Oncology

Undifferentiated Thyroid Cancer

Undifferentiated (Anaplastic) Thyroid Cancer *The original source for this chapter was Prof. Furio Pacini. The chapter was revised for this program by David Gerber, MD.

What every physician needs to know:

Undifferentiated thyroid carcinoma (UTC) refers to a cancer arising from the follicular thyroid epithelium but lacking the typical differentiation feature of the thyroid gland (iodine uptake, thyroglobulin secretion, response to TSH stimulation). These are the most aggressive types of thyroid malignancy.

UTC is also known as anaplastic thyroid cancer. By contrast, differentiated thyroid cancer includes papillary and follicular thyroid cancers. Like UTC, medullary thyroid cancer has a distinctly worse prognosis than differentiated thyroid cancer.

The female-to-male ratio of UTC is of approximately 2:1. The peak incidence is in the sixth-seventh decades (mean age at diagnosis 55-65 years). In most cases, UTC develops from a pre-existing well-differentiated thyroid tumor which has undergone additional mutational events (primarily p53 mutations).

Regardless of treatment, mean survival is invariably very poor at approximately 6-8 months from diagnosis.

Are you sure your patient has undifferentiated thyroid cancer? What should you expect to find?

Symptoms

Patients may complain of a neck mass which appeared a few months or weeks prior to presentation. The mass is rapidly growing and usually accompanied by hoarseness, dysphagia, and dyspnea secondary to compression and/or infiltration of the laryngeal nerves, the esophagus, and the trachea, respectively. Local pain may also be present, both with and without palpation. Other symptoms may include weight loss, weakness, and fatigue.

Signs

On physical examination, the mass is usually easily visible and palpable. Its consistency is very firm and the mass is fixed. The underlying skin may be inflamed and painful. A dilated venous reticulum under the skin of the neck and thorax may be appreciated on inspection. Multiple enlarged lymph nodes may be palpable on the ipsilateral neck. More rarely, the skin may be ulcerated with protrusion of a necrotic and bleeding tumor.

Weight loss is common due to dysphagia or the underlying malignancy itself. Distant metastases to the lung, bone, skin, and brain are common at presentation or develop soon after the diagnosis. Lung metastases may be seen on chest X-ray, with CT scanning, usually demonstrating additional small metastases.

These lesions can be associated with respiratory failure and hemoptysis. Bone metastases may be visible on scintigraphy. Brain metastases are less frequent; as they may be asymptomatic, brain MRI should always be performed at the time of diagnosis. Metastases to the liver and adrenals may occur late in the course of the disease. Death occurs mainly due to progressive airway invasion and progression.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Serum thyroid hormone levels are usually in the normal range, but subclinical hypothyroidism may be found when significant portions of the thyroid gland have been affected by the tumor. Serum thyroglobulin levels are usually normal or slightly elevated secondary to thyroid destruction. Sedimentation rate may be elevated as well as C-reactive protein. Leukocytosis may be present.

Imaging should include careful neck ultrasonography to assess the presence of regional lymph node metastases. CT scanning of the chest/abdomen/pelvis, brain MRI, and nuclear bone scintigraphy (or FDG-PET/CT) are recommended for tumor staging.

Staging

Table I. TNM staging of thyroid cancer.

Table I

What therapies should you initiate immediately i.e., emergently?

Tracheal invasion/compression may require immediate tracheostomy.

What should the initial definitive therapy for the cancer be?

Surgical resection

Currently, there are no effective treatments for anaplastic thyroid cancer. The prognosis is very poor without exception. Whenever possible, radical surgery is the primary treatment. Unfortunately, this is possible in only a few cases. The majority of patients present with massive local invasion which precludes surgery, leaving only tumor debulking or biopsy to confirm the diagnosis as the only remaining options.

Even when radical surgery is performed, local recurrence is very frequent and rapid. For this reason, external beam radiotherapy is indicated in all patients immediately after surgery.

