Factors Influencing Prognosis and Outcome

The prognosis of DTC may be determined by an interaction of three factors:

Patient variables Age Gender

Other thyroid diseases Family history Tumor variables Histology

Multifocality Lymph-node metastases Capsular invasion Extrathyroid extension Distant metastases Irradiation-induced carcinoma Oncogenes

Therapy variables Extent of resection Radioiodine therapy

Patient Variables

Age: Age over 40 years at the beginning of the therapy is the most important adverse prognostic factor. Prognosis becomes progressively worse thereafter, particularly after 60 years of age (40,41). Children usually have more advanced tumors, with local and distant metastases and higher recurrence rates; however, their prognosis is excellent (42). An exception is children under age 10 who have very high mortality rates (43-45).

Gender: Thyroid cancer recurrence and mortality rates are higher in men. Although estrogen and progesterone receptors are expressed in up to 50% of PTCs, this does not explain the risk imposed by male gender (41,46).

Other thyroid diseases: One study of PTC associated with Graves' disease found that the tumors were more often multifocal with distant metastases (47). Serum from patients with Graves' disease has been shown to stimulate the progression of follicular cells to carcinoma in vitro (48).

PTC appears to carry a better prognosis when Hashimoto's thyroiditis or lymphocyte infiltration are associated (49,50). Hashimoto's thyroiditis itself, however, is considered a risk factor for DTC.

Family history: About 5% of PTCs are familial tumors inherited as an autosomal dominant trait although the responsible gene is still unknown. Familial PTC seems to have a worse prognosis. It can be inherited with other diseases, such as familial adenomatous polyposis (Gardner's syndrome), Cowden disease (a very rare familial syndrome of multiple hamartomas and breast carcinoma), or Carney complex (a familial syndrome of hypercortisolism and pigmen-ted adrenal nodules, spotty skin pigmentation, myxomas, schwannomas, pituitary adenomas, and testicular endocrine tumors).

Tumor Variables

Histology: Outcome is more favorable with PTC than with FTC. The poorer prognosis in FTC patients is also related to an older age and to a more extensive tumor burden at initial diagnosis. Within these two histological entities the outcome may be different for their respective variants (Table 2). Hurthle cell carcinoma (oncocytic carcinoma or oxyphilic variant FTC) may have a worse prognosis than FTC (51) although some studies show that overall mortality is similar. Older age, greater tumor size, and extensive disease predict poor outcome in Hurthle cell carcinoma (52,53).

Multifocality: Multifocal disease is frequently found in PTC and much less frequently in FTC. Multifocality in one lobe is almost always associated with bilateral thyroid cancer when complete thyroidectomy is performed. It has been associated with higher rates of lymph-node metastases, persistent local disease, regional recurrences, and distant metastases (54,55).

Table 2 Prognostic Factors Associated with Poor Outcome

Patient variables Older age

Male gender

DTC and Graves' disease Familial PTC

Tumor variables PTC variants: tall cells; columnar cells; diffuse sclerosing subtypes FTC variants: widely invasive Multifocality and bilaterality Lymph-node extension Capsular invasion

Extension beyond the thyroid capsule Distant metastases Irradiation-induced PTC RET/PTC oncogenes. Initial lack of radioiodine uptake or loss during the course of the disease Therapy Time of treatment is more than one year

Incomplete tumor resection No postoperative iodine-131 therapy when other poor prognostic factors exist

Abbreviations: DTC, differentiated thyroid cancer; FTC, follicular thyroid cancer; PTC, papillary thyroid cancer.

Lymph-node metastases: They are frequent in PTC—from 35% to 70% in different series, and in up to 80% in children—depending on the extent of lymph-node surgery, and much less frequent (less than 20%) in FTC (7,56).

Even in papillary microcarcinoma local nodes may be involved (57). The prognostic impact of lymph-node metastases is still controversial. Some report that the presence of lymph-node metastases has no predictive value for recurrence or survival (58). Others find an increased risk for local tumor recurrence (40,59). Persistent or recurrent lymph-node metastases are also considered a risk factor for developing lung metastases.

Capsular invasion and extrathyroidal extension: Tumor extension beyond the thyroid capsule is present in 8% to 32% of PTC and is frequently observed in widely invasive follicular carcinoma. It is an independent risk factor, exposing patients to higher local recurrence rates, distant metastases, and mortality (11,60,61).

Distant metastases: Distant metastases at the time of initial diagnosis signal a poor prognosis in patients with both PTC and FTC. They are initially present in 1% to 3% of PTC and in 7% to 15% of FTC. Bone metastases are sometimes the first clinical manifestation of thyroid cancers. Distant metastases of differentiated thyroid cancer are usually localized in the lungs and bones; less common sites include the brain, liver, and skin. They are the main cause of death from DTC. Children and young adults with pulmonary metastases have a more favorable prognosis when their distant metastases are discovered early, are small, and concentrate I-131 (62).

Irradiation-induced carcinoma: Papillary thyroid cancers associated with radiation are usually large and multicentric. They have high recurrence rates, although no higher mortality rate (63).

Oncogenes: RET/PTC rearrangements are present in about 40% of PTCs and may play a role in metastatic behavior. In Chernobyl children, RET/ PTC3 oncogenes were found and PTC3 may be present in more aggressive tumors, however, the importance of tumor genetics remains controversial (41,64).

Therapy Variables

Tumor staging systems and prognostic scoring systems: Several staging and prognostic scoring systems have been used to discriminate between low-risk patients with favorable outcome, who require less aggressive therapy and higher risk patients at risk for greater morbidity and mortality from thyroid carcinoma and require aggressive therapy regimens. The most frequently used system is tumor node metastases (TNM).

Tumor node Metastases scoring system

TO No evidence of primary tumor

T1 Tumor <2 cm limited to the thyroid

T2 Tumor >2 cm <4 cm limited to the thyroid

T3 Tumor >4 cm limited to the thyroid or with minimal extrathyroid extension T4a Invasion of any: subcutaneous soft tissue, larynx, trachea, esophagus, and recurrent laryngeal nerve T4b Invasion of any: prevertebral fascia, mediastinal vessels, and carotid artery NO No regional lymph node metastasis

N1a Metastases in pretracheal and paratracheal nodes

N1b Metastases in other unilateral, bilateral, or contralateral cervical or upper mediastinal lymph nodes MO No distant metastases

Ml Distant metastases

Tumor node

Metastases scoring system

Age <45 years Stage I Stage II

Age >45 years Stage I Stage II Stage III Stage IVa Stage IVb Stage IVc

T3, N0, M0 or any Tl-3, Nla, M0 Tl-3, Nlb, M0 or T4a, any N, M0 T4b, any N, M0 Any T, any N, Ml

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