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__NOTOC__
__NOTOC__
{{Papillary thyroid cancer}}
{{Papillary thyroid cancer}}
{{CMG}}; {{AE}} {{Ammu}}
{{CMG}}; {{AE}} {{Sahar}} {{Ammu}}
==Overview==
==Overview==
On gross pathology, a painless enlarging mass is a characteristic finding of papillary thyroid cancer. On microscopic histopathological analysis, Orphan Annie eye nuclear inclusions and [[psammoma]] bodies are characteristic findings of papillary thyroid cancer.
The exact [[pathogenesis]] of papillary thyroid cancer is not fully understood. Papillary thyroid cancer has been associated with [[somatic]] [[rearrangement]] of [[RET proto-oncogene|RET protooncogene]]. On gross [[pathology]], an ill-defined [[tumor]], irregular [[borders]], and firm consistency are characteristic findings of papillary thyroid cancer. There is no unique consensus on the definition of [[histological]] [[subtypes]] of papillary thyroid cancer.
==Physiology==
* The [[mitogen-activated protein kinase]] ([[MAPK]]) pathway is involved in signal transduction of [[receptor tyrosine kinase]] such as [[RET proto-oncogene|RET]] and [[NTRK1]].<ref name="pmid16434896">{{cite journal |vauthors=Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, Biddinger PW, Nikiforov YE |title=Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas |journal=Am. J. Surg. Pathol. |volume=30 |issue=2 |pages=216–22 |date=February 2006 |pmid=16434896 |doi= |url=}}</ref>
*[[Tyrosine kinase]] [[receptor]] activation leads to [[RAS]] activation which subsequently result in [[GTP]] substitution of GDP. The [[GTP-binding protein|GTP]]-bound form of [[RAS]] makes [[BRAF]] active which in turn activates [[MAP kinase kinase kinase|MEK]] and [[ERK]].
*[[ERK]] is engaged in the regulation of [[gene transcription]] including [[cell differentiation]], [[proliferation]], and survival.
 
 
{{familytree/start |summary=Sample 1}}
{{familytree | | | | | | | E04 | | | | | | |E04=Growth factor binds to [[Receptor]] [[tyrosine kinase]] ([[RET]], [[NTRK1]])}}
{{familytree | | | | | | | |!| | | | | | | |}}
{{familytree | | | | | | | E05 | | | | | | |E05=GDP substitution by [[GTP]]}}
{{familytree | | | | | | | |!| | | | | | | |}}
{{familytree | | | | | | | C05 | | | | | | |C05=[[RAS]] activation}}
{{familytree | | | | | | | |!| | | | | | | |}}
{{familytree | | | | | | | C04 | | | | | | |C04=[[BRAF]] activation}}
{{familytree | | | | | | | |!| | | | | | | |}}
{{familytree | | | | | | | D05 | | | | | | |D05=[[MEK]] ativation}}
{{familytree | | | | | | | |!| | | | | | | |}}
{{familytree | | | | | | | G05 | | | | | | |G05=[[ERK]] activation}}
{{familytree | | | | | | | |!| | | | | | | |}}
{{familytree | | |,|-|-|-|-|+|-|-|-|-|.| | |}}
{{familytree | | B01 | | | B02 | | | B03 | |B01=[[cell differentiation]]|B02=cell [[proliferation]]|B03=cell survival}}
 
 
{|
! colspan="2" style="background:#DCDCDC;" align="center" + |The above algorithm is adopted from Endocrine patology book<ref name="Lloyd2010">{{cite journal|last1=Lloyd|first1=Ricardo V.|year=2010|doi=10.1007/978-1-4419-1069-1}}</ref>
|-
|}
 
