Pathogenesis

Mutations or rearrangements in the genes encoding for the proteins in the MAPK pathway such as RET/PTC, RAS, or BRAF have been implicated in the development and progression of differentiated thyroid cancer. It has been thought that the BRAF mutation is associated with more aggressive tumors with higher rates of extrathyroidal extension, lymph node metastases, and recurrence; however, this remains controversial. A major advance in recent years has been the discovery of mutations that have prognostic value, such as TERT (telomerase reverse transcriptase) promoter mutations.

Epidemiology

PTC accounts for 80 to 90% of all thyroid cancers. Its peak incidence is between ages 30 to 50 years. Females are more commonly affected than males.

Risk Factors

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  History of radiation exposure during childhood, such as that received as a treatment of childhood malignancies, is a risk factor. Prior to about 1960, external radiation to the head and neck was commonly used to treat a wide variety of conditions, including enlarged tonsils or thymus and even acne.

  
  
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  History of thyroid cancer in a first-degree relative or a family history of a thyroid cancer syndrome is a risk factor.

  
  
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  Suggestive signs of a nodule′s being malignant include a rapid increase in its size, its fixation to surrounding tissues, new-onset hoarseness or vocal fold paralysis, and the presence of ipsilateral cervical lymphadenopathy.

Clinical Presentation

PTC typically presents as a painless discrete mass in the thyroid gland. These tumors may be multicentric. The tumor generally grows slowly and is late to break through the capsule of the gland. Once it has become extrathyroidal, however, it may ultimately become invasive. Nodal metastases appear classically in paratracheal nodes but may be present anywhere in the neck. Bilateral spread is found in 8% of patients. It usually spreads via the lymphatic system. It is not uncommon to find microscopic foci of papillary carcinoma at autopsy or incidentally in a thyroid removed for other indications.

Pathology

Characteristic cytopathologic features seen on fine-needle aspiration biopsy (FNAB) or after surgical resection are diagnostic, including psammoma bodies (layered accumulations of calcium); nuclei with empty centers (Orphan Annie nuclei, based on the comic-strip character Little Orphan Annie) and the formation of papillary structures.

Prognosis

With treatment, overall outcome is generally favorable. However, a small group of patients develop local recurrence and/or distant metastases. Features associated with increased risk of recurrence or mortality include age at diagnosis (age > 45 years), size of the primary tumor (> 2 cm), and the presence of soft tissue invasion and cervical lymph node or distant metastases.

Variants

PTC has several histologic subtypes, including a follicular variant, an oxyphilic variant, a solid or trabecular variant, and a clear cell variant. The follicular variant consists of several distinct subtypes. The diffuse follicular variant seems to present and behave in a more aggressive fashion.

Other biologically aggressive variants include a columnar variant, a tall cell variant, a diffuse sclerosing variant, and poorly differentiated carcinoma.

Epidemiology

Follicular thyroid cancer (FTC) is more common in the iodine-deficient regions of the world. It tends to occur in an older population, with a peak incidence between ages 40 and 60 years. Like most thyroid malignancies, FTC is more common in women (by about a 3:1 ratio).

Risk Factors

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  Iodine deficiency may have a role in the pathogenesis, as there is a higher prevalence of FTC in iodine-deficient regions of the world, compared with iodine-sufficient regions.

  
  
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  FTC is rarely associated with radiation exposure, RET/PTC mutations, or TSH receptor mutations.

  
  
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  FTC has no association with familial syndromes.

  
  
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  FTC may be associated with RAS mutations. PAX8-PPARγ1 (a gene rearrangement) can be seen both in follicular adenomas and cancers.

Clinical Presentation

FTC typically presents as a painless solitary, mostly encapsulated nodule in the thyroid. FTC is more aggressive than PTC and usually spreads by hematogenous routes to bone or lung, and less commonly to brain and liver. It rarely invades lymphatics. The tumor is classified on the basis of degree of invasiveness into minimally invasive (encapsulated) or widely invasive. Metastases are more common with the widely invasive variant.

Diagnosis

FNAB cannot distinguish between follicular adenomas and carcinomas, because diagnosis of malignancy requires identification of tumor capsule and/or vascular invasion. Therefore, the actual diagnosis of follicular thyroid cancer is made on permanent pathologic evaluation of the thyroid specimen after surgery.

Prognosis

Factors associated with adverse prognosis in FTC include older age, distant metastases, large tumor size, vascular invasion, capsular extension, histologic grade (widely invasive variant, Hürthle cell, insular and trabecular variants), and male sex.

Variants

Clear cell tumor, oxyphilic cell type or Hürthle cell type, and insular carcinoma are FTC variants.

Radioactive Iodine Remnant Ablation

All patients with FTC and those PTC patients who have features associated with increased risk of recurrence or mortality (see the discussion of Prognosis under Papillary Thyroid Cancer) may undergo radioactive iodine (RAI) remnant ablation (RAI treatment or ¹³¹I remnant ablation). The RAI is taken up by the residual normal and tumor cells, leading to destruction or death of these cells. This not only reduces future recurrence risk but also facilitates surveillance for future recurrence. Before the treatment, plasma Tg is measured and a whole-body scan is performed after administration of a very small dose of RAI. Several days after the treatment, another whole-body scan is obtained (posttreatment scan).

Well-differentiated thyroid cancer has a reduced capacity to concentrate iodine compared with normal thyroid tissue. An elevated serum TSH stimulates the thyroid cancer cells to take up iodide enough to be detected by RAI imaging and synthesize and secrete Tg. TSH levels can be increased in two ways; one being withdrawal of thyroid hormone therapy. To achieve this, patients should be off of L-thyroxine (LT₄) for weeks prior to the whole-body scan (because of longer half-life). Alternatively, patients may be started on liothyronine (Cytomel, Pfizer Inc., New York, NY; or LT₃) for 4 weeks after surgery, stopping 2 weeks before the whole-body scan. This has a shorter half-life than L-thyroxine, and TSH levels rapidly rise after its discontinuation. Alternatively, the TSH level can also be increased by administration of recombinant human TSH (RhTSH; Thyrogen, Sanofi Genzyme, Cambridge, MA).