Anaplastic carcinoma of the thyroid (ATC) is the most aggressive thyroid gland malignancy. Although ATC accounts for less than 2% of all thyroid cancers, it causes up to 40% of deaths from thyroid cancer. The aggressive nature of ATC makes treatment studies difficult to perform. The overall 5-year survival rate is reportedly less than 10%, and most patients do not live longer than a few months after diagnosis.
See the figure below.
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Algorithm for the management of a solitary thyroid nodule. FNAB = fine needle aspiration biopsy; US = ultrasonography.
Patients with ATC typically present with a rapidly growing neck mass. Metastases, particularly in the lung, are likely to be present at diagnosis more than 50% of the time. Treatment is mostly palliative. Surgical resection with adjuvant radiation therapy and chemotherapy may prolong survival somewhat and improve quality of life.
For patient education resources, see the Endocrine System Center, as well as Thyroid Problems.
Anaplastic carcinoma of the thyroid (ATC) generally occurs in people in iodine-deficient areas and in a setting of previous thyroid pathology (eg, pre-existing goiter, follicular thyroid cancer, papillary thyroid cancer). Local invasion of adjacent structures (eg, trachea, esophagus) commonly occurs.
The Global Anaplastic Thyroid Cancer Initiative (GATCI) studied the mutational landscape of 329 thyroid cancer regions from 292 patients, including 213 regions from patients with ATC and 115 regions from patients with papillary thyroid cancer. The GATCI demonstrated that ATC arises in the context of differentiated thyroid cancers but acquires additional characteristic clonal driver mutations. Sequencing studies showed that ATCs have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. In addition to genes commonly altered in cancer or previously linked to ATC, such as BRAF, RAS, TP53, PIK3CA, BRCA1, BRCA2, and USH2A, the GACTI identified tens of novel alterations enriched in ATC, including recurrent non-synonymous single-nucleotide variants in the pathways related to MAPK signaling, DNA damage repair, cell division, and cell adhesion.[1]
ATC has a genetic association with oncogenes C-myc, H-ras, and Nm23. Mutations in genes that code for BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC have been found in ATC, and chromosomal abnormalities are common.[2, 3] TJonker and collegues performed functional genomic RNA profiling on 25 ATCs and 80 normal thyroid samples and identified 301 significantly upregulated genes, of which the following were seen as potential therapeutic targets[4] :
Anaplastic carcinoma of the thyroid (ATC) constitutes less than 2% of all thyroid malignancies in the United States, which equates to slightly more than 1000 new cases annually.[5, 6] Fortunately, the incidence of thyroid cancer appears to be declining. Worldwide frequency likely approximates that in the United States.
Although papillary thyroid cancer shows a strong female predominance, with a female-to-male ratio of approximately 3:1, ATC affects females and males relatively equally.[1] Peak incidence occurs during the sixth to seventh decades of life. The age range of affected patients reportedly is 15-90 years.
Although ATC remains deadly, in recent years the prognosis for patients with ATC appears to have improved. A review of the Surveillance, Epidemiology, and End Results (SEER) database found that estimated 1-year survival rose from 15% for patients diagnosed from 2011 to 2016, to 25% for patients diagnosed from 2017 to 2020.[7]
ATC has a rapidly progressive course and early dissemination. In 80%-90% of patients, the disease has already spread beyond the thyroid gland at presentation.[5] The most common sites of distant spread include, in descending order, the lung, bone, and brain. Metastases, particularly in the lung, are likely to be present at diagnosis in more than 50% of cases. The overall 5-year survival rate is reportedly less than 10%, and most patients do not live longer than a few months after diagnosis.[8]
One study has shown that patients younger than 60 years who have ATC confined to the thyroid have a better prognosis than patients who are older and have distant metastases.[9] A retrospective study from Korea found that age less than 60 years, tumor size less than 7 cm, and lesser extent of disease were independent predictors of lower disease-specific mortality.[10]
While some studies have suggested that postoperative radiotherapy may be of benefit in terms of survival, definitive prospective trials are lacking.
