Diagnosis
Most patients with thyroid carcinoma are recognized because of the observation of a neck mass, and the result of FNA. The question of thyroid carcinoma arises whenever a discrete solitary nodule is found in the thyroid gland by accident or because it has produced local symptoms. It also arises when an unusually hard or dominant nodule is found in multinodular goiter, when enlarged cervical lymph nodes are detected, or when unidentified metastatic lesions are found elsehwere in the body. It must be strongly considered whenever an expanding lesion is present in the thyroid gland, especially when it is painful. Usually cancers present as discrete lumps, but occasionally papillary cancer may present as a diffuse goiter or as a "multinodular" goiter (354). Anaplastic cancers and lymphomas commonly present as a smooth goiter. Stony hardness, fixation to the trachea, and damage to recurrent laryngeal or cervical sympathetic nerves are other important clinical signs. The problems of differentiating carcinoma from other lesions of the thyroid have been reviewed in the preceding discussion of thyroid nodules. A few additional comments are given here. FNA and US studies, constitute the basic and most useful laboratory studies. TSH and fT4 are usually measured to verify metabolic status, and anti-TPO and TG antibodies may be useful in helping differentiate thyroiditis. Isotope scans and TG assay have a limited role in initial diagnosis. Chest xray may be informative but is often omitted. In lesions which extend outside the thyroid, or have metastasis, ultrasound of the neck, CAT scanning of the lungs, and MRI of the neck can provide useful information prior to surgery, and especially when following disease progress.
Currently, as described previously in the section on diagnosis of thyroid nodules, most reliance is placed on needle aspiration cytology. Fine needle aspiration cytology of cervical nodes under ultrasound guidance also must be remembered as a very useful technique (355).
Ultrasound
Ultrasonic scanning, angiography, thermography, iodopaque "thyrography", and fluorescent scanning have all been applied to the diagnosis of thyroid carcinoma. The techniques are discussed above. Of these approaches, only ultrasonic scanning has greatly improved diagnostic accuracy.
Thyroglobulin assay-Although TG assay has been suggested as an important marker for thyroid cancer (356), practice shows that elevated TG levels can be caused by adenoma, multinodular goiter, and other diseases; thus the determination is of little value before operation.
Calcitonin Immunoassay-
Calcitonin assay on all patients with nodules has been recommended by some
groups, to allow pre-operative diagnisis of MTC. To date this concept has not
been generally accepted because of cost and false positive events. Costante et
al reported CT assays on a series of 5817 patients with thyroid nodules.. Basal
values above 20 were considered suspicious, and a pentagastrin stimulation test
was performed (356a). Values above 100 on the stimulation test were considered
an indication for surgery, and 6 of 9 with this response had MTC. Patients with
basal values between 20 and 100 pg/ml who came to operation had either CCH or
MTC, in equal proportions. Thirteen percent of suspicious values (above 20) were
associated with Hashimoto’s thyroiditis. These authors find the CT immunoassay
to be more sensitive than FNA in diagnosing MTC. However the high incidence of
false negatives associated with sensitive assays diminishes the cost
effectiveness of routine assay on all patients with nodules.
Scintiscanning using 131-I is currently usually omitted in the initial evaluation of a possible malignancy. Most of the anatomic information needed is provided by US. Occasionally isotope scanning is useful in demonstration of hyperfunction in a nodule, lack of a lobe, extension below the sternum, or other factors. Demonstrate of failure of the involved area to concentrate RAI used to be important, since this is typical of a malignant lesion. however it in no way proves the presence of cancer, nor does its absence rule out this possibility. Whole body scintiscanning is useful to determine whether lesions in lung or bone are thyroid tumor metastases. Significant accumulation of RAI by the metastasis definitely proves thyroid origin. Occasionally uptake of RAI can be demonstrated in metastases in the neck before surgery. This finding is almost certain evidence for cancer. Usually normal thyroid tissue must be destroyed and TSH elevated before a metastasis will accumulate 131I. 131I whole body scanning in management of previously diagnosed thyroid cancer is discussed later in this chapter.
