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.
[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.
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 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].
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 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].
[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.
Development of [disease name] is the result from multiple genetic mutations.
Genes involved in the [[pathogenesis]] of [disease name] include [gene1], [gene2], and [gene3].
Genes involved in the [[pathogenesis]] of [disease name] include [gene1], [gene2], and [gene3].
The progression to [disease name] usually involves the [molecular pathway].
The progression to [disease name] usually involves the [molecular pathway].
The pathophysiology of [disease name] depends on the histological subtype.
The pathophysiology of [disease name] depends on the histological subtype.
==Pathogenesis==
==Pathogenesis==
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{{#widget:ThyroidNodulePatho}}
{{#widget:ThyroidNodulePatho}}
<ref name="pmid3755697">{{cite journal |vauthors=Aozasa K, Inoue A, Katagiri S, Matsuzuka F, Katayama S, Yonezawa T |title=Plasmacytoma and follicular lymphoma in a case of Hashimoto's thyroiditis |journal=Histopathology |volume=10 |issue=7 |pages=735–40 |year=1986 |pmid=3755697 |doi= |url=}}</ref><ref name="pmid862558">{{cite journal |vauthors=Bastomsky CH |title=Enhanced thyroxine metabolism and high uptake goiters in rats after a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin |journal=Endocrinology |volume=101 |issue=1 |pages=292–6 |year=1977 |pmid=862558 |doi=10.1210/endo-101-1-292 |url=}}</ref><ref name="pmid8612537">{{cite journal |vauthors=Brix K, Lemansky P, Herzog V |title=Evidence for extracellularly acting cathepsins mediating thyroid hormone liberation in thyroid epithelial cells |journal=Endocrinology |volume=137 |issue=5 |pages=1963–74 |year=1996 |pmid=8612537 |doi=10.1210/endo.137.5.8612537 |url=}}</ref><ref name="pmid8608777">{{cite journal |vauthors=Burch HB |title=Evaluation and management of the solid thyroid nodule |journal=Endocrinol. Metab. Clin. North Am. |volume=24 |issue=4 |pages=663–710 |year=1995 |pmid=8608777 |doi= |url=}}</ref><ref name="pmid2627756">{{cite journal |vauthors=Coclet J, Foureau F, Ketelbant P, Galand P, Dumont JE |title=Cell population kinetics in dog and human adult thyroid |journal=Clin. Endocrinol. (Oxf) |volume=31 |issue=6 |pages=655–65 |year=1989 |pmid=2627756 |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="pmid2164546">{{cite journal |vauthors=Di Carlo A, Mariano A, Pisano G, Parmeggiani U, Beguinot L, Macchia V |title=Epidermal growth factor receptor and thyrotropin response in human thyroid tissues |journal=J. Endocrinol. Invest. |volume=13 |issue=4 |pages=293–9 |year=1990 |pmid=2164546 |doi=10.1007/BF03349565 |url=}}</ref><ref name="pmid1661579">{{cite journal |vauthors=Dumont JE, Maenhaut C, Pirson I, Baptist M, Roger PP |title=Growth factors controlling the thyroid gland |journal=Baillieres Clin. Endocrinol. Metab. |volume=5 |issue=4 |pages=727–54 |year=1991 |pmid=1661579 |doi= |url=}}</ref><ref name="pmid7920658">{{cite journal |vauthors=Duprez L, Parma J, Van Sande J, Allgeier A, Leclère J, Schvartz C, Delisle MJ, Decoulx M, Orgiazzi J, Dumont J |title=Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism |journal=Nat. Genet. |volume=7 |issue=3 |pages=396–401 |year=1994 |pmid=7920658 |doi=10.1038/ng0794-396 |url=}}</ref><ref name="pmid1995765">{{cite journal |vauthors=Ericsson UB, Lindgärde F |title=Effects of cigarette smoking on thyroid function and the prevalence of goitre, thyrotoxicosis and autoimmune thyroiditis |journal=J. Intern. Med. |volume=229 |issue=1 |pages=67–71 |year=1991 |pmid=1995765 |doi= |url=}}</ref><ref name="pmid8026388">{{cite journal |vauthors=Farid NR, Shi Y, Zou M |title=Molecular basis of thyroid cancer |journal=Endocr. Rev. |volume=15 |issue=2 |pages=202–32 |year=1994 |pmid=8026388 |doi=10.1210/edrv-15-2-202 |url=}}</ref><ref name="pmid11172729">{{cite journal |vauthors=Liekens S, De Clercq E, Neyts J |title=Angiogenesis: regulators and clinical applications |journal=Biochem. Pharmacol. |volume=61 |issue=3 |pages=253–70 |year=2001 |pmid=11172729 |doi= |url=}}</ref><ref name="pmid7714083">{{cite journal |vauthors=Gaitan E, Cooksey RC, Legan J, Lindsay RH |title=Antithyroid effects in vivo and in vitro of vitexin: a C-glucosylflavone in millet |journal=J. Clin. Endocrinol. 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>