Akaishi et al conducted a review of 100 patients with ATC in a single hospital (Ito Hospital) from 1993-2009.[11] The 1-year survival rates were as follows:
Stage IVA - 72.7%
Stable IVB- 24.8%
Stable IVC - 8.2%
Multivariate analysis demonstrated worse prognosis with age older than 70 years, white blood cell count of 10,000/μL or more, extrathyroidal invasion, and distant metastases at the time of diagnosis. Survival was significantly better if the patient received complete resection, external radiation at doses of 40 Gy or more, or both.[11]
Orita et al developed a prognostic index that can predict prognosis and assist in the early treatment of ATC.[12]
Patients with anaplastic thyroid carcinoma (ATC) typically present with a rapidly growing neck mass. Patients with metastases may also note bone pain, weakness, and cough. Neurologic deficits may be observed with brain metastases. The rapidly growing neck mass may produce the following symptoms:
Physical examination typically reveals a dominant neck mass. More than 40% of affected patients have lymph node enlargement, indicating local metastases. Pleural effusions may lead to decreased breath sounds on auscultation. With metastases, the patient may have findings such as bone pain and neurologic deficits.
Diagnosis of anaplastic thyroid carcinoma (ATC) requires cytologic examination of tumor tissue. Fine-needle aspiration often yields enough cytologic information to allow diagnosis; however, if the fine-needle aspiration does not provide definitive results, the patient may require an open surgical biopsy.
ATC cannot be definitively diagnosed with laboratory examinations of the blood or urine. Obtain serum calcium levels to rule out medullary thyroid carcinoma or parathyroid neoplasms. Imaging studies are used to assess local spread and distant metastasis.
Although the 2012 American Thyroid Association guidelines do not advocate molecular testing of anaplastic thyroid carcinoma tumors, selective BRAF inhibitors are being tested in patients with BRAF-mutated anaplastic thyroid carcinoma and may hold promise.[3] Uncommon genetic mutations, such as TSC1 mutation and ALK rearrangements, have reportedly responded to everolimus and crizotinib, respectively, in patients with ATC.[14, 15] Thus, molecular testing is needed to identify mutations for targeted therapy. Because molecular testing can take 2 to 3 weeks to complete, this test needs to be peformed as quickly as possible.
Ultrasonography is an essential imaging technique for evaluation of thyroid masses and is used to guide fine-needle aspiration cytologic and core needle biopsy procedures. The dominant sonographic findings of ATC are heterogeneous echogenicity, an irregular shape, an uncircumscribed margin, hypoechogenicity, and solitary nodules.[16] Preoperative cervical ultrasonography can detect lymph node metastases.
Chest radiography may be used to determine the presence of lung metastases.
Cervical CT scanning can be used to define the local spread of disease. Detection of distant metastases to the mediastinum, liver, lung, bone, and brain is also possible via CT scanning or MRI.
Bone scanning can be used to determine the presence of bone metastases.
Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) can visualize primary tumors, lymph node metastases, lung metastases, and other distant metastases.[17]
Grossly, anaplastic carcinoma of the thyroid (ATC) is a large, fleshy, off-white tumor. Infiltration of adjacent structures can be observed grossly and microscopically. Histologically, the tumor may contain regions of spontaneous necrosis and hemorrhage. Typically, angioinvasion is detectable.
The main histologic variants include spindle cell, giant cell (osteoclastlike), squamoid, and paucicellular. The giant cell subtype typically exhibits local calcification with significant osteoid formation. The paucicellular subtype demonstrates rapid growth, intense fibrosis, focal infarction, diffuse calcification, and encroachment of adjacent vascular tissue by atypical spindle cells.
Thyroid lymphoma is the only curable condition that may be confused with ATC. Rule out lymphoma in the presence of a poorly differentiated large cell thyroid tumor. This investigation involves lymphoid tissue markers (eg, cytoplasmic immunoglobulin, immunoglobulin receptors, gene rearrangement studies).
All patients with anaplastic thyroid carcinoma are classified as having stage IV disease, because of the high mortality of the disease. Stage subdivisions are as follows:
Stage IVA – Intrathyroidal tumors
Stage IVB – Extrathyroidal tumors but no distant metastatic disease
Treatment of anaplastic thyroid carcinoma (ATC) is mostly palliative. Surgical resection with adjuvant radiation therapy or chemoradiotherapy may prolong survival somewhat and improve quality of life.[18] The role of adjuvant therapy in ATC has not been clearly defined. Radiotherapy and chemotherapy regimens continue to be investigated.