==Pathogenesis==
==Pathogenesis==
* Papillary thyroid tumors are most commonly unencapsulated, and they have a high tendency to metastasize locally to [[lymph nodes]], which may produce cystic structures near the thyroid that are difficult to diagnose because of the paucity of malignant tissue.<ref>{{cite journal|last1=Grani|first1=G|last2=Fumarola|first2=A|title=Thyroglobulin in Lymph Node Fine-Needle Aspiration Washout: A Systematic Review and Meta-analysis of Diagnostic Accuracy.|journal=The Journal of Clinical Endocrinology and Metabolism|date=Jun 2014|volume=99|issue=6|pages=1970–82|pmid=24617715|doi=10.1210/jc.2014-1098}}</ref><ref name="The Thyroid and its Diseases">{{cite web|url=http://www.thyroidmanager.org/Chapter18/18-cause.htm| title=The Thyroid and its Diseases|date=|accessdate= 2010-07-15}}</ref>
* The exact [[pathogenesis]] of papillary thyroid cancer (PTC) is not fully understood.<ref>{{cite journal |vauthors=Nikiforov YE |title=RET/PTC rearrangement in thyroid tumors |journal=Endocr. Pathol. |volume=13 |issue=1 |pages=3–16 |date=2002 |pmid=12114746 |doi= |url=}}</ref><ref>{{cite journal |vauthors=Tallini G, Asa SL |title=RET oncogene activation in papillary thyroid carcinoma |journal=Adv Anat Pathol |volume=8 |issue=6 |pages=345–54 |date=November 2001 |pmid=11707626 |doi= |url=}}</ref><ref>{{cite journal |vauthors=Nikiforov YE, Koshoffer A, Nikiforova M, Stringer J, Fagin JA |title=Chromosomal breakpoint positions suggest a direct role for radiation in inducing illegitimate recombination between the ELE1 and RET genes in radiation-induced thyroid carcinomas |journal=Oncogene |volume=18 |issue=46 |pages=6330–4 |date=November 1999 |pmid=10597232 |doi=10.1038/sj.onc.1203019 |url=}}</ref>
* Although papillary carcinoma has a propensity to invade [[lymphatics]], it is less likely to invade [[blood vessels]].<ref>{{cite web|url=http://emedicine.medscape.com/article/282276-overview| title=Thyroid, Papillary Carcinoma|date=|accessdate= 2010-07-15}}</ref>
* Papillary thyroid cancer has been [[Association (statistics)|associated]] with [[somatic]] rearrangement of [[RET proto-oncogene|RET protooncogene]] se well as point mutation in [[BRAF]] and [[RAS]] [[genes]].
* Furthermore, papillary tumors may metastasize to the [[lungs]] and produce a few nodules or the lung fields may exhibit a [[snowflake]] appearance throughout.
* All of the aforementioned [[genetic]] alterations leads to [[mitogen-activated protein kinase]] ([[MAPK]]) pathway activation.
* Lateral aberrant thyroid is actually a [[lymph node]] metastasis from papillary thyroid carcinoma.<ref name="pmid17319317">{{cite journal |author=Escofet X, Khan AZ, Mazarani W, Woods WG |title=Lessons to be learned: a case study approach. Lateral aberrant thyroid tissue: is it always malignant? |journal=J R Soc Health |volume=127 |issue=1 |pages=45–6 |year=2007 |pmid=17319317 |doi=10.1177/1466424007073207}}</ref>
* The [[RET gene|RET]] rearrangement encodes for a [[tyrosine kinase]] [[receptor]].
* Other characteristics of the papillary carcinoma is that E.M. shows increased [[mitochondria]], increased RER, as well as increased apical microvilli. Moreover, papillary carcinomas have an indolent growth, and 40 percent of cases spread out of the [[capsule]].<ref>{{cite web|url=http://www.pathology.vcu.edu/education/endocrine/endocrine/newthyroid/| title=Papillary Carcinomas|date=|accessdate= 2010-07-15}} {{Dead link|date=October 2010|bot=H3llBot}}</ref>
* This rearrangement has also been observed in mice with a history of [[ionizing radiation]] exposure.
 