<ref name="pmid3755697">{{cite journal |vauthors=Aozasa K, Inoue A, Katagiri S, Matsuzuka F, Katayama S, Yonezawa T |title=Plasmacytoma and follicular lymphoma in a case of Hashimoto's thyroiditis |journal=Histopathology |volume=10 |issue=7 |pages=735–40 |year=1986 |pmid=3755697 |doi= |url=}}</ref><ref name="pmid862558">{{cite journal |vauthors=Bastomsky CH |title=Enhanced thyroxine metabolism and high uptake goiters in rats after a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin |journal=Endocrinology |volume=101 |issue=1 |pages=292–6 |year=1977 |pmid=862558 |doi=10.1210/endo-101-1-292 |url=}}</ref><ref name="pmid8612537">{{cite journal |vauthors=Brix K, Lemansky P, Herzog V |title=Evidence for extracellularly acting cathepsins mediating thyroid hormone liberation in thyroid epithelial cells |journal=Endocrinology |volume=137 |issue=5 |pages=1963–74 |year=1996 |pmid=8612537 |doi=10.1210/endo.137.5.8612537 |url=}}</ref><ref name="pmid8608777">{{cite journal |vauthors=Burch HB |title=Evaluation and management of the solid thyroid nodule |journal=Endocrinol. Metab. Clin. North Am. |volume=24 |issue=4 |pages=663–710 |year=1995 |pmid=8608777 |doi= |url=}}</ref><ref name="pmid2627756">{{cite journal |vauthors=Coclet J, Foureau F, Ketelbant P, Galand P, Dumont JE |title=Cell population kinetics in dog and human adult thyroid |journal=Clin. Endocrinol. (Oxf) |volume=31 |issue=6 |pages=655–65 |year=1989 |pmid=2627756 |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="pmid2164546">{{cite journal |vauthors=Di Carlo A, Mariano A, Pisano G, Parmeggiani U, Beguinot L, Macchia V |title=Epidermal growth factor receptor and thyrotropin response in human thyroid tissues |journal=J. Endocrinol. Invest. |volume=13 |issue=4 |pages=293–9 |year=1990 |pmid=2164546 |doi=10.1007/BF03349565 |url=}}</ref><ref name="pmid1661579">{{cite journal |vauthors=Dumont JE, Maenhaut C, Pirson I, Baptist M, Roger PP |title=Growth factors controlling the thyroid gland |journal=Baillieres Clin. Endocrinol. Metab. |volume=5 |issue=4 |pages=727–54 |year=1991 |pmid=1661579 |doi= |url=}}</ref><ref name="pmid7920658">{{cite journal |vauthors=Duprez L, Parma J, Van Sande J, Allgeier A, Leclère J, Schvartz C, Delisle MJ, Decoulx M, Orgiazzi J, Dumont J |title=Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism |journal=Nat. Genet. |volume=7 |issue=3 |pages=396–401 |year=1994 |pmid=7920658 |doi=10.1038/ng0794-396 |url=}}</ref><ref name="pmid1995765">{{cite journal |vauthors=Ericsson UB, Lindgärde F |title=Effects of cigarette smoking on thyroid function and the prevalence of goitre, thyrotoxicosis and autoimmune thyroiditis |journal=J. Intern. Med. |volume=229 |issue=1 |pages=67–71 |year=1991 |pmid=1995765 |doi= |url=}}</ref><ref name="pmid8026388">{{cite journal |vauthors=Farid NR, Shi Y, Zou M |title=Molecular basis of thyroid cancer |journal=Endocr. Rev. |volume=15 |issue=2 |pages=202–32 |year=1994 |pmid=8026388 |doi=10.1210/edrv-15-2-202 |url=}}</ref><ref name="pmid11172729">{{cite journal |vauthors=Liekens S, De Clercq E, Neyts J |title=Angiogenesis: regulators and clinical applications |journal=Biochem. Pharmacol. |volume=61 |issue=3 |pages=253–70 |year=2001 |pmid=11172729 |doi= |url=}}</ref><ref name="pmid7714083">{{cite journal |vauthors=Gaitan E, Cooksey RC, Legan J, Lindsay RH |title=Antithyroid effects in vivo and in vitro of vitexin: a C-glucosylflavone in millet |journal=J. Clin. Endocrinol. 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 cells in thyroid parenchyma. The [[pathogenesis]] of developing a thyroid nodule differ based on the type of the nodule, and whether it is malignant or benign. Basically thyroid nodules may develop secondaru to hyperplasia, neoplastic mutations and secondary carcinoma, excess colloid accumulation, and inflammation of thyroid tissue.


