Initial Evaluations

Laboratory, biopsy, and imaging procedures

When a patient presents with a thyroid mass or metastatic lesion that has been characterized as ATC through appropriate cytological and/or histological assessment, there are a number of preoperative staging procedures that are likely to be of value. These consist of a physical examination and laboratory studies to appropriately characterize the physiological status of the patient and provide baseline parameters for further medical care issues, as well as radiological studies to determine the extent of disease for tumor staging and determine the best medical and/or surgical therapy.

Requisite laboratory studies include a complete blood count and differential to evaluate for anemia, assess adequacy of platelets, and to discern any underlying leukocytosis suggestive of active infection (86) or diminished white blood cell components indicating immunodeficiency. It should be noted that rare ATC patients present with marked leukocytosis consequent to tumor secretion of lymphokines (87,88). Blood chemistry evaluation could include: electrolytes, serum urea nitrogen, creatinine, glucose, and liver function tests. Free thyroxine and thyrotropin should be assessed because large tumor masses may have compromised thyroid function, and some cases of ATC are associated with significant thyrotoxicosis (89,90). Calcium and phosphorus should be measured because tumor invasion may compromise parathyroid function, and unusual ATC cases can present with humoral hypercalcemia of malignancy (91). Since ATC is most common in elderly patients, often with diminished nutrition, ionized calcium provides superior assessment of calcium status (92), although calculations involving serum protein levels and total calcium values may be useful when ionized calcium values are not available (93). Coagulation studies, prothrombin time and activated partial thromboplastin time, should also be obtained. Considering the technical difficulties of surgical resection for invasive ATC and the likely need for blood transfusion, it is reasonable to provide a preoperative blood sample for type and cross-match rather than just utilizing a type-and-hold approach if surgical resection is being planned.

It is axiomatic that adjunctive preoperative radiological studies should not delay urgent therapeutic intervention and that required radiologic tests should be scheduled expeditiously. Cross-sectional imaging of the neck and chest should be performed to assess the extent of disease and to plan any subsequent surgery and/or radiation therapy (94). A high resolution ultrasound of the neck should be obtained because it is able to provide rapid evaluation of the primary thyroid tumor and to assess for involvement of the central and lateral lymph node basins and to assist in evaluating airway patency. If accessible, positron emission tomography (PET), utilizing 18F-fluorodeoxyglucose (18FDG) and fused to a coincident CT scan (brain to pelvis), is particularly valuable in evaluating metastatic sites (95–98). This may be useful in the context of distinguishing ATC metastases from coincident DTC metastases due to the greater glucose transport of ATC cells from enhanced expression of the Glut-1 glucose transporter with resultant significantly elevated modified standard uptake values (increased uptake of 18FDG) (99). Cross-sectional imaging of the neck and chest with magnetic resonance imaging (MRI) and/or CT scan is also imperative to determine the presence of regional disease and exclude distant metastasis. For better evaluation of the extent of disease, CT scan with intravenous contrast will be helpful. Alternatively, MRI using gadolinium contrast can evaluate the neck and superior mediastinum (100).

  • RECOMMENDATION 6 Adjunctive preoperative radiological tumor staging should not delay therapy and should make use of appropriate cross-sectional imaging including neck ultrasound,CT scans or MRI (for the neck and chest), and PET/CT fusion scans.
       Strength of Recommendation: Strong
       Quality of Evidence: Moderate

Biopsy of distant masses. It is common for ATC and DTC to coexist in the same patient (24,55) because ATC usually arises by dedifferentiation of preexisting DTC. In this context, it may be necessary to attempt to distinguish macroscopic distant metastases of ATC from those of DTC, because of the significant differences in prognostic implication and because it could alter the therapeutic approach. Likewise, ATC may be diagnosed in patients with separate cancers (previously diagnosed or not) such as primary lung carcinomas, metastatic prostate cancers, or metastatic breast cancers. Under such circumstances, therapeutic modalities vary considerably depending upon the proper tumor diagnosis.

There may be some clinical clues that could prove informative. PET/CT fusion studies may be able to distinguish hypermetabolic ATC metastases, which have increased uptake of 18FDG, from more indolent metastases typically observed in DTC or some other cancers. Likewise, severely elevated tumor markers (i.e., prostate-specific antigen for prostate cancer, Tg for DTC) may suggest the need to distinguish and characterize distant metastases. Fine-needle biopsy of distant metastatic sites, along with appropriate immunohistochemical analysis, can be used to resolve such questions.

Although it is important to properly characterize the etiology of metastatic tumor sites, it would be unusual for this knowledge to have a significant effect upon the planning or implementation of primary surgery for ATC. For this reason, in most circumstances primary surgery should not be delayed to biopsy distant metastases. Such biopsies may be pursued after primary surgery is completed in the rare circumstances when such questions arise. It is not expected that this will be needed in most cases of ATC.

