The Problem of the Patient with Thyroglobulin Elevation but Negative Iodine Scintigraphy: The TENIS Syndrome

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The available data upon which to act in caring for patients with functioning thyroid cancer and thyroglobulin elevation/negative iodine scintigraphy (TENIS) are imperfect, almost never coming from randomized, blinded studies. When the serum thyroglobulin exceeds 2-10 ng/mL, one should use the latest imaging equipment available to find metastatic disease, especially in areas in which it is potentially resectable, ie, neck, bone, and occasionally brain, and collaborate with an experienced surgeon in removing such metastases. If one cannot locate operable metastases and/or tumor location remains elusive, empiric high-dose 131I therapy, preceded by dosimetry, should be considered. There are no randomized studies to prove that this treatment prolongs life, although there is definite evidence of cell killing, because the serum thyroglobulin level frequently diminishes after radioiodine therapy. In selected cases External beam radiotherapy will be helpful when the tumor has been located but cannot be fully removed, for example, with invasion of the trachea, spine, or muscles. There are several tyrosine kinase inhibitors that have shown some effectiveness against the TENIS syndrome, but these should ideally be used in the context of a clinical trial. Tyrosine kinase inhibitor drugs should be preferred to conventional chemotherapy at this time; data on lenalidominde have only appeared in abstract form. The return of NIS function, to permit functioning thyroid cancer with the TENIS syndrome to again concentrate therapeutic amounts of 131I, remains an elusive goal, with few drugs showing real promise. Gene therapy to restore the function of the NIS gene and enhance cellular immunomodulatory and tumor suppressive activity has not yet succeeded clinically. Physicians caring for patients with the TENIS syndrome are urged to enter them into clinical therapeutic studies whenever possible.

Section snippets

TSH Suppression

What then are the available for the treatment of thyroid cancer which no longer possesses the functioning NIS symporter but can still produce thyroglobulin? First, one must continue TSH suppression, even though an increasing serum tg in the presence of a low TSH strongly suggests poor tumor responsiveness to suppression of this growth factor. There are, however, many clinicians who believe that more aggressive TSH suppression is required for high-risk disease and recurrent tumor, as documented

Serum tg Thresholds

Far more likely as causes of the TENIS syndrome presentation in FTC are microscopic remnants of normal tissue or of metastatic disease not visible with the diagnostic dosage of 131I, inadequate serum TSH stimulation, macroscopic metastatic disease that has mutated to lose NIS, or a combination of these factors. The physician must decide at what level of serum tg further investigation is necessary. The American Thyroid Association guidelines suggest level of stimulated tg >2 ng/mL as a

Tumor Detection

After excluding an antibody-induced false-positive tg assay and dilution of the iodine pool, the clinician must attempt to localize the site or sites of metastatic thyroid tissue if possible. A detailed review of the medical history and current systems should be undertaken and then a thorough physical examination. Metastases are most likely in lymph nodes of the neck but also are found not uncommonly in the lungs and bone. Metastatic FTC in lymph nodes of the neck may be detected by ultrasound

Surgical Resection

If there are suspicious nodal findings in the neck, surgical exploration and resection would follow before any consideration of systemic therapy, with its attendant side effects, would be considered.14 Lung metastases are generally multiple and therefore unresectable. However, especially in smokers, one must be aware that a synchronous bronchogenic carcinoma may be detected and tends to have a different, more spiculated pattern than metastases from thyroid cancer, and lung cancer may be

Empiric High-Dose 131I

Whether the clinician has found resectable thyroid cancer that no longer concentrates diagnostic activities of radioiodine, or whether he or she is now confronted with a patient with the TENIS syndrome and no identifiable or resectable tumor, he or she should at least consider therapy with an empiric, high dose of 131I. To provide high-dose empiric therapy requires a dosimetric measure of that radioiodine activity that will give the patient's bone marrow no more than 2 Gy, a radiation dose

External Beam Radiation Therapy

External beam radiotherapy (XBRT) has only a limited role in metastatic thyroid cancer in the neck. The tumor is not very radiosensitive, and radiotoxicity to the trachea and spinal cord, which are often adjacent to neck metastases, is dose-limiting. Doses in the range of 65-70 Gy are employed when invasive, partially unresectable thyroid cancer involves the trachea, esophagus, or other extrathyroidal sites in the neck because microscopic residual tumor is usually still present. Other

Chemotherapy

Standard chemotherapeutic agents, for example, doxorubicin, multiple doxorubicin and epirubicin combinations, cisplatin, and several taxanes, have an unimpressive record of efficacy, with limited partial responses (PR) up to 35%-40% and time to progression of only a few months, at the cost of considerable toxicity.24, 25, 26

In a trial of thalidomide involving 36 patients, of whom 28 were evaluable, there were 5 (18% PR) with a mean duration 4 months and 9 patients (32%) with stable disease,

Biological/Molecular Targeting Agents

The phrase “biological targeting agents” for cancer therapy is widely used, with the implication that this is a new concept for a different kind of therapeutic agent. In fact every form of chemotherapy has one or more membrane or intracellular targets. For example, doxorubicin targets and stabilizes the topoisomerase II complex, preventing the double helix of DNA from being resealed, thus blocking DNA replication. All the agents to be discussed in the subsections to follow are not unique in

Problems of Available Therapeutic Choices

Patients with the TENIS syndrome provide a therapeutic dilemma for which clear answers, based on randomized, double blind studies of various forms of therapy are lacking. In the currently active field of angiogenesis inhibitors in thyroid cancer, a review of 832 publications found no unbiased, double-blinded studies with clear endpoints and complete data.59 Few physicians who treat thyroid cancer have enough patients with the TENIS syndrome for a single-site double-blinded therapeutic study,

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