoplasm]]
* Must be distinguished from [[Clear cell tumor|clear cell carcinomas]] of other organs such as the [[kidney]] or [[colon]] that have [[metastasized]] to the [[thyroid]]
|
|-
|Diffuse sclerosing variant
|
* Diffuse involvement of the [[thyroid]]
* Stromal [[fibrosis]]
* Prominent [[lymphocytic]] infiltration
|
|-
|Cribriform morular variant
|
* Prominent [[cribriform]] pattern with solid and [[Spindle cells|spindle cell]] areas as well as [[squamous]] morules
* Often associated with [[familial adenomatous polyposis]]
|
|-
|Hobnail variant
|
* Multifocal with variably sized complex papillary structures lined by [[Cells (biology)|cells]]
* [[Cells (biology)|Cells]] with increased [[nuclear]] to [[Cytoplasm|cytoplasmatic]] ratios
* Apically placed [[nuclei]] that lead to a surface bulge (hobnail appearance)
*: 19956062
|
|}
|}
*


==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 [http://pathinfo.wikia.coom/wiki/Pathology_Resident_Wiki <nowiki>[3]</nowiki>] and Ask Dr. Wiki [http://askdrwiki.com/mediawiki/index.php?title=Category:Pathology <nowiki>[4]</nowiki>].
*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==
==References==
{{reflist|2}}
{{reflist|2}}

Latest revision as of 15:35, 3 November 2017


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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.

Pathogenesis

A summary of thyroid nodule pathophysiology is presented in the slides below: [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]

(a) Hyperplastic nodules

1. TSH role in thyroid nodule formation

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:[32][33]

3. Hyperplasia development phase:
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. 
  • Activation of oncogenes is considered the underlying event leading to uncontrolled cell growth.

(b) Neoplastic nodules

Papillary thyroid carcinoma

Abbrevaitions:

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. 

2. Iodine related nodules pathogenesis:

Iodine excess can lead to colloid nodules in thyroid gland, leading to a 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:

(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:

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 non-medullary thyroid cancer (FNMTC), with the following features:

The most important genetic mutations associated with thyroid neoplasia development

Oncogenes and growth factors Gene mechanism Mutation effect Neoplasia
N&H ras
RET
  • Encodes a receptor for glial-derived neurotrophic GF
  • Fusion proteins with constitutive thyrosine kinase activities
  • Dimerization of RET thyrosine kinase receptors (TRK)
Gsp
  • Hot adenomas
C-MET (α and β subunit)
  • Increased receptors for HGF/SF
  • Enhancement of receptor kinase activity
TRK
  • Mitogen activated TK cascade
EGF / EGF-R
P53
  • Lack of activation of p21/Waf l gene expression
  • Loss of regulation at the critical G1 to S phase

Associated Conditions

Preoperative serum TSH is an independent risk factor for predicting malignancy in a thyroid nodule, and is associated with:[42][43]

Gross Pathology

Microscopic Pathology

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[44][45][46][45]

Cytology classification Also referred to as: Efficient diagnosis May be seen in: FNA cytology
FNA Surgical biopsy
Follicular lesions  Benign (macrofollicular) +
  • May have areas of cystic degeneration with cellular debris and hemosiderin-laden macrophages
  • Cellular characteristics:
    • Small and flat
    • Uniform in size
    • Non-crowded
    • Smeared colloid is seen in the background
    • Follicle size may vary, with a few microfollicles interspersed among the macrofollicles, especially if the sample was obtained from an area close to the capsule of the lesion
  • Colloid:
    • May smear across the slide or occasionally aggregated into droplets due to disruption of follicles during FNA
    • Stains blue on a Papanicolaou stain
    • May be abundant in the background of macrofollicular lesions
Follicular neoplasm/microfollicular  +
  • Well-developed microfollicles
  • Crowding of cells
    • May form clusters and clumps
  • Scant colloid
  • Varying nuclear atypia
  • Varying cellular pleomorphism
  • Follicular carcinoma:
    • Focal microscopic invasion
  • Cellular or trabecular adenomas:
    • Lesions with less definite or no follicle formation
    • May show vascular or capsule invasion
Follicular lesion of undetermined significance (FLUS) +
  • Commonly, especially in nodular goiters
  • FLUS:
    • The lesion has approximately equal number of macrofollicular fragments and microfollicles
  • AUS:
  • Mostly due to compromised speciemens:
    • Poor fixation or obscuring blood (FLUS)
Atypia of undetermined significance (AUS)
Hürthle cells  +
Papillary cancer
  • The follicular variant of papillary cancer
 + Epithelioid giant cells