  • RECOMMENDATION 7 Primary management of ATC should not be delayed in order to biopsy tumors at distant sites. If clinically indicated, such biopsies could be performed after completion of primary surgery.
       Strength of Recommendation: Weak
       Quality of Evidence: Low

Timing and nature of evaluation studies

In the assessment of a rapidly growing neck mass, necessary preoperative evaluations must be completed quickly. All initial staging procedures should be expedited by the treating physician and should not be relegated to any schedule that delays treatment. It is critical that preoperative medical and anesthesia assessments be accomplished in the briefest time if required.

  • RECOMMENDATION 8 All critical appointments and assessments that are required prior to primary treatment of ATC should be prioritized and completed as rapidly as possible.
       Strength of Recommendation: Strong
       Quality of Evidence: Low

Airway and vocal cord assessment. Vocal cord paralysis is quite common in patients with ATC, as compared with those with well-differentiated thyroid cancer. Because of the rapid increase in tumor size, the patient may present with obvious hoarseness of voice, raising the question of vocal cord mobility. The best way to evaluate vocal cord mobility is laryngeal evaluation, which can easily be performed in the office with mirror or fiber optic laryngoscopy. Most patients will present with one paralyzed vocal cord and an adequate airway. The endolaryngeal mucosa is generally normal. The fiber optic laryngoscopy will also help to evaluate whether there is direct involvement of the tumor, either in the larynx or the upper trachea. In patients with airway invasion on laryngoscopy, a bronchoscopy to evaluate the trachea is helpful to determine extent of disease and resectability.

  • RECOMMENDATION 9 Every patient should undergo initial evaluation of the vocal cords. The best way to evaluate the vocal cords is with fiber optic laryngoscopy; however, mirror examination may be acceptable. Fiber optic laryngoscopy will also help to assess the opposite vocal cord, mobility of the vocal cord, and endolaryngeal pathology and whether there is any extension of disease in the subglottic or upper tracheal area.
       Strength of Recommendation: Strong
       Quality of Evidence: Low

Staging and order of therapies. In the context of a rapidly growing neck mass that may compromise the airway and cause thoracic outlet syndrome, there are very few findings from staging that could delay planned local therapies. For example, impending neurological crisis, either from a growing brain metastasis or vertebral metastases that compromise the spinal cord, would constitute sufficient cause for delaying primary thyroid site surgery until after emergent surgical or radiosurgical care is rendered. Likewise, pulmonary hemorrhage from metastatic disease may demand priority if life threatening.

Preoperative medical assessment may indicate significant surgical risk, particularly in the context of severe ischemic cardiac or cerebrovascular disease. Considering the almost certain lethality of unresected primary ATC, it may be considered reasonable to proceed with surgery in situations that would preclude elective procedures.

  • RECOMMENDATION 10 Only imminently threatening disease elsewhere (e.g., brain or spine metastases or pulmonary hemorrhage) should prevent primary surgical management of neck disease if achievable.
       Strength of Recommendation: Strong
       Quality of Evidence: Low

Indications for neoadjuvant therapy. More than 80% of ATC patients present with extensively invasive primary tumors (101). Careful radiological assessment of tumor involvement in the visceral compartment, nearby vascular structures, and posterior paraspinous structures may reveal significant obstacles to successful primary surgery. This is because a 69% rate of tracheal invasion, 55% rate of esophageal invasion, and 39% rate of carotid artery involvement have been reported (102). Endoscopic evaluation of hypopharynx, esophagus, larynx, and trachea may be needed to supplement radiographic studies. The aggressiveness of the operative resection should be considered in the context of morbidities that may occur from resecting adjacent involved structures. Extensive tumor involvement in the thoracic inlet and upper mediastinum may presage involvement of mediastinal vascular structures that warrant emergent sternotomy to control hemorrhage. Approximately 38% of primary thyroidectomies for ATC require extended resections (2). Ultimately, preoperative staging and assessment of local tumor extent are balanced against the experience, judgment, and technical expertise of the surgeon to determine whether a primary tumor resection should be attempted with acceptable morbidity and risk. Thus, the definition of unresectable can vary among different surgeons.

If a primary tumor is deemed unresectable, then there are alternative approaches. Full or partial course external beam radiotherapy may be followed by primary surgical resection, then completion of radiotherapy if there had been a partial course. This can be as efficacious as initial primary resection (103). Likewise, neoadjuvant chemotherapy (104) may prove effective in permitting delayed primary resection in similar circumstances.