=== Hyperplastic nodules ===
=== Hyperplastic nodules ===

Revision as of 20:17, 19 October 2017


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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

A summary of thyroid nodule pathophysiology is presented in the powerpoint 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]

Thyroid nodules may arise from different cells in thyroid parenchyma. The pathogenesis of developing a thyroid nodule differ based on the type of the nodule, and whether it is malignant or benign. Basically thyroid nodules may develop secondaru to hyperplasia, neoplastic mutations and secondary carcinoma, excess colloid accumulation, and inflammation of thyroid tissue.

Hyperplastic nodules

Hyperplastic nodule pathogenesis seems to start with an increase in thyroid proliferation, which lead to thyroid hyperplasia. Rapid thyroid proliferation mainly occur in response to certain stimulants. Stimulants mainly act through TSH mediated activity and production. Following the hyperplasia development phase, a new phase may begin, leading to a neoplasia.

TSH role in thyroid nodule formation

Growth signals in thyroid tissue start their pathways by an stimulant, that attaches to the thyroid receptors. The following signals can be transmitted through 3 distinct pathways:

The most important and effective pathway for thyroid growth is the activation of adenylate cyclase/protein kinase A system. Activation of phospholipase C and phospholipase A2 have only a minor or absent effect on thyroid growth.

TSH acts as an stimulant by binding to the receptor and activating both the adenylate cyclase and phospholipase C pathways. As mentioned, the phospholipase C pathways has minor effects, and most of the TSH effect on cell growth is generated by adenylate cyclase pathway. The signal generated by the adenylate cyclase cAMP-dependent pathways is then transduced into the nucleus where transcription factors–upon phosphorylation–induce the expression of cAMP-inducible genes. It has been definitely established that TSH has a main mitogenic role, through cAMP, Gs proteins and protein kinase A, which activates the metabolic cascade leading to the stimulation of growth.

However, to produce hyperplasia, overproduction of cAMP must be continuous, as it occurs in mutations constitutive of the genes which regulate cAMP production. Constitutive cAMP overproduction has been demonstrated to be due to point mutation of the TSH receptor or Gs protein

Constitutive cAMP overproduction not only stimulates growth but also function.

Hyperplastic thyroid nodule pathogenesis can be divided into 2 phases:

1. Thyroid overgrowth stimulants:

Thyroid normally has a low proliferative activity, although it can start proliferation rapidly in response to certain stimulants. Stimulants mainly act through TSH mediated activity and production. The following stimulants look like to have the most important role in pathogenesis of hyperplastic nodules:[32][33]

  • Iodine deficiency:
    • Effects directly or indirectly 
    • The most important potent stimulator of the replicative potential of the gland 
    • Mechanism of action:
      • Acting as an initiator for TSH rise
      • May enhance the effect of other chemicals that induce a rise in TSH by inducing the promotor overactivity
      • The most important reason of high prevalence of thyroid hyperplasia and nodules in iodine-deficient areas
  • Industrial chemicals:
    • DDT
    • Polychlorinated byphenyls
    • Pesticides
  • Goitrogens:
    • Complex anions and inorganic atoms (iodine, lithium, CLO4–, TcO4–, BF4–)
    • Thiocyanate (SCN–)
    • Goitrin, isolated in plants of the genus brassica
    • Aniline derivatives (sulfonamides, tolbutamide, sulfaguanidine, sulfamethoxazole, etc.)
    • Phenol derivatives and polyhydroxyphenols
    • Flavonoids:
      • TPO inhibitors
      • Also act on thyroid metabolism by interacting with the nuclear receptor for thyroid hormones
  • Antithyroid drugs:
    • Thionamides that are used in the treatment of hyperthyroidism
  • Tobacco:
    • May be the reason of high prevalence of thyroid hyperplasia and nodules in iodine-sufficient areas 

