Interesting abnormalities in iodide metabolism are typical of thyroid adenomas (described above) and in thyroid carcinomas. In general, the tumors are cold at 131I scintiscan, because they tend to lose the ability to accumulate iodide from the plasma, to bind iodide to TG, or to synthesize thyroid hormone (331). The pattern is one of dedifferentiation, the loss of those functions peculiar to the thyroid gland. The functional deficit represents loss of expression of the iodide transporter gene, or thyroid peroxidase, or other genes related to iodide oxidation and binding to tyrosine.Follicular carcinomas tend to retain iodide metabolism more completely than other tumors, and therefore may be susceptible to treatment with RAI. Localization of 131I in tumors, if present at all, is spotty rather than homogeneous.
Occasionally follicular thyroid cancers express high levels of Type 2 iodothyronine deiodinase, and cause "consumptive hypothyroidism" (332). This surprising phenomenum has also been observed in patients who have highly vascular tumors which express the deiodinase (333).In rare cases follicular tumors or their metastases produce significant amounts of thyroid hormone. In many instances the thyroid gland has been completely removed or destroyed, but the metastases have been sufficiently active to maintain the patient in a thyrotoxic state. More frequently, the metastases produce enough hormone to maintain the patient in a euthyroid condition, but not enough to produce thyrotoxicosis. This action indicates that the tumor may be responsive to thyrotrophic hormone, like the observation that thyrotropic hormone can induce growth of the tumors. Carcinomas usually are associated with elevated serum TG levels. Growing differentiated tumors may cause levels of TG of > 2000 mg/ml. In Hurthle cell tumors and anaplastic cancers, TG levels are usually minimally elevated. Differentiated thyroid cancers tend to retain a normal affinity and capacity for binding of TSH to their membrane receptors (334), and TSH stimulates cAMP production normally in tumor tissue. Perhaps in keeping with the clinically recognized unresponsiveness to TSH, undifferentiated tumors lack high-affinity TSH receptors. Genetic studies show that in these tumors the expression of the TSH receptor gene, and other thyroid differentiation genes is usually lost (335). In autonomous thyroid nodules, TSH stimulates cAMP accumulation normally; hypersensitivity to the hormone has sometimes been found (336, 337).
Information is accumulating on the relation of of specific genes to clinical
expression of thyroid tumors. The frequency of
PAX8-PPARgamma rearrangement is similar in Follicular Variant of PTCs
(37.5%), FTCs (45.5%), and FTAdenomas (33.3%). The same holds true regarding the
frequency and type of RAS mutations. In FVPTCs, the PAX8-PPARgamma rearrangement was significantly associated with multifocality and
vascular invasion, whereas the RAS mutations were significantly associated with
the large tumor size. A subset of FVPTC shares some of the molecular features of
follicular tumors (337a). In a
multicenter study of 219 PTC patients, a significant association was found
between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node
metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial
surgery. BRAF mutation was also significantly associated with tumor recurrence.
BRAF mutation may be a useful molecular marker to assist in risk stratification
for patients with PTC. Osteopontin is frequently expressed in PTC, and
expression correlates with aggressive features. OPN might be used as a
diagnostic and prognostic marker for these tumors(337c).
The role of oncogenes in causation of thyroid cancers is further discussed below under "Cause of tumors"