  • RECOMMENDATION 11 If preoperative staging and primary tumor assessment define the tumor extent as precluding safe or effective surgical resection, neoadjuvant external beam radiotherapy and/or chemotherapy should be considered to permit delayed primary surgical resection.
       Strength of Recommendation: Strong
       Quality of Evidence: Moderate

Postdiagnostic care of ATC

Once the diagnosis of ATC has been established, optimal initial management requires close coordination and communication among multiple specialties. The timely, decisive input of all specialties is critical in defining the initial management plan.

Since the point of entry to the multidisciplinary team may be through an initial endocrine consultation, patients and family members may also expect the endocrinologist to remain involved in, and potentially also coordinate, the decision-making process and to serve as an advocate for the patient and their family. Early interactions with pain and palliative care specialists, social workers, clergy, and/or psychologists or psychiatrists are often also important components of a comprehensive approach.

Furthermore, it is important to also have readily available gastroenterological expertise (evaluation of nutritional status and potential need for enteral or parenteral nutritional support) and radiological expertise (timely interpretation of imaging studies needed to assess the extent and spread of the disease) in parallel.

Because formulation of the initial management plan requires rapid, complex, and integrated decision making, these patients should ideally be evaluated and cared for at medical centers that have in place highly functional multidisciplinary management teams. The rarity of the disease, coupled with the breadth of knowledge required to arrive at initial treatment recommendations, makes it quite challenging for even the most experienced thyroid cancer specialist to care for these patients outside of an established thyroid cancer disease management team.

On the other hand, should logistic or geographic issues preclude rapid access to a medical center with appropriate multidisciplinary management teams, the urgency of appropriate care for ATC requires that such care be rendered by the best available clinicians in local facilities.

  • RECOMMENDATION 12 A comprehensive multimodality management plan should be rapidly formulated and implemented by a multidisciplinary thyroid cancer management team.
    Strength of Recommendation: Strong
    Quality of Evidence: Low

Prognostic factors

ATC is an aggressive tumor with a poor prognosis (1,84,105–107); median survival is only about 5–6 months and 1-year survival is 20% (1,106). Relevant prognostic features include socioeconomic status, tumor stage, increasing age, and sex (108). In a retrospective review of 121 patients with ATC, age <60 years, tumor size <7 cm, and less extensive disease at presentation were independent characteristics of decreased disease-related mortality (109). In a separate study of 47 patients with ATC, the presence of acute symptoms, tumor size >5 cm, distant metastases, and leukocytosis were each independent significant risk factors predicting a poor outcome and increased risk of death (61). Increased survival is associated with greater extent of surgery, younger age, smaller tumor size, higher dose radiotherapy, absence of distant metastases at presentation, coexistence of DTC, and management using multimodal therapy (1,84).

Kebebew et al. (110) utilized the SEER (Surveillance, Epidemiology, and End Results) database to analyze clinical characteristics of 171 men and 345 women with ATC. Thyroid cancer–specific mortality rates were 68% at 6 months and 81% at 1 year. Similar to the studies noted above, poor prognostic characteristics included male sex, age >60 years, and the presence of extrathyroidal involvement. Women under age 60 years had a better prognosis when they had surgical excision and/or external beam radiotherapy. Tan et al. (101) also observed enhanced survival in women as compared to men, but this sex difference has not been consistently observed (14,15,58,107,108,111,112). Further studies assessing the ability of markers to predict mortality are needed.

With regard to risk factors, ATC frequently occurs in a setting of previous or concurrent benign or malignant thyroid disorders. Demeter et al. (113) studied 340 patients with thyroid cancer. Of the 17 (5%) with ATC, 13 (76%) had a history of a previous thyroid disorder, primarily benign goiter, or DTC. Clinical factors such as younger age, smaller tumor size, disease confined to the thyroid gland, absence of distant metastases, and complete resection of the primary tumor are associated with the subset of ATC patients with the best prognosis.

Akaishi et al. (114) reviewed 100 patient charts with ATC. Only six patients were noted to have a small ATC within a more DTC component. Total resection was achieved in 24 of 70 patients who were operated upon. External radiation was administered to 78 subjects; 15 patients were able to receive multiple treatment modalities (e.g., surgery, radiotherapy, and chemotherapy). Survival rates at 1 year were 72.7%, 24.8%, and 8.2% for patients with disease stage IVA, IVB, and IVC, respectively. Several characteristics, such as age ≥70 years, extrathyroidal invasion, and distant metastases at presentation were associated with poorer outcomes. A complete resection, as compared to no resection for debulking, is associated with better overall survival.

  • RECOMMENDATION 13 ATC is an aggressive tumor with a poor prognosis and high mortality. Assessment of predictive factors such as age, sex, tumor size, histology, and clinical stage should be performed in all patients.
       Strength of Recommendation: Strong
       Quality of Evidence: Moderate