Thyroid stromal cells interact with thyroid follicular cells by cytokines. Inappropriate cytokine activities also seem to be related to TSH overproduction and thyroid hyperplastic nodule formation. The most important cytokines that can exert an action of differentiation or inhibition of thyroid growth are:

  • TGFβ
  • IFNγ
  • IL-6
  • Somatostatin
2. Hyperplasia development phase:

Thyroid cells produce the angiogenic vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) sensitive to TSH stimulation. The vascular growth factor induces neovascularization by binding to specific receptors on endothelial cells and stimulating new vessel production. In response, endothelial cells produce growth factors that increase thyroid proliferaion and lead to thyroid hyperplasia. Neovascularization in thyroid matrix is accompanied by the production of proteolytic enzymes, which facilitate the expansion of thyroid tissue into the extracellular matrix.

Neoplasia development phase:

each follicle is composed of different clones of cells (polyclonal) but during nodule formation they replicate in a simultaneous and coordinated manner, so each follicle of the nodule reproduces the same heterogeneity of the mother follicle. When a neoplasm arises in the nodule, then the neoplastic follicle shows a monoclonal pattern, suggesting that cancer arises from a single cell. 

activated oncogenes are considered the underlying event leading to uncontrolled cell growth.

Neoplastoc nodules

Neoplastic nodules development mainly involve the activation of proto-oncogenes as the underlying event leading to uncontrolled cell growth. Proto-oncogens activation are associated with thyroid adenoma, hyperplasia, and malignancies. Thyroid gland is made of different follicles, and each follicle is composed of different clones of cells (polyclonal). During nodule formation, cells replicate in a coordinated way simultanously, so each follicle of the nodule share the same heterogenity with other cells. Hyperplastic thyroid nodules are considered as risk factor for neoplasia development, as these cells may express neoplasia during their rapid proliferation phase. During neoplasm formation in the nodule, the neoplastic follicle mostly shows a monoclonal pattern. These findings may indicate that neoplasia arises from a single cell genetic mutation. The most important oncogens related to thyroid neoplasia development are mentioned in the genetic table below.[34][35][36][37][38][39]

Environmental factors can play an important role in triggering the oncogen mutation. The most important carcinogens involved in the pathogenesis of neoplastic thyroid nodules are:

  • Thionamid compounds
    • Thiourea
    • Methimazole
    • Ethylenethiourea (ETU)
    • Thiouracil
    • Propylthiouracil
  • Aminotriazole: Herbicide
  • Acetylaminofluorene (AAF)
    • Use: Insecticide
  • Oxydianiline (ODA)
    • Use: Azo-Dye
  • Methylene benzenamine
    • Use: Dye intermediate
  • Nitrosamines
  • Nitrosoureas (NMU), (NBU), (ENU)
    • Use: derivatives (BCNU, CCNU, MeCCNU) are drugs against tumors
    • Streptozocin (naturally occurring nitrosourea) is used in the treatment of islet-cell carcinoma of the pancreas)

Papillary thyroid carcinoma

The most important pathogenic factor in developing papillary thyroid cancer is related to intracellular signaling pathway calldes MAPK (Mitogen-activated protein kinases), tha can also be called as ERK pathway (extracellular signal-regulated kinase). Antigen binding to thyrosine receptors, MAPK is translocated into the nucleus. As an intracellular receptor activity, it promotes cell division when it is phosphorylated by MEK (a serine/threonine kinase). Other steps leading to MAPK physphorylation include phosphorylation of RAS which activates BRAF, a serine/threonine kinase followed by MEK and MAPK phosphorylation. In papillary thyroid carcinoma, a somatic genetic mutation in each one of these steps may lead to activation of this linear signaling cascade. As the end result of the mutations, there will be more transcription of nuclear proteins, which lead to unregulated activity and reproduction of cancerous cells. It suggests that any single alteration is sufficient to play an early role in tumorigenesis.

ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase. thyrosin kinase RAS BRAF MEK MAPK nucleus tumorogenesis[40][41]

Colloid and cystic nodules

Colloid nodules

The colloid nodules consist of colloid droplets and thyroglobulin vesicles. Thyroid gland keeps a balance between colloid and thyroglobulin production by interacting between secretion of thyroglobulin into colloid and reabsorption of colloid into thyroid follicular cells. The mentioned interaction is processed by macro-pinocytosis (pseudopods) and micro-pinocytosis (microvilli). Any imbalance between secretion and reabsorption of thyroglobulin equilibrium produces a colloid appeared thyroid nodule. These nodules may also be produced as a defect of intraluminal thyroglobulin reabsorption. 

Iodine related nodules pthogenesis:

Iodine excess can lead to colloid nodules in thyroid gland, leading to a colloid goitre. The mechanism is due to several idoine effects on thyroid cells:

  • Endocytosis inhibition: High dosage of iodine may lead to inhibition of the protease activity of thyroid lysosomes, and thereby inhibiting endocytosis
  • Exocytosis inhibition: Iodine reduces the expression of the TSH receptor on the surface of thyroid cells, and thereby inhibiting and decreasing colloid reabsorption
  • Iodine excess in combination with TSH over activity may lead to colloid goitre

Another mechanism that may lead to colloid goitre formation is due to loss of thyroglobulin packaging ability, that may lead to an enormous enlargement of the follicles and flattening of the epithelium. Therefore a colloid nodular goitre can be made.

Cystic thyroid nodules

Cystic thyroid nodules can be classified into the following types:

  • Necrotic cystic nodules:
    • May be due to a relative insufficiency of blood supply
      • Inadequate blood supply for a neoplastic cells growth
      • Imbalance between angiogenesis and cell growth
      • Compression of new vessels due to lack of cellular outgrow, leading to cell damage, necrosis and colliquation
    • Hyperplastic thyroid nodules may proceed towards necrosis, colliquation, and pseudocyst formation
  • Serum-like cystic nodules:
    • May be related to autoimmunity
  • Apoptotic cystic nodules:
    • Cysts that may be related to normal cellular apoptosis or neoplastic/infected cellular apoptosis
  • Vascular growth factor related cystic nodules:
    • Cyst formation may be the result of an increased concentration of VEGF/VPF inside the cystic area
    • VEGF/VPF lead to stimulation of vascular permeability and promoting the accumulation of fluids in the cysts
    • VEGF/VPF are particularly found in the cystic fluid of rapidly enlarging or recurrent cysts

Thyroiditic nodule

Nodular lymphocytic thyroiditis almost always present in combination with other thyroiditic diseases. They can also present as a part of infection. It has been shown that the ability of super antigens (SAgs) to activate the immune system may play a role in the course of autoimmune disorders. In most of these thyroiditis diseases, the mechanism of nodular lesion is the same as the mechanism of the main disease, meaning that the thyroid nodule is a part of normal disease pattern. Many of these nodules are not identifiable based on physical exam, and are detected during thryoid scintigraphy. The most important thyroiditic diseases that may present as lymphocytic nodular thyroid are:

  • Local infections:
    • Piogenic infection
    • Tuberculosis
    • Parasites
  • Subacute de Quervain’s thyroiditis
  • Fibrosing (Riedel’s) thyroiditis
  • Plasmacell granuloma
  • Plasmacytoma
  • Primary amyloid tumor and amyloidosis
  • Thymoma
  • Primary thyroid lymphoma
    • Thyroiditic nodule due to diffuse B-cell infiltration into lymphoma presented areas
  • Histocytosis X
  • Medullary carcinoma
  • Papillary carcinoma
    • Thyroiditic nodule may be due to an immune response to some abnormal thyroid antigen expressed in the tumor

Genetics

Genetic mutation is considered as one of the most important mechanisms of developing thyroid nodules, especially neoplastic thyroid nodules. Most of these mutations occur as somatic mutations, while some may occur in a familial order. The most important category of familial thyroid cancers are due to genetic mutations, and are called familial nonmedullary thyroid cancer FNMTC, with the following features:

  • A rare group ofcancers
  • Mostly related to non-medullary tumors
  • Inheritance: autosomal dominant with incomplete penetrance and variable expressivity
  • Affected patients have a earlier age of thyroid cancer onset
  • Associated with:
    • More benign thyroid nodules
    • Multifocal disease
    • A higher rate of locoregional recurrence

The most important genetic mutations associated with thyroid neoplasia development