Consider patients with unresectable tumors who are in good general condition for phase I studies, which represent the only opportunity to identify drugs with some activity against this uncommon disease. These studies are available in any major cancer center, are generally financed by the industry, and may help individual patients.
Despite the fact that ATC is largely radioresistant, external-beam radiotherapy is used for local control. Some evidence shows that hyperfractionation may lead to better success at local control by permitting delivery of higher doses of total radiation with less toxicity.
Bhatia et al reported on the use of conformal 3-dimensional radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT) in 53 consecutive patients with anaplastic thyroid cancer (ATC). Median radiation dose was 55 Gray (Gy; range, 4-70 Gy); IMRT was given to a median 60 Gy (range, 39.9-69.0 Gy). Superior survival was noted in patients without distant metastases who received ≥50 Gy.[19]
Currently, no available chemotherapeutic agent or combination of chemotherapeutic agents shows sufficient antineoplastic activity to prevent death; yet, in rare instances, chemotherapy may prolong life by a few weeks or perhaps months. Doxorubicin and cisplatin are the two most commonly used agents; however, resistance from cellular extrusion of the drugs occurs. Valproic acid has been introduced into treatment regimens because it induces apoptosis, modulates differentiation gene expression of thyroid tumors, and enhances the sensitivity of anaplastic cancer cell lines to doxorubicin.[20]
A study from the Netherlands reported significantly improved local control and improved median survival with a protocol consisting of locoregional radiotherapy in 46 fractions of 1.1 Gy, given twice daily, followed by prophylactic irradiation of the lungs in 5 daily fractions of 1.5 Gy. Low-dose doxorubicin (15 mg/m2) is administered weekly during radiotherapy, followed by adjuvant doxorubicin (50 mg/m2) 3 times a week up to a cumulative dose of 550 mg/m2.[21]
Since ATC is a relatively uncommon disease, large phase III clinical trials of systemic therapies are not possible to perform. For that reason, the value of newer therapies, such as taxanes, gemcitabine, and irinotecan; and targeted therapies, such as receptor tyrosine kinase inhibitors, is unknown.
In 2018, the US Food and Drug Administration (FDA) approved dabrafenib in combination with trametinib for locally advanced or metastatic ATC with the BRAF V600E mutation in patients with no satisfactory locoregional treatment options. Approval was based on the ROAR trial (NCT02034110), in which 57% of the 23 evaluable patients in the ATC cohort achieved a partial response and 4% reached a complete response; 645 of responses lasted for 6 months or longer. ROAR was a nine-cohort, multicenter, nonrandomized, open-label trial in patients with rare cancers with the BRAF V600E mutation.[22, 23]
The final efficacy and safety results of ROAR included an overall response rate of 56% in the ATC cohort. Secondary endpoints for ATC were median duration of response, 14.4 months; median progression-free survival, 6.7 months; and median overall survival, 14.5 months.[24]
Wang et al demonstrated the benefit of neoadjuvant use of dabrafenib and trametinib in BRAF V600E–mutated ATC. In their case series of six co patients, all patients received dabrafenib and trametinib followed by surgical resection and adjuvant chemoradiation; three patients also received the programmed cell death-1 (PD-1) inhibitor pembrolizumab. Complete surgical resection was achieved in all patients. Overall survival was 100% at six months and 83% at one year.[25]
A retrospective study by Hamidi et al reported that the addition of pembrolizumab to dabrafenib/trametinib may significantly prolong survival in BRAF V600E–mutated ATC. In their comparison of dabrafenib/trametinib in 23 patients with dabrafenib/trametinib plus pembrolizumab (added upfront or at progression, before or after surgery) in 48 patients, the patients who received pembrolizumab had significantly longer median overall survival than those receiving dabrafenib/trametinib alone (17.0 versus 9.0 months, respectively) and significantly longer median progression-free survival (11.0 versus 4.0 months, respectively). Overall survival was longest — 63.0 months — in the 23 patients who received neoadjuvant therapy.[26]
Pembrolizumab is curerently approved for second-line treatment of unresectable or metastatic solid tumors that are microsatellite instability-high (MSI-H), mismatch repair deficient (dMMR), or mutational burden-high (TMB-H).
