Papillary thyroid cancer pathophysiology

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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

The mitogen-activated protein kinase (MAPK) pathway is involved in signal transduction of receptor tyrosine kinase such as RET and NTRK1.^[1]
Tyrosine kinase receptor activation leads to RAS activation which subsequently result in GTP substitution of GDP. The GTP-bound form of RAS makes BRAF active which in turn activates MEK and ERK.
ERK is engaged in the regulation of gene transcription including cell differentiation, proliferation, and survival.

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

The exact pathogenesis of papillary thyroid cancer (PTC) is not fully understood.^[3]^[4]^[5]
Papillary thyroid cancer has been associated with somatic rearrangement of RET protooncogene se well as point mutation in BRAF and RAS genes.
All of the aforementioned genetic alterations leads to mitogen-activated protein kinase (MAPK) pathway activation.
The RET rearrangement encodes for a tyrosine kinase receptor.
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/PCT rearrangement and is believed to be related to PTC carcinogenesis.
Papillary thyroid cancer metastasize through lymphatics.

Genetics

Genetic alteration associated with papillary thyroid cancer include:^[6]
- Mutations in RET proto-oncogene
- Mutations in the BRAF oncogene
- RAS mutations
- TRK rearrangements
- HMGA2 overexpression

Associated Conditions

Papillary thyroid cancer may be associated with:^[6]^[7]
- Gardner syndrome (especially seen with cribriform-Morular Variant of PTC)
- Cowden syndrome

Gross Pathology

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:
- Cystic nodule with attached papillary growth
- A well-circumscribed, encapsulated nodule with a fleshy appearance that may show some cystic change

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	Follicles with variable size Dark, eosinophilic colloid with scalloping ‘‘bubble gum’’ appearance Cytologic features including prominent nucleoli and increased mitotic activity are diagnostic
Conventional	Papillae with fibrovascular cores Enlarged nuclei with nuclear clearing Squamous metaplasia may be present
Tall cell	With a height 2 to 3 times greater than the width Cytologic features are diagnostic
Columnar cell	Pseudostratified cells Overlapping enlarged nuclei
Oncocytic	Large cells with abundant eosinophilic cytoplasm Enlarged nuclei with nuclear clearing
Solid	Sheets of tumor cells with abundant cytoplasm Enlarged nuclei with nuclear clearing
Diffuse sclerosing	Abundant psammoma bodies, and squamoid changes in the tumor cells Lymphocytic infiltrates in the background
Papillary thyroid carcinoma with prominent hobnail features	Hobnail cells with loss of polarity High-grade cytologic features including prominent nucleoli increased mitotic activity
Clear cell	Clear cells with a papillary architecture Cytological features of papillary thyroid cancer
Cribriform-Morular	Cribriform pattern with solid and spindle cell areas Squamous morules Nuclei with clearing and groove Involving both thyroid lobes
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
Micrograph of metastatic papillary thyroid carcinoma to a lymph node Papillary architecture -- papillae with fibrovascular cores are present Lymph node with several germinal centers (left, top/right of image) Adipose tissue (fat) is seen at the edge of the image (bottom and left)	H&E stain. Contributed in wikimedia.commons
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	H&E stain. Contributed in wikimedia.commons

Immunohistochemistry

Papillary thyroid cancer may be positive for following markers:^[2]
- TTF-1
- Thyroglobulin
- Thyroid peroxidase
- CD56 (NCAM)
- PAX8
- HBME-1
- CITED1
- Cytokeratin 19
- 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.

Histopathological Video

Video

References

↑ 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.
↑ ^2.0 ^2.1 ^2.2 ^2.3 Lloyd, Ricardo V. (2010). doi:10.1007/978-1-4419-1069-1. Missing or empty |title= (help)
↑ Nikiforov YE (2002). "RET/PTC rearrangement in thyroid tumors". Endocr. Pathol. 13 (1): 3–16. PMID 12114746.
↑ Tallini G, Asa SL (November 2001). "RET oncogene activation in papillary thyroid carcinoma". Adv Anat Pathol. 8 (6): 345–54. PMID 11707626.
↑ 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.
↑ ^6.0 ^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.
↑ 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.
↑ Image courtesy of Dr David Cuete. Radiopaedia (original file ‘’here’’.Creative Commons BY-SA-NC
↑ 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.

[pmid16434896-1] 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.

[Lloyd2010-2] 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.

[LloydBuehler2011-6] 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.

[HallAbdollahian2013-7] 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.

[radio-8] Image courtesy of Dr David Cuete. Radiopaedia (original file ‘’here’’.Creative Commons BY-SA-NC

[KunjumonUpadhyaya2014-9] 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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