* [[Ionizing radiation]] has been well recognized for its role in papillary thyroid cancer [[etiology]].
* The rearranged form of this [[gene]] is well-known as [[RET gene|ret]]/PCT [[rearrangement]] and is believed to be related to PTC [[carcinogenesis]].
* Papillary thyroid cancer [[metastasize]] through [[lymphatics]].
==Genetics==
==Genetics==
* [[Mutation]]s associated with papillary thyroid cancer are mainly two forms of [[chromosomal translocation]] and one form of [[point mutation]]. These alterations lead to activation of a common [[carcinogenesis|carcinogenic]] pathway known as the [[MAPK/ERK pathway]].
*[[Genetic]] alteration [[Association (statistics)|associated]] with papillary thyroid cancer include:<ref name="LloydBuehler2011">{{cite journal|last1=Lloyd|first1=Ricardo V.|last2=Buehler|first2=Darya|last3=Khanafshar|first3=Elham|title=Papillary Thyroid Carcinoma Variants|journal=Head and Neck Pathology|volume=5|issue=1|year=2011|pages=51–56|issn=1936-055X|doi=10.1007/s12105-010-0236-9}}</ref>
* Chromosomal translocations involving the [[RET proto-oncogene]] (encoding a tyrosine kinase receptor that plays essential roles in the development of [[neuroendocrine cell]]s) located on chromosome 10q11 occur in approximately a fifth of papillary thyroid cancers. The fusion oncoproteins generated are termed RET/PTC proteins (ret/papillary thyroid carcinoma), and constitutively activate RET and the downstream MAPK/ERK pathway. The frequency of ret/PTC translocations is significantly higher in papillary cancers arising in children and after radiation exposure. The gene [[NTRK1]] (encoding the TrkA receptor), located on chromosome 1q, is similarly translocated in approximately 5 percent to 10 percent of papillary thyroid cancers.
**[[Mutations]] in [[RET proto-oncogene]]
* Approximately a third to a half of papillary thyroid carcinomas harbor point mutations in the BRAF oncogene, also activating the MAPK/ERK pathway. In those cases the BRAF mutations found were V600E mutation. According to recent studies, papillary cancers carrying the common V600E mutation tend to have a more aggressive long term course. BRAF mutations are frequent in papillary carcinoma and in undifferentiated cancers that have developed from papillary tumors.
**[[Mutations]] in the [[BRAF]] oncogene
 