Soll et al reported that in five patients with metastatic ATC who received pembrolizumab and lenvatinib as systemic first-line therapy, the median progression-free survival was 4.7 months (range, 0.8-5.9 months), and the median overall survival was 6.3 months (range 0.8 month–not reached).[27] Lenvatinib is a VEGF inhibitor approved for treatment of differentiated thyroid cancer.
Use surgery to obtain a definitive diagnosis when fine-needle aspiration is unsuccessful. Surgery is performed in conjunction with radiation and chemotherapy. An early prophylactic tracheostomy may be required for protection of the airway during surgery.
Despite the typically large size of these tumors, the extent of resection is limited when the diagnosis is made. Rather than performing complete thyroidectomy, resect as much thyroid tissue as possible without attempting resection of all adjacent structures because of the high incidence of postoperative morbidity (eg, vocal cord paralysis, esophageal fistula).
A greater extent of resection may be associated with slightly longer survival. For example, in a study of 55 patients with stage IVB or IVC ATC, Brignardello et al reported that maximal debulking—macroscopically complete resection (R0, R1), or R2 resection with minimal macroscopic residual tumor—followed by adjuvant therapy, can lengthen survival and improve quality of life by preventing airway compromise.[28]
In both stage IVB and IVC ATC, survival was 6.57 months with maximal debulking versus 3.25 months with partial debulking. Moreover, death secondary to local progression of tumor occurred in 21% of patients who had maximal debulking, compared with 69% of patients treated with partial debulking or no surgery.
See Thyroid Cancer Treatment Protocols for summarized information.
Risk of local complications from thyroid surgery (eg, permanent hypoparathyroidism, recurrent laryngeal nerve palsy) may be increased with anaplastic thyroid carcinoma (ATC) if aggressive resection is attempted. With limited thyroid resection, incidence of these local complications should not be significantly greater.
ATC may cause airway obstruction. Patients with impending airway obstruction who are not candidates for local resection or chemoradiation should undergo tracheostomy. Interventional bronchoscopy, including Nd-YAG laser and airway stenting, is an alternative to surgery in inoperable cases of tracheal obstruction.[29]
Guidelines Contributor: Kemp M Anderson Medical University of South Carolina College of Medicine
The following organizations have released guidelines for the diagnosis and/or management of thyroid cancer:
American Thyroid Association (ATA)[30, 31]
National Comprehensive Cancer Network (NCCN)[32]
American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA[33] (diagnosis only)
Diagnosis
The ATA and AACE/AME/ETA guidelines advocate ultrasound evaluation of thyroid nodules along with measurement of serum thyroid-stimulating hormone (TSH) levels to determine whether a fine needle aspiration biopsy (FNAB) is indicated. A routine measurement of serum thyroglobulin (Tg) for the initial evaluation of thyroid nodules is not recommended because Tg levels are elevated in most benign thyroid conditions.[30, 32, 33]
Although all the guidelines recommend FNAB as the procedure of choice in the evaluation of solid thyroid nodules, there is variance in the size of the nodule as an indication for FNAB, as follows[30, 32, 33] :
> 0.5 cm in diameter (ATA)[30]
> 1 cm, in the absence of suspicious sonographic features (AACE/AME/ETA)[33]
AACE/AME/ETA suggest a serum calcitonin assay as an optional test,[33] but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin because of insufficient evidence.[30] Both guidelines recommend radionuclide imaging in patients with a low TSH level.[30, 32, 33]
The ATA guidelines also include the following recommendations regarding diagnosis and staging of anaplastic thyroid carcinoma (ATC)[34] :
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 testing.
Every effort should be made to establish a diagnosis via biopsy before proceeding with surgical resection.
Routine surgical pathology evaluation of resection specimens should focus on confirming a definitive diagnosis of ATC, documenting the extent of disease, and defining the presence of any coexisting differentiated thyroid cancer and/or other pathologies.