Oncogenes and growth factors Gene mechanism Mutation effect Neoplasia
N&H ras
  • Ras-constitutively bound to GTPase-activating protein (GAP)
  • Activation of adenylate cyclase and calcium channels
RET
  • Encodes a receptor for glial-derived neurotrophic GF
  • Fusion proteins with constitutive thyrosine kinase activities
  • Dimerization of RET thyrosine kinase receptors (TRK)
  • Mitogenic through constitutive activation of TKR
  • Increased auto-phosphorylation and alteration of substrate specificity
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
TRK
  • Receptor for nerve growth factor
  • Mitogen activated TK cascade
EGF / EGF-R
  • Competence factor in cell cycle
  • Transition through G0-G1 phase
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]

  • Higher differentiated thyroid cancer stage
  • Gross extrathyroidal extension
  • Neck node metastases

Gross Pathology

  • On gross pathology, cystic lesions, multiple or a single nodule, and encapsulated lesions are the most important and prevalent characteristic findings of thyroid nodules.
  • On gross pathology, follicular thyroid adenoma may present as a big lesion with thick capsule.

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)
  • Adenomatoid adenoma
  • Hyperplastic adenoma
  • Colloid adenoma
 +
  • Normal thyroid tissue
  • Sporadic nodular goiter
  • Monoclonal macrofollicular tumors
  • Hyperplastic nodules
  • Colloid adenomas (most common)
  • 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 
  • Cellular adenoma
  • Indeterminate adenoma
  • Trabecular adenoma
 +
  • Follicular adenomas
  • Follicular carcinomas
  • Follicular variant of papillary cancer
  • Occasionally from autonomously functioning thyroid nodules
  • 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:
    • Cells with mild nuclear atypia
  • Mostly due to compromised speciemens:
    • Poor fixation or obscuring blood (FLUS)
Atypia of undetermined significance (AUS)
Hürthle cells 
  • Oncocytes
  • Askanazy cells
  • Oxyphil cells
 +
  • Focal Hürthle-cell change:
    • Degenerating macrofollicular lesions
    • Hashimoto's thyroiditis
  • Large polyclonal cells
  • Oxyphil cytoplasm
  • Considered benign if there is no evidence of vascular or capsular invasion
  • Considered malignant if invasion is present
    • Hürthle-cell cancer
    • Follicular cancer
    • Oxyphil cell type cancer
Papillary cancer
  • The follicular variant of papillary cancer
 + Epithelioid giant cells
  • Papillary cancer
  • Degenerating areas of macrofollicular nodules
  • Subacute granulomatous thyroiditis

Psammoma bodies

  • Papillary carcinoma
  • Benign thyroid lesions
  • Large cells and nuclei 
  • Ground glass appearance of cytoplasm 
  • Nuclei appearance:
    • Clefts 
    • Grooves 
    • Holes 
    • Intranuclear cytoplasmic inclusions = Orphan Annie eyes 
    • Small nucleoli 
  • Psammoma bodies
    • Small laminated calcifications
  • Sticky colloid
    • Colloid "stick" to debris and cell clusters, instead of smearing across the slide
  • Epithelioid giant cells
    • Can also be seen in:
      • Degenerating areas of macrofollicular nodules
      • Subacute granulomatous thyroiditis
Medullary cancer  +
  • Medullary cancer
  • Spindle-shaped cells
  • Frequently pleomorphic cells without follicle development
  • Supporting stroma may frequently stains for amyloid
  • Red cytoplasmic granules
  • Eccentrically placed nuclei
  • Slightly granular Cytoplasm that may be configured as a tear drop or cytoplasmic tail
Anaplastic thyroid cancer +
  • Anaplastic thyroid cancer
  • Spindle cells
  • Pleomorphic giant cell
  • Squamoid
  • Mitosis
    • Numerous mitotic figures
    • Atypical mitoses
  • Extensive necrosis.
  • Both polyclonal and monoclonal nodules appear similar on fine needle aspiration (FNA) (macrofollicular) and are benign 8426623
  • The diagnosis of follicular cancer can not be made based on FNA, because vascular or capsular invasion is required to make the diagnosis of follicular cancer. 8420446


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
  • Tumor cells with eosinophilic cytoplasm that are twice as tall as they are wide
  • The primary 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 cancers.
Columnar variant
  • Elongated cells with palisading nuclei.
Hürthle or oxyphilic variant
  • Cellular features of Hürthle cell carcinomas but cells that are arranged in papillary formations.
Clear cell variant
Diffuse sclerosing variant
  • Diffuse involvement of the thyroid
  • Stromal fibrosis
  • Prominent lymphocytic infiltration
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

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  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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