b) Follicular Carcinoma

Follicular tumours are well differentiated carcinomas that arise from the follicular cells of the thyroid gland, but lack nuclear features that allow them to be classified as papillary tumours.


Follicular carcinoma is less common than papillary carcinoma, and is a rare tumour in childhood. The mean age of incidence is about 10 years later than papillary carcinoma (but earlier than the undifferentiated thyroid carcinoma). Importantly, follicular carcinoma is more common in areas with low iodine.


Follicular carcinoma, like papillary carcinoma, is associated with radiation exposure in childhood and adolescent life. Another important aetiological factor in the development of follicular carcinoma is iodine deficiency.
Familial follicular thyroid cancer (FFTC) is rare and usually due to mutations of the PTEN gene, a tumour suppressor, that is inherited in an autosomal dominant fashion. About 10-20% of patients with the gene abnormality develop thyroid cancer.

Natural History

Lesions are usually unifocal. Lymphatic spread is rare (< 5%). Metastases occur in up to 20% of patients, most commonly to the lungs and bones.

Clinical Features

Most patients present with a painless lump arising from the thyroid. Other symptoms or signs are rare unless there is extensive local invasion. Lymph nodes are usually not enlarged or involved.
Thyroid imaging demonstrates a cold nodule.

Tumour Features


Follicular tumours are usually encapsulated and tan-brown in appearance. Aggressive tumours often have obvious breaches of the capsule or no capsule at all.


The diagnosis of follicular carcinoma is controversial. The definition is “invasive neoplasm of follicular cells that lack the nuclear features of papillary thyroid carcinoma”. Diagnosis is made by the lack of these nuclear features (excluding papillary thyroid carcinoma) and by the presence of invasion. Invasion consists of capsule penetration or vessel involvement, not seen in benign lesions.


Immunohistochemistry shows positivity for thyroglobulin and TTF-1 as well as cytokeratins. BCL2 is usually positive. E-cadherin is normally present except in highly invasive tumours.


The most important variant is the oncocytic variant. This accounts for about 5% of all thyroid carcinomas and contains oncocytic cells.

Oncocytic cells contain abundant mitochondria. They have a large cytoplasm (onco-, Greek origin meaning 'swollen'). The large number of mitochondria give the cytoplasm a granular appearance which is often deeply staining.

The cut surface of oncocytic tumours is classicly described as ‘mahogany brown’. A variety of architectural arrangements have been described.


The special mutation of follicular carcinomas is PPARG re-arrangements. PPARG, or peroxisome proliferators-activated receptor gamma, is a cell surface molecule that binds peroxisome proliferators (involved in lipid metabolism). It is normally found in adipocytes and some other cells. It is thought to have some role in the development of dyslipidaemia and/or diabetes.
The most common PPARG rearrangement occurs with PAX8 (paired box 8). This is a transcription factor for thyroid cell specific genes. The chimeric PAX8/PPARG protein product inhibits apoptosis, promotes proliferation and allows follicular cells to survive if not anchored to the basement membrane.
Other genetic abnormalities include RAS (about 50% of cases), and poorly differentiated tumours frequently have TP53 or PTEN mutations as well.


Staging depends on the age of the patient (see the parent page). Patients under 45 are either Stage I or Stage II depending on distant metastases. Those over 45 are staged conventionally.