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follicular thyroid carcinoma

Monday 1 December 2003

FTC; thyroid follicular carcinomas; follicualr carcinomas

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- microfollicular thyroid carcinoma

Digital cases

- JRC:2665 : Minimally invasive follicular carcinoma (with focal Hurthle cell features), in a 78 y/o male.
- JRC:3316 : Well differentiated follicular carcinoma of the thyroid.
- JRC:3317 : Minimally invasive follicular carcinoma.
- JRC:18762 : Thyroid anaplastic carcinoma, arising from thyroid follicular carcinoma.
- JRC:18923 : Follicular carcinoma with extensive soft tissue invasion and with massive blood vessel invasion.
- JRC:18924 : Follicular carcinomna with limited invasion and with probable blood vessel invasion.

High grade follicular carcinoma of the thyroid
- JRC:3332 : High grade follicular carcinoma of the thyroid.

Poorly differentiated follicular carcinoma
- JRC:14575 : Poorly differentiated follicular carcinoma of the thyroid.

Hurthle cell variant (oxyphilic cell variant, oncocytic cell variant)
- JRC:18922 : Thyroid follicular carcinoma, oxyphil cell variant.

Clear cell variant
- JRC:18914 : Follicular carcinoma, clear cell type

Definition: Thyroid carcinoma with follicular differentiation but no papillary nuclear features; excludes Hurthle cell and poorly differentiated carcinoma.

The tumour characteristically metastasises haematogenously with secondaries predominantly in the skeleton and lungs.


Follicular carcinoma comprises approximately 5% of thyroid cancers; however, in iodide-deficient areas, this tumor is more prevalent, making up 25% to 40% of thyroid cancers. These malignant thyroid epithelial tumours show evidence of follicular differentiation with no features to suggest any of the other subtypes.

- 75% women, older age than papillary carcinoma
- Risk factors: radiation exposure, iodine deficiency, older age
- Does not arise from preexisting adenoma

Clinical synopsis

- Usually solitary, but not occult
- Usually "cold" on radionuclide scan

- Follicular tumor of uncertain malignant potential: questionable capsular invasion and no papillary carcinoma nuclear features.


The true incidence of follicular carcinoma is difficult to determine because the follicular variant of papillary carcinoma may still be placed into this category.

Follicular carcinoma is the second most common type of thyroid carcinoma, constituting approximately 25% of the total. It shows a female predominance in the ratio of 2.5:1 and presents most commonly in the 40–60 age range.

Risk factors include iodine deficiency, older age, female gender, and radiation exposure. When iodide is added to the diet, papillary cancer increases, and follicular tumors decrease.

Clinically, follicular carcinoma usually presents as a solitary mass in the thyroid.

Follicular carcinoma has a marked propensity for vascular invasion (not lymphatics). It is possible that follicular cancers produce certain factors that alter the venous endothelium, allowing the tumor easy access.

Follicular carcinoma is characterised by the architectural features of local and vascular invasion. Some carcinomas appear totally encapsulated and are so defined on the basis of vascular invasion in capsular vessels. Such lesions can be difficult to diagnose, requiring the examination of multiple histological blocks of the capsule.

Differential diagnosis

Follicular carcinomas range from well-differentiated to poorly differentiated. Well-differentiated carcinomas may be cytologically bland and resemble adenomas; indeed well-differentiated follicular carcinoma may appear cytologically less atypical than the benign atypical adenoma.


Treatment for encapsulated or minimally invasive lesions can be by lobectomy and isthmusectomy; widely invasive lesions require total thyroidectomy followed by ablative radioactive 131I and thyroxine replacement therapy.

Clinical synopsis

- Mainly adults / rare in children
- Thyroidal mass lesion


- Mass lesion within thyroid
- Usually solid
- Encapsulated or infiltrating
- Vascular and lymphatic spread
- Gray-tan-pink
- Usually single encapsulated nodule, focally hemorrhagic
- Variable fibrosis and calcification
- Large lesions may often be infiltrative
- Extensive sampling of capsule recommended (Am J Surg Pathol 1992;16:392)


- Follicular architecture
- No characteristic nuclei of papillary carcinoma

  • Nuclei usually round / ovoid and bland
  • nuclear atypia does not necessarily relate to aggressive behavior

- Need convincing evidence of invasion of adjacent thyroid parenchyma, capsule (complete penetration) or blood vessels (medium sized veins or larger vessels in or beyond the capsule).
- Capsule is typically thick with calcification.
- Common architectural patterns are follicular or solid.
- May have nuclear atypia, Hürthle cells, focal spindled areas, mitotic figures.
- Usually no squamous metaplasia, no nuclear features of papillary carcinoma, no psammoma bodies, no / rare lymphatic invasion.

Grading MI-FTC and WI-FTC

- minimally invasive follicular thyroid carcinoma
- widely invasive follicular thyroid carcinoma

  • depending on extent of
    • capsular invasion
    • vascular invasion (beyond capsule)

FTC is defined in accordance with the 2004 WHO classification of thyroid tumors as an invasive neoplasm of follicular cell origin without the typical nuclear features of PTC.

Tumors are divided into MI-FTC when limited capsular and/or vascular invasion was found and WI-FTC in the case of widespread infiltration of thyroid tissue and/or blood vessels.

Tumors with ≤3 foci of vascular invasion are classified as MI-FTCs, whilst tumors with >3 foci of vascular invasion were classified as WI-FTCs.

Hürthle cell thyroid tumors are excluded from this grading as oncocytic cell tumor can be considered as a distinctive clinical entity. The follicular variant of papillary thyroid cancer is a differential diagnosis.