Once the diagnosis of ATC is considered, expeditious assessment of BRAF V600E mutation should be performed by immunohistochemistry (IHC) and confirmed/assessed by molecular testing.
Molecular profiling should be performed at the time of ATC diagnosis to inform decisions about targeted therapies.
Initial radiologic tumor staging should include cross-sectional imaging—in particular, CT with contrast (or MRI) of the neck, chest, abdomen, and pelvis and, if available, FDG PET/CT. Contrast-enhanced imaging of the brain (MRI preferred) should also be performed, if clinically indicated.
Evaluation of the vocal cords should be performed in every patient with ATC at initial presentation, and subsequently as indicated by changing symptoms.
Comprehensive disease-specific input from a multidisciplinary team — including specialists highly experienced in treating ATC — should be attained before defining goals of care or conducting therapeutic discussions with patients.
Treatment
No curative treatment currently exists for ATC. The majority of patients present with unresectable or metastatic disease. NCCN guidelines recommend attempting total thyroidectomy in patients with resectable disease.[32]
The ATA guidelines strongly recommend surgical resection for patients with confined (stage IVA/IVB) ATC in whom R0/R1 resection is anticipated. Radical resection (eg, laryngectomy, tracheal resections, esophageal resections, major vascular or mediastinal resections) is generally not recommended, given the poor prognosis of ATC and should be considered only very selectively after thorough discussion by the multidisciplinary team.
If a primary tumor is deemed unresectable, ATA guidelines advise that in carefully selected patients, neoadjuvant therapy (eg, full or partial course external beam radiotherapy, chemotherapy, or chemoradiotherapy) may permit delayed primary resection.[31] NCCN guidelines recommend considering molecularly targeted neoadjuvant therapy for borderline resectable disease when safe to do so. Targeted regimens for neoadjuvant therapy include the following[32] :
BRAF V600E mutations - Dabrafenib/trametinib
RET fusion–positive tumors - Selpercatinib or pralsetinib
NTRK gene fusion–positive tumors - Larotrectinib or entrectinib
Both the NCCN and ATA guidelines recommend adjuvant radiation therapy, chemotherapy, or both.[31, 32] ATA recommendations for adjuvant therapy include the following[31] :
After R0/R1 resection, patients with good performance status (PS) and no evidence of metastatic disease who wish an aggressive approach should be offered standard fractionation intensity-modulated radiation therapy (IMRT) with concurrent systemic therapy.
Patients who have undergone R2 resection or have unresectable but nonmetastatic disease with good performance status and who wish an aggressive approach should be offered standard fractionation IMRT with systemic therapy. In BRAF V600E–mutated ATC, combined BRAF/MEK inhibitors can be considered. In some patients with initially unresectable disease, response to this treatment may permit reconsideration of surgical resection.
For patients treated with definitive-intention radiation therapy, cytotoxic chemotherapy involving a taxane, with or without an anthracycline or a platin, is recommended.
In BRAF V600E–mutated stage IVC ATC and unresectable stage IVB ATC in patients who decline radiation therapy, initiation of BRAF/MEK inhibitors (dabrafenib plus trametinib) is preferred.
In May 2018, FDA approved dabrafenib in combination with trametinib for locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation in patients with no satisfactory locoregional treatment options. Approval was based on a small, open-label trial showing a 57% partial response with the combination.[22]
Clinical Context:
This is an antineoplastic agent of the anthracycline antibiotic class. Inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. The combination of these 2 events can in turn inhibit the growth of neoplastic cells. In metastatic thyroid carcinoma, doxorubicin is probably the most effective antineoplastic agent.
Clinical Context:
Dabrafenib is a BRAF kinase inhibitor. It is indicated in combination with trametinib for locally advanced or metastatic ATC in patients with BRAF V600E mutation and with no satisfactory locoregional treatment options.
Clinical Context:
Trametinib reversibly inhibits mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and activity. It is indicated in combination with dabrafenib for locally advanced or metastatic ATC in patients with BRAF V600E mutation and with no satisfactory locoregional treatment options.
Anastasios K Konstantakos, MD, Clinical Associate Surgeon, Department of Cardiovascular Surgery, Billings Clinic
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Julie E Hallanger Johnson, MD, FACP, ECNU, Assistant Professor of Oncