Papillary thyroid cancer pathophysiology

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

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.

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.
• Although papillary carcinoma has a propensity to invade lymphatics, it is less likely to invade blood vessels.
• Furthermore, papillary tumors may metastasize to the lungs and produce a few nodules or the lung fields may exhibit a snowflake appearance throughout.
• Lateral aberrant thyroid is actually a lymph node metastasis from papillary thyroid carcinoma.
• 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.

Genetics

• Mutations 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 carcinogenic pathway known as the MAPK/ERK pathway.
• Chromosomal translocations involving the RET proto-oncogene (encoding a tyrosine kinase receptor that plays essential roles in the development of neuroendocrine cells) 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.
• 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.

Associated Conditions

• Gardner syndrome
• Cowden syndrome

Gross Pathology

• Solitary nodule which can extend into trachea and vocal cords.

Papillary thyroid cancer gross pathology

Microscopic Pathology

• Characteristic Orphan Annie eye nuclear inclusions (nuclei with uniform staining, which appear empty) and psammoma bodies on light microscopy. The former is useful in identifying the follicular variant of papillary thyroid carcinomas.
• Histologically papillary carcinoma demonstrates 'delicate stalks of epithelial cells' which account for its name.

Papillary thyroid cancer subtype	Features on Histopathological Microscopic Analysis	Image
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
Tall cell	With a height 2 to 3 times greater than the width Cytologic features are diagnostic	Micrograph of papillary thyroid carcinoma, tall cell variant - high magnification. H&E stain, Contributed by in wikimedia.commons
Columnar cell	Pseudostratified cells Overlapping enlarged nuclei
Oncocytic	Large cells with abundant eosinophilic cytoplasm Enlarged nuclei with nuclear clearing	H&E stain, Contributed by Nephron in wikimedia.commons
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	H&E stain, Contributed by Sarahkayb in wikimedia.commons
Macrofollicular	Composed of macrofollicles Cytological features of papillary thyroid cancer

Papillary thyroid cancer	Image

• 
  Micrograph of metastatic papillary thyroid carcinoma to a lymph node. H&E stain.
• 
  Micrograph of metastatic papillary thyroid carcinoma to a lymph node. H&E stain.
• 
  Micrograph of papillary thyroid carcinoma demonstrating prominent papillae with fibrovascular cores. H&E stain.
• 
  Micrograph (high power view) of PTC demonstrating nuclear clearing and overlapping nuclei. H&E stain.
• 
  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.

Histopathological Video

Video

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