**[[RAS]] [[mutations]]
**[[TRK]] rearrangements
**[[HMGA2]] [[overexpression]]
==Associated Conditions==
==Associated Conditions==
* [[Gardner syndrome]]<ref name="Radiopaedia2015">{{cite web | title = Papillary thyroid cancer [Dr Yuranga Weerakkody and Dr Frank Gaillard et al.].Radiopedia 2015| url = http://radiopaedia.org/articles/papillary-thyroid-cancer Accessed on October, 29 2015 }}</ref>
* Papillary thyroid cancer may be [[Association (statistics)|associated]] with:<ref name="LloydBuehler2011">{{cite journal|last1=Lloyd|first1=Ricardo V.|last2=Buehler|first2=Darya|last3=Khanafshar|first3=Elham|title=Papillary Thyroid Carcinoma Variants|journal=Head and Neck Pathology|volume=5|issue=1|year=2011|pages=51–56|issn=1936-055X|doi=10.1007/s12105-010-0236-9}}</ref><ref name="HallAbdollahian2013">{{cite journal|last1=Hall|first1=Joseph E.|last2=Abdollahian|first2=Davood J.|last3=Sinard|first3=Robert J.|last4=Eisele|first4=David W.|title=Thyroid disease associated with cowden syndrome: A meta-analysis|journal=Head & Neck|volume=35|issue=8|year=2013|pages=1189–1194|issn=10433074|doi=10.1002/hed.22971}}</ref>
* [[Cowden syndrome]]
**[[Gardner syndrome]] (especially seen with cribriform-Morular Variant of PTC)
** [[Cowden syndrome]]
==Gross Pathology==
==Gross Pathology==
* On gross pathology, an ill-defined tumor, irregular borders, and firm consistency are characteristic findings of papillary thyroid cancer.<ref name="Lloyd2010">{{cite journal|last1=Lloyd|first1=Ricardo V.|year=2010|doi=10.1007/978-1-4419-1069-1}}</ref>
{| align="right"
* Clacification may also be present.  
|[[File:Papillary thyroid carcinoma.jpeg|thumb|right|200px|Papillary thyroid cancer gross pathology<ref name="radio"> Image courtesy of  Dr David Cuete. [http://www.radiopaedia.org Radiopaedia] (original file [http://radiopaedia.org/articles/papillary-thyroid-cancer ‘’here’’].[http://radiopaedia.org/licence Creative Commons BY-SA-NC]</ref>]]
* Other less common features include:
|}
** Cystic nodule with attached papillary growth
* On gross pathology, an ill-defined [[tumor]], irregular borders, and firm consistency are characteristic findings of papillary thyroid cancer.<ref name="Lloyd2010">{{cite journal|last1=Lloyd|first1=Ricardo V.|year=2010|doi=10.1007/978-1-4419-1069-1}}</ref>
** A well-circumscribed, encapsulated  nodule with a fleshy appearance that may show some cystic change
*[[Calcification]] may also be present.
[[File:Papillary thyroid carcinoma.jpeg|thumb|center|Papillary thyroid cancer gross pathology<ref name="radio"> Image courtesy of  Dr David Cuete. [http://www.radiopaedia.org Radiopaedia] (original file [http://radiopaedia.org/articles/papillary-thyroid-cancer ‘’here’’].[http://radiopaedia.org/licence Creative Commons BY-SA-NC]</ref>]]
* Other less common features include:
**[[Cystic]] [[nodule]] with attached [[papillary]] [[growth]]
** A well-circumscribed, encapsulated  [[nodule]] with a [[fleshy]] appearance that may show some [[cystic]] change
==Microscopic Pathology==
==Microscopic Pathology==
* Papillary thyroid carcinoma has numerous histological subtypes. Each subtype has some specific characteristics.<ref name="Lloyd2010">{{cite journal|last1=Lloyd|first1=Ricardo V.|year=2010|doi=10.1007/978-1-4419-1069-1}}</ref><ref name="LloydBuehler2011">{{cite journal|last1=Lloyd|first1=Ricardo V.|last2=Buehler|first2=Darya|last3=Khanafshar|first3=Elham|title=Papillary Thyroid Carcinoma Variants|journal=Head and Neck Pathology|volume=5|issue=1|year=2011|pages=51–56|issn=1936-055X|doi=10.1007/s12105-010-0236-9}}</ref>
