- Anaplastic thyroid cancer (ATC) is derived from follicular thyroid cells (“thyrocytes”) and is associated with the highest mortality risk of any thyroid-arising tumor, but accounts for only a small percentage of thyroid cancer cases overall.
- ATC patients have a historical median survival of about 5 months and a 1-year overall survival of 20%.
Guideline Grading System
|Strength of Recommendation||Quality of Evidence|
|S||Strong Recommendation||H||High-quality evidence|
|C||Conditional Recommendation||M||Moderate-quality evidence|
|W||Weak Recommendation||L||Low-quality evidence|
|GPS||Good Practice Statement||VL||Very low evidence|
Table 1. Key Steps in the Management of Anaplastic Thyroid Cancer
Terms and Definitions
- All ATCs are stage 4 (AJCC 8th Edition). Stage IVA lesions (T1-T3a, N0, M0) are still localized within the thyroid gland and have not definitely spread to lymph nodes (N0) or to distant sites (M0). In Stage IVB ATC, the primary tumor has grown outside/through the thyroid capsule (T3b, T4) and/or is involving locoregional lymph nodes (≥N1), but it has not spread to distant sites (M0). In Stage IVC (Any T, Any N, M1), the tumor has spread to distant site(s).
Extent of Resection
- R0 designates complete resection with negative microscopic margins, R1 designates complete resection of all grossly visible tumors but with involved surgical resection margins (microscopically involved resection margins), and R2 designates resection in which gross cancer was left in place (macroscopically involved resection margins).
Adjuvant Therapy and Neoadjuvant Therapy
- Radiation, systemic therapy, or the combination given after surgery with curative intention is referred to as adjuvant therapy; and when given before surgery, neoadjuvant therapy.
- Some cancers are associated with only a small number of macrometastases (termed oligometastatic cancer). In general, most studies of oligometastatic cancer have included patients with one to five distinct metastases. With a limited number of metastases, it becomes theoretically possible to treat detectable tumors with curative intention using surgery and/or locally ablative therapies, realizing that occult metastatic disease may nevertheless exist.
Definition of Therapeutic Terms
Standard Radiation Prescription
- The unit dose of radiation is the Gray, abbreviated to Gy. Some prescriptions are given in centiGray or cGy (1 Gy = 100 cGy). A radiation prescription describes the total dose of radiation to be delivered, the number of fractions (number of daily treatments), the dose of each daily treatment, and the overall length of the treatment course. The usual daily fraction size is 1.8 or 2 Gy. A standard prescription in the setting of neck irradiation in ATC would be, for instance: 66 Gy over 61/2 weeks, given as 33 daily fractions of 2 Gy per day, 5 days a week for definitive treatment, but this is adjusted depending on the clinical setting as discussed later in the document.
- Altered fractionation implies a larger number of fractions (hyperfractionated), or a smaller number of fractions (hypofractionated), or a shorter overall treatment time (accelerated). By using hyperfractionated treatment with more than one daily fraction given, it enables the prescription to be given over a shorter treatment time (accelerated hyperfractionated radiotherapy). In a rapidly growing tumor such as ATC, accelerating the treatment has the potential to minimize tumor growth that may occur over the radiotherapy treatment course. By giving multiple small fractions, the toxicity may also be reduced. An example of an accelerated hyperfractionated prescription would be: 60 Gy over 4 weeks given as 40 twice-daily fractions of 1.5 Gy, 5 days a week.
There are many different potential radiation prescription doses. For the purpose of this report they have been grouped as definitive-intention or palliative-intention.
Definitive-intention radiotherapy is high-dose radiation given with or without concurrent chemotherapy with the intent of maximizing the chance of long-term local control. Examples range from 50 Gy in 20 fractions, 2.5 Gy per fraction over 4 weeks at the low end, to 70 Gy in 35 fractions, 2 Gy per fraction over 7 weeks at the high end.
Palliative-intention Radiotherapy is lower dose radiotherapy given over a shorter time period with the primary aim of improving local symptoms and achieving initial disease control while minimizing hospital/clinic visits. This may be directed to the primary tumor or to metastases. Typical examples could be 20 Gy in 5 fractions, 4 Gy per fraction over 1 week and 30 Gy in 10 fractions, 3 Gy per fraction over 2 weeks.
- In conformal radiotherapy, the volume treated is tailored to and “conforms” to the shape of the tumor. The toxicity of radiation to the surrounding normal tissues is thereby reduced.
Intensity Modulated Radiotherapy (IMRT)
- By modulating the intensity of the radiation fields as well as shape of the fields, the radiation can be made more conformal (tailored), thereby reducing toxicity to the adjacent normal structures and potentially enabling a higher radiation dose to be given to the tumor areas.
Radiosurgery and Stereotactic Body Radiotherapy (Stereotactic Radio-surgeries)
- Radiosurgery and stereotactic body radiotherapy (SBRT) are highly conformal/focused radiation that allows a single large fraction of radiation to be given. Stereotactic radiosurgery usually refers to radiosurgery to the brain (e.g., Gamma Knife®). Stereotactic body radiosurgery usually refers to radiosurgery to parts of the body other than to the brain (e.g., CyberKnife®, X-Knife®) and SBRT usually refers to highly conformal radiotherapy given in 3–10 fractions.