Psammoma bodies

Medullary cancer  +
  • Medullary cancer
Anaplastic thyroid cancer +


Neoplastic thyroid nodules subclassification microscopic pathology:

Neoplasm Subclass Features
Follicular thyroid lesions Minimally invasive follicular carcinoma
  • Only invasion of the capsule of the tumor without vascular invasion
Widely invasive follicular carcinoma
  • Extensive invasion of the tumor capsule
  • A multinodular tumor without a well-defined capsule invading the normal thyroid surrounding the tumor
  • Extensive vascular invasion (>4 foci of angioinvasion)
Encapsulated follicular variant of papillary thyroid cancer
  • Minor vascular invasion (≤4 foci of angioinvasion within the tumor or capsule of the tumor) with or without capsular invasion
Infiltrative variant of papillary thyroid cancer
Papillary thyroid cancer Tall cell variant
Insular varient
Columnar variant
  • Elongated cells with palisading nuclei
Hürthle or oxyphilic variant
Clear cell variant
Diffuse sclerosing variant
Cribriform morular variant
Hobnail variant
  • Multifocal with variably sized complex papillary structures lined by cells
  • Cells with increased nuclear to cytoplasmatic ratios
  • Apically placed nuclei that lead to a surface bulge (hobnail appearance)
    19956062

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ Burch HB (1995). "Evaluation and management of the solid thyroid nodule". Endocrinol. Metab. Clin. North Am. 24 (4): 663–710. PMID 8608777.
  5. ↑ 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. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ Liekens S, De Clercq E, Neyts J (2001). "Angiogenesis: regulators and clinical applications". Biochem. Pharmacol. 61 (3): 253–70. PMID 11172729.
  13. ↑ 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.
  14. ↑ Gaskin D, Parai SK, Parai MR (1992). "Hashimoto's thyroiditis with medullary carcinoma". Can J Surg. 35 (5): 528–30. PMID 1356609.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ Gharib H (1997). "Changing concepts in the diagnosis and management of thyroid nodules". Endocrinol. Metab. Clin. North Am. 26 (4): 777–800. PMID 9429860.
  18. ↑ 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.
  19. ↑ Greenspan FS (1991). "The problem of the nodular goiter". Med. Clin. North Am. 75 (1): 195–209. PMID 1987443.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ Livolsi VA, Merino MJ (1981). "Histopathologic differential diagnosis of the thyroid". Pathol Annu. 16 (Pt 2): 357–406. PMID 7036066.
  24. ↑ 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.
  25. ↑ Maceri DR, Sullivan MJ, McClatchney KD (1986). "Autoimmune thyroiditis: pathophysiology and relationship to thyroid cancer". Laryngoscope. 96 (1): 82–6. PMID 3484533.
  26. ↑ 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.
  27. ↑ McKee RF, Krukowski ZH, Matheson NA (1993). "Thyroid neoplasia coexistent with chronic lymphocytic thyroiditis". Br J Surg. 80 (10): 1303–4. PMID 8242306.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ Gaitan E (1990). "Goitrogens in food and water". Annu. Rev. Nutr. 10: 21–39. doi:10.1146/annurev.nu.10.070190.000321. PMID 1696490.
  34. ↑ Taccaliti A, Boscaro M (2009). "Genetic mutations in thyroid carcinoma". Minerva Endocrinol. 34 (1): 11–28. PMID 19209125.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
  41. ↑ 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.
  42. ↑ 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.
  43. ↑ 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.
  44. ↑ 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. ↑ 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.
  46. ↑ 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.

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