* Papillary thyroid carcinoma has numerous [[histological]] subtypes. Each subtype has some specific characteristics.<ref name="Lloyd2010">{{cite journal|last1=Lloyd|first1=Ricardo V.|year=2010|doi=10.1007/978-1-4419-1069-1}}</ref><ref name="LloydBuehler2011">{{cite journal|last1=Lloyd|first1=Ricardo V.|last2=Buehler|first2=Darya|last3=Khanafshar|first3=Elham|title=Papillary Thyroid Carcinoma Variants|journal=Head and Neck Pathology|volume=5|issue=1|year=2011|pages=51–56|issn=1936-055X|doi=10.1007/s12105-010-0236-9}}</ref><ref name="KunjumonUpadhyaya2014">{{cite journal|last1=Kunjumon|first1=DeepaThomas|last2=Upadhyaya|first2=Krishnaraj|title=Histopathological features of Papillary Thyroid Carcinoma with special emphasis on the significance of nuclear features in their diagnosis|journal=Archives of Medicine and Health Sciences|volume=2|issue=1|year=2014|pages=16|issn=2321-4848|doi=10.4103/2321-4848.133786}}</ref>
* However, there is no unique consensus on the definition of each subtype, so different pathologists may not agree with these definitions.
* There is no unique consensus on the definition of each subtype, so different [[pathologists]] may not agree with these definitions.
* [[Cytologic]] features of papillary thyroid cancer are [[diagnostic]] for this [[tumor]]. These features include:
* [[Cytologic]] features of papillary thyroid cancer are [[diagnostic]] for this [[tumor]]. These features include:
** enlarged, irregular, oval shape nuclei that are overlapped because of the nuclear enlargement  
** Enlarged, irregular, oval shape [[nuclei]] that are overlapped because of the [[nuclear]] enlargement  
** Nuclear clearing  
** [[Nuclear]] clearing  
** Ground glass appearance with prominent nuclear grooves
** [[Ground glass]] appearance with prominent [[nuclear]] grooves
** Pink cytoplasmic invaginations
** Pink cytoplasmic invaginations
{| {{table}} cellpadding="4" cellspacing="0" style="border:#c9c9c9 1px solid; margin: 1em 1em 1em 0; border-collapse: collapse;"
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|-
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* Micrograph of psammoma body in papillary thyroid cancer
* Micrograph of [[psammoma body]] in papillary thyroid cancer
* A single necrotic tumor cell in the center of this structure acts as the nidus for its formation  
* A single [[necrotic]] [[tumor cell]] in the center of this structure acts as the nidus for its formation
|[[File:WBR0863.jpg|thumb|none|250px| H&E stain. Contributed in wikimedia.commons]]
|[[File:WBR0863.jpg|thumb|none|250px| H&E stain. Contributed in wikimedia.commons]]
|}
|}
==Immunohistochemistry==
==Immunohistochemistry==
* Papillary thyroid cancer may be positive for following markers:
* Papillary thyroid cancer may be positive for following markers:<ref name="Lloyd2010">{{cite journal|last1=Lloyd|first1=Ricardo V.|year=2010|doi=10.1007/978-1-4419-1069-1}}</ref>
** TTF-1
**[[TTF-1]]
** Thyroglobulin
**[[Thyroglobulin]]
** Thyroid peroxidase
**[[Thyroid peroxidase]]
** CD56 (NCAM)
**[[CD56]] (NCAM)
** PAX8
**[[PAX8]]
** HBME-1
** HBME-1
** CITED1
**[[CITED1]]
** Cytokeratin 19
**[[Cytokeratin]] 19
** Galectin 3
**[[Galectin-3|Galectin 3]]
* These markers are helpful in the confirmation of thyroid origin of the tumor particularly when the tumor is outside of the thyroid gland.  
* These markers are helpful in the confirmation of [[thyroid]] origin of the [[tumor]] particularly when the [[tumor]] is outside of the [[thyroid gland]].
==Histopathological Video==
==Histopathological Video==
===Video===
===Video===
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[[Category:Hereditary cancers]]
[[Category:Hereditary cancers]]
[[Category:Thyroid disease]]
[[Category:Thyroid disease]]
[[Category:Primary care]]

Latest revision as of 23:34, 29 July 2020

Papillary thyroid cancer Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2] Ammu Susheela, M.D. [3]

Overview

The exact pathogenesis of papillary thyroid cancer is not fully understood. Papillary thyroid cancer has been associated with somatic rearrangement of RET protooncogene. On gross pathology, an ill-defined tumor, irregular borders, and firm consistency are characteristic findings of papillary thyroid cancer. There is no unique consensus on the definition of histological subtypes of papillary thyroid cancer.

Physiology



 
 
 
 
 
 
Growth factor binds to Receptor tyrosine kinase (RET, NTRK1)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GDP substitution by GTP
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RAS activation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BRAF activation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEK ativation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ERK activation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cell differentiation
 
 
cell proliferation
 
 
cell survival
 
The above algorithm is adopted from Endocrine patology book[2]

Pathogenesis

Genetics

Associated Conditions

Gross Pathology

Papillary thyroid cancer gross pathology[8]
  • On gross pathology, an ill-defined tumor, irregular borders, and firm consistency are characteristic findings of papillary thyroid cancer.[2]
  • Calcification may also be present.
  • Other less common features include:

Microscopic Pathology

  • Papillary thyroid carcinoma has numerous histological subtypes. Each subtype has some specific characteristics.[2][6][9]
  • There is no unique consensus on the definition of each subtype, so different pathologists may not agree with these definitions.
  • Cytologic features of papillary thyroid cancer are diagnostic for this tumor. These features include:
    • Enlarged, irregular, oval shape nuclei that are overlapped because of the nuclear enlargement
    • Nuclear clearing
    • Ground glass appearance with prominent nuclear grooves
    • Pink cytoplasmic invaginations
Papillary thyroid cancer subtype Features on Histopathological Microscopic Analysis
Follicular
Conventional
Tall cell
Columnar cell
  • Pseudostratified cells
  • Overlapping enlarged nuclei
Oncocytic
Solid
Diffuse sclerosing
Papillary thyroid carcinoma with prominent hobnail features
Clear cell
Cribriform-Morular
Macrofollicular
  • Composed of macrofollicles
  • Cytological features of papillary thyroid cancer
Papillary thyroid cancer Image
  • Micrograph of papillary thyroid carcinoma, tall cell variant - high magnification
  • "Tall cells": the largest dimension is 3x the smaller dimension
  • Abundant eosinophilic cytoplasm
  • Lack of pseudostratification is a significant differentiator from columnar cell variant of papillary thyroid carcinoma
H&E stain. Contributed in wikimedia.commons
  • Micrograph showing oncocytic variant of papillary thyroid carcinoma
  • Large cells with abundant eosinophilic cytoplasm
H&E stain, Contributed in wikimedia.commons
  • Micrograph showing cribriform-Morular variant of papillary thyroid carcinoma
  • Cribriform pattern with solid and spindle cell areas
  • Squamous morules
H&E stain, Contributed in wikimedia.commons
  • Micrograph (high power view) showing nuclear changes in papillary thyroid carcinoma (PTC), which include:
    • Groove formation
    • Optical clearing
    • Eosinophilic inclusions and overlapping of nuclei
H&E stain. Contributed in wikimedia.commons
  • Micrograph (high power view) of PTC demonstrating nuclear clearing and overlapping nuclei
H&E stain. Contributed in wikimedia.commons
  • Micrograph of papillary thyroid carcinoma demonstrating prominent papillae with fibrovascular cores
H&E stain. Contributed in wikimedia.commons
H&E stain. Contributed in wikimedia.commons
H&E stain. Contributed in wikimedia.commons

Immunohistochemistry

Histopathological Video

Video

{{#ev:youtube|JwymE_Lfs44}}

References

  1. ↑ Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, Biddinger PW, Nikiforov YE (February 2006). "Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas". Am. J. Surg. Pathol. 30 (2): 216–22. PMID 16434896.
  2. ↑ 2.0 2.1 2.2 2.3 Lloyd, Ricardo V. (2010). doi:10.1007/978-1-4419-1069-1. Missing or empty |title= (help)
  3. ↑ Nikiforov YE (2002). "RET/PTC rearrangement in thyroid tumors". Endocr. Pathol. 13 (1): 3–16. PMID 12114746.
  4. ↑ Tallini G, Asa SL (November 2001). "RET oncogene activation in papillary thyroid carcinoma". Adv Anat Pathol. 8 (6): 345–54. PMID 11707626.
  5. ↑ Nikiforov YE, Koshoffer A, Nikiforova M, Stringer J, Fagin JA (November 1999). "Chromosomal breakpoint positions suggest a direct role for radiation in inducing illegitimate recombination between the ELE1 and RET genes in radiation-induced thyroid carcinomas". Oncogene. 18 (46): 6330–4. doi:10.1038/sj.onc.1203019. PMID 10597232.
  6. ↑ 6.0 6.1 6.2 Lloyd, Ricardo V.; Buehler, Darya; Khanafshar, Elham (2011). "Papillary Thyroid Carcinoma Variants". Head and Neck Pathology. 5 (1): 51–56. doi:10.1007/s12105-010-0236-9. ISSN 1936-055X.
  7. ↑ Hall, Joseph E.; Abdollahian, Davood J.; Sinard, Robert J.; Eisele, David W. (2013). "Thyroid disease associated with cowden syndrome: A meta-analysis". Head & Neck. 35 (8): 1189–1194. doi:10.1002/hed.22971. ISSN 1043-3074.
  8. ↑ Image courtesy of Dr David Cuete. Radiopaedia (original file ‘’here’’.Creative Commons BY-SA-NC
  9. ↑ Kunjumon, DeepaThomas; Upadhyaya, Krishnaraj (2014). "Histopathological features of Papillary Thyroid Carcinoma with special emphasis on the significance of nuclear features in their diagnosis". Archives of Medicine and Health Sciences. 2 (1): 16. doi:10.4103/2321-4848.133786. ISSN 2321-4848.
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