- Some chemotherapeutic agents when given concurrently with radiation can potentiate the antitumor effects of radiation and thereby act as “radiation sensitizers.” This therapeutic advantage may be at the cost of increased toxicity, and in some regimens may require a reduction of the radiation dose. The principal aim of chemotherapy given concurrently with radiation is to increase the chance of local control of the tumor, and also with the intentions to affect more rapid tumor cytoreduction (assuming that the systemic therapy involved may be active in ATC) and, aspirationally, in parallel to control systemic micrometastatic disease if present.
- Chemotherapy, for the purposes of these guidelines, denotes cytotoxic agents that target basic cellular components and processes that are commonly altered in cancers. Examples include agents targeted toward cell division machinery (e.g., antimicrotubule inhibitors, paclitaxel and docetaxel), DNA repair pathways (e.g., topoisomerase inhibitors and poly-ADP ribose polymerase inhibitors), or DNA structure (e.g., platins).
Genomic Tumor Assessment
- Genomic tumor assessment denotes rigorous analysis of tumor DNA for the purposes of defining altered genes of potential or actual relevance to cancer growth and/or survival. Various platforms are available for this assessment, each with their own strengths and weakness as discussed in the Pathology section.
Genetically-informed Targeted Therapy
- “Targeted therapy” denotes systemic treatment intended to be specifically directed toward an actually or presumed altered molecule or pathway relevant to cancer growth or survival. In general, an agent or agents are selected to target a specifically identified “driver” mutation.
- “Bridging therapy” is used to denote interim approaches to the treatment of general applicability in ATC intended to contain disease while information is being attained that may better inform subsequent individualization of systemic therapy such as via targeted approaches.
- Response Evaluation Criteria in Solid Tumors (RECIST) are used to assess objectively the effects of systemic therapy on tumor dimensions/size (10). After determining the baseline diameters of index lesions (must be >1 cm for visceral lesions, >1.5 cm short axis for nodal metastases; only two measured lesions per disease site/organ allowed, generally the largest) with cross-sectional imaging (computed tomography [CT], magnetic resonance imaging [MRI]), follow-up measurements of the same lesions are determined at defined intervals and compared with baseline as a percentage of the sum of all index lesions. A complete response (CR) means disappearance of all lesions; a partial response (PR) is at least a 30% reduction in the lesional sum, confirmed at least once at a ≥4-week interval once observed; progressive disease (PD) is a 20% or greater increase in lesional sum from baseline or nadir; and stable disease (SD) refers to tumors not reaching criteria for either PR or PD. Of note is that these criteria require the absence of new locations of disease. and the absence of growth of any nontarget lesions.
Cytology, Histopathology, And Differential Diagnosis
- FNA cytology can play an important diagnostic role in the initial evaluation of ATC, but parallel core biopsy may be necessary for definitive diagnosis and to obtain sufficient material for molecular interrogation. (S-L)
- Every effort should be made to establish a diagnosis via biopsy before proceeding with surgical resection, as surgical resection may be inappropriate.(S-L)
- Routine surgical pathology evaluation of resection specimens should focus on confirming a definitive diagnosis of ATC, documenting extent of disease, and defining the presence of any coexisting DTC and/or other pathologies. The proportion of tumor that represents ATC should also be documented. (S-L)
- Once ATC diagnosis is considered, assessment of BRAFV600E mutation should be expeditiously performed by IHC and confirmed/expeditiously assessed by molecular testing. (S-M)
- Molecular profiling should be performed at the time of ATC diagnosis to inform decisions related to the use of targeted therapies, especially as there are now FDA-approved mutation-specific therapies in this context. (S-M)
- Initial radiological tumor staging should include cross-sectional imaging, in particular, CT neck, chest, abdomen, and pelvis with contrast (or MRI), and, if available, FDG PET/CT. Contrast-enhanced imaging of the brain (MRI preferred) should also be performed, if clinically indicated. (S-M)
Good Practice Statement 1
- In the event that biopsy of a suspected metastatic disease site is clinically indicated, primary management of ATC should not be delayed until biopsy is obtained. (GPS)
Good Practice Statement 2
- All critical appointments and assessments that are required before primary treatment of ATC should be prioritized and completed as rapidly as possible. (GPS)
- Every patient with ATC should undergo evaluation of the vocal cords at initial presentation, and thereafter based upon changing symptoms. (S-L)
Table 2. Panel of Routine Immunohistochemical Markers for the Evaluation of Suspected Anaplastic Thyroid Cancer and Expected Results Compared to Other Tumor Types
|Thyroid-transcription factor 1||+++||+/−||−/+||+/−||−||−|
|CD45, other lymphoid markers||−||−||−||−||−||+++|
a PAX8 antibodies can cross react with PAX5, which is expressed in lymphoid cells.
b Percentage of nuclei positive for Ki-67.
+ indicates relative positive staining, − indicates negative staining, +/− indicates variable positivity.
Table 3. Initial Evaluation for Staging, Tests, and Procedures
|Recommended and if clinically indicatedb|
a If PET/CT unavailable, bone scan may be useful to identify bone metastases.
b Clinically indicated if the patient has symptoms suggestive of brain metastases (i.e. neurologic deficit, headache, etc.).
c BRAF IHC provides a rapid result and if positive NGS testing may not be necessary. If BRAF IHC is negative, NGS should be performed as it is more sensitive.