Some tumors accumulate iodide but do not organify it. They are delineated by radiotechnetium scans done during the early "iodide phase" of isotope distribution, but not by scans using 131-I or 125-I done at 24 - 72 hours, when the storage of organified isotope is primarily recorded. Conversely, some metastases accumulate small amounts of 131-I but are not shown on short-term technetium scans (357). Radiolabelled antithyroglobulin has shown potential in scanning for thyroid cancer metastasis, and in some studies has proven more sensitive than 131Iodide (358). Radio-labelled anti-CEA has been used to identify MTC, but has so far not proven sensitive enough for routine use (359).
[32P]-Phosphate and 75Se-Selenium scanning did not prove useful (360). Thallium201 chloride is concentrated by most thyroid cancers and may be useful for identifying metastatic tumor (361). Gallium is occasionally used to identify deposits of anaplastic cancer, and is used routinely to visualize lymphomas (363). 131-I metaiodobenzylguanidine (MIBG) is useful in imaging MTC as is radioiodine labelled octreitide (364, 365). 99mTc-MIBI is highly effective (up to 94% of patients positive) in detecting deposits of metastatic thyroid cancer. It thus needs to be recognized as a useful scanning agent in follow-up of patients, although with obvious limitations that it is not able to detect small lung metastases, and of course is not useful for judging the therapeutic efficacy of 131I administration. It is, however, a useful addition for finding lesions in patients who are 131I scan negative-TG positive, in whom surgical resection or radiotherapy may be appropriate (366).
PET Scans-
Recently, PET scan has been introduced and found informative for the imaging of metastatic disease devoid of 131-I uptake. 18-F Fluorodeoxyglucose Positron Emission tomography can localize tumor and determine tumor volume. Large deposits (>125ml) have a very adverse prognostic implication (367). It appears that stimulation of metastatic deposits by elevated TSH makes PET scanning more sensitive(367a).Unfortunately,
FDG-PET scanning does not appear to distinguish between benign and malignant
follicular thyroid nodules(367b).
A most interesting new way to recognize the presence of thyroid cancer is by detection of thyroglobulin mRNA in peripheral blood. Presumably thyroid tumor cells are sloughed from the malignancy and occur in blood, and the thyroglobulin mRNA can be detected by RT-PCR. The utility of this technique has been established for diagnosing the presence of residual or recurrent malignancy after initial operation and thyroid ablation, but it does not have a role in preoperative diagnosis.. The technique is not generally available as of this time (368, 369). Controversy remains as to the sensitivity and specificity of this technique, and it is probable that it will not prove as useful as TG measurement. Results that appear to represent false positives are common (369a). However the test may find a role in patients whose positive TG antibodies prevent reliance on the TG assay. TSHR mRNA can also be detected in blood, apparently from circulating cancer cells. Similarly, CEA mRNA can be detected by RT-PCR and helps distinguish between malignant and benign follicular thyroid neoplasms.(369b)
TSH- mRNA
Chia et al report that TSHR mRNA measured
with FNA enhances the preoperative detection of cancer in patients with thyroid
nodules, reducing unnecessary surgeries, and immediate postoperative levels can
predict residual/metastatic disease. TSHR mRNA levels measured by RT-PCR in
cancer patients were significantly higher than in benign disease. At a cutoff
value of 1.02 ng/microg total RNA, the TSHR mRNA correctly classified 78.7% of
patients preoperatively. TSHR mRNA correctly diagnosed DTC in 16 of 24 (67%),
and benign disease in 29 of 39 (74%) patients with indeterminate FNA. Combining
TSHR mRNA and ultrasound correctly classified all follicular cancers and could
have spared surgery in 31% of these patients with benign disease. Normal levels
on postoperative d 1 correlated with disease-free status, whereas elevated
levels predicted residual/metastatic disease.(369bb). While seemingly hopeful, this technology has not gained much attention.
Genetic Diagnosis-Molecular biology is rapidly entering the field of diagnostic studies. For example, Weber et al (369c) reported that gene profiling by gene arrays identified three genes- cyclin D2, protein convertase 2, and prostate differentiation factor- that allow molecular classification of follicular adenomas and carcinomas.
G