- oncocytic thyroid follicular carcinoma (Hürthle cell variant of follicular carcinoma)

  • Hürthle cell or oncocytic variants of follicular carcinoma constitute approximately 5% of the total.
  • They show different genetic alterations to usual follicular carcinomas.
  • Hurthle cell thyroid cancer is often considered a variant of follicular cell carcinoma.
  • Hurthle cell forms are more likely than follicular carcinomas to be bilateral and multifocal and to metastasize to lymph nodes.
  • Like follicular carcinoma, unilateral hemithyroidectomy is performed for non-invasive disease, and total thyroidectomy for invasive disease.
  • These have been thought to be intrinsically more aggressive than other follicular carcinomas but the consensus view is that these lesions behave similarly according to their invasiveness, grade and stage.
  • They do not take up radioactive iodine well and hence treatment may be less successful.
  • Hürthle cell tumours may undergo clear cell change caused by swelling of the numerous mitochondria which they contain and this is one of the derivations of clear cell variants of follicular carcinoma.

- clear cell thyroid follicular carcinoma

Immunohistochemical staining

- Cytokeratin+
- Thyroglobulin+
- TTF-1+
- Ck19+
- Bcl2+
- Beta catenin+
- Chromogranin−

Molecular biology

- RASs gene mutations

  • Approximately one-half of follicular thyroid carcinomas have mutations in the Ras subfamily of oncogenes, most notably HRAS, NRAS, and KRAS.

- PAX8-PPARγ1 fusio

  • Also, a chromosomal translocation specific for follicular thyroid carcinomas is one between paired box gene 8 (PAX-8), a gene important in thyroid development, and the gene encoding peroxisome proliferator-activated receptor γ 1 (PPARγ1), a nuclear hormone receptor contributing to terminal differentiation of cells.
  • The PAX8-PPARγ1 fusion is present in approximately one-third of follicular thyroid carcinomas, specifically those cancers with a t(2;3)(q13;p25) translocation, permitting juxtaposition of portions of both genes.

Tumors tend carry either a RAS mutation or a PAX8-PPARγ1 fusion, and only rarely are both genetic abnormalities present in the same case. Thus, follicular thyroid carcinomas seem to arise by two distinct and virtually non-overlapping molecular pathways.

miRNAs (23150679)

The most difficult thyroid tumors to be diagnosed by cytology and histology are conventional follicular carcinomas (cFTCs) and oncocytic follicular carcinomas (oFTCs).

Several microRNAs (miRNAs) have been previously found to be consistently deregulated in papillary thyroid carcinomas; however, very limited information is available for cFTC and oFTC.

Different histopathological types of follicular thyroid carcinomas have distinct miRNA expression profiles (23150679):
- MiR-885-5p is highly up-regulated in oncocytic follicular carcinomas and may serve as a diagnostic marker for these tumors.
- A small set of deregulated miRNAs allows for an accurate discrimination between follicular carcinomas and hyperplastic nodules and can be used diagnostically in fine-needle aspiration biopsies.


The overall 5-year survival rate for follicular thyroid cancer is 91%, and the 10-year survival rate is 85%.

By overall cancer staging into stages I to IV, follicular thyroid cancer has a 5-year survival rate of 100% for stages I and II, 71% for stage III, and 50% for stage IV.[6]

- Poor prognostic factors

  • distant metastases
  • age > 45 years
  • large size
  • extensive vascular invasion
  • extrathyroidal extension
  • poorly differentiated or widely invasive tumors

- Metastases: does not invade lymphatics but does spread to lungs, liver, bone, brain via veins

- Distant metastases common in grossly invasive disease:

  • 50% if vascular and capsular invasion
  • 75% if local invasion and vascular or capsular invasion
  • Metastases may pulsate because of their vascularity (as metastatic renal cell carcinoma)


The overall prognosis gives a 5-year survival of approximately 70%, dependent on the grade, invasiveness and stage of the tumour.

Well-differentiated skeletal metastases can be very indolent with survival for many years.

- Rosai and others (Am J Surg Pathol 1986;10:246) recommend classifying definitive follicular carcinomas as follows: Encapsulated

  • With capsular invasion only
  • With limited (@<@ 4 vessels) vascular invasion
  • With extensive (4 or more vessels) vascular invasion
  • Widely invasive

Treatment and management

- T3 / T4 to suppress endogenous TSH, then thyroidectomy and radioactive iodine
- No need for nodal dissection since tumors don’t metastasize to lymph nodes

See also

- thyroid carcinomas

  • thyroid follicular carcinoma
  • thyroid poorly differentiated carcinoma
  • thyroid anaplastic carcinoma
  • thyroid squamous carcinoma
  • thyroid mucoepidermoid carcinoma
  • thyroid mucinous carcinoma

Open references

- Follicular thyroid carcinoma: the role of histology and staging systems in predicting survival.
Lo CY, Chan WF, Lam KY, Wan KY.
Ann Surg. 2005 Nov;242(5):708-15.
PMID: 16244545

- Follicular thyroid carcinoma: histology and prognosis.
D’Avanzo A, Treseler P, Ituarte PH, Wong M, Streja L, Greenspan FS, Siperstein AE, Duh QY, Clark OH.
Cancer. 2004 Mar 15;100(6):1123-9.
PMID: 15022277


- MicroRNA Expression Array Identifies Novel Diagnostic Markers for Conventional and Oncocytic Follicular Thyroid Carcinomas. Dettmer M, Vogetseder A, Durso MB, Moch H, Komminoth P, Perren A, Nikiforov YE, Nikiforova MN. J Clin Endocrinol Metab. 2012 Nov 12. PMID: 23150679