Radiation therapy

Radiotherapy is best performed with a hyperfractionated approach, consisting of 160 cGy twice a day, three times a week for 40 days, delivering a total dose of about 6000 cGy. Many centers combine radiation therapy with chemotherapy regimens (usually cisplatin or doxorubicin). Such an aggressive treatment regimen should be proposed for patients with high chance of long-term local control. In those with poor general prognosis, aggressive local disease, and distant metastases, palliative supportive measures should be the primary treatment.

Chemotherapy

The two classes of cytotoxic agents with greatest evidence supporting their use in the treatment of UTC are the anthracyclines and the taxanes. In clinical trials, these agents have demonstrated response rates up to 50%, although responses are usually transient. Combination regimens have been employed, although it is not clear if they yield clinical benefit over single-agent treatment.

Single-agent chemotherapy

  • Doxorubicin 60 to 75mg/m² IV every 3 weeks

  • Doxorubicin 20mg/m² IV weekly

  • Paclitaxel 60 to 90mg/m² weekly

Combination chemotherapy

  • Cisplatin 50mg/m² IV plus doxorubicin 50mg/m² IV every 3 weeks

  • Doxorubicin 50mg/m² IV plus docetaxel 50mg/m² IV every 3 weeks (with growth factor support)

  • Doxorubicin 50mg/m² IV plus Paclitaxel 220mg/m² IV every 3 weeks

Small molecule tyrosine kinase inhibitors

Multiple clinical trials of small molecule tyrosine kinase inhibitors (primarily antiangiogenic agents) have been performed in thyroid cancer. In studies enrolling both UTC and differentiated thyroid cancer, UTC generally accounts for a minority of cases and has lower response rates than differentiated thyroid cancer (where stable disease rates may approach 80%). None of these agents are currently FDA approved for the treatment of UTC.

Commercially available TKIs that have been studied in thyroid cancer:

  • Sorafenib 400mg PO bid (taken without food)

  • Sunitinib 50mg PO daily 4 weeks on/2 weeks off (taken with or without food)

  • Pazopanib 800mg PO daily (taken without food)

  • Axitinib 5mg PO bid (taken with or without food)

  • Vandetanib (approved for medullary thyroid cancer) 300mg PO daily (taken with or without food)

Class side effects include gastrointestinal (GI) symptoms, hand-foot syndrome, hypertension, and potential for bleeding/thrombosis. Additionally, vandetanib has been associated with prolonged QTc, Torsades de Pointes, and sudden death; regular EKG monitoring is mandated. Pazopanib has been associated with severe, fatal hepatotoxicity. Cases of cardiomyopathy have been described with sunitinib and sorafenib.

What’s the evidence?

Ain, KB. "Anaplastic thyroid carcinoma: behavior, biology, and therapeutic approaches". Thyroid. vol. 8. 1998. pp. 715-26.

Brierley, JD. "Update on external beam radiation therapy in thyroid cancer". J Clin Endocrinol Metab. vol. 96. 2011. pp. 2289-95.

Edge, SB, Byrd, DR, Compton, CC. AJCC Cancer Staging Manual. Springer SBM, LLC. 2009.

Haigh, PI, Ituarte, PH, Wu, HS. "Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival". Cancer. vol. 91. 2001. pp. 2335-42.

Sherman, EJ, Lim, SH, Ho, AL. "Concurrent doxorubicin and radiotherapy for anaplastic thyroid cancer: a critical re-evaluation including uniform pathogic review". Radiother Oncol. vol. 101. 2011. pp. 425-30.

Wunderlich, A, Fisher, M, Schlosshauer, T. "Evaluation of Aurota kinase inhibitor as a new therapeutic strategy in anaplastic and poorly differentiated follicular thyroid cancer". Cancer Sci. vol. 2. 2011. pp. 762-8.

Smallridge, RC, Marlow, LA, Copland, JA. "Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies". Endoc Relat Cancer. vol. 16. 2009. pp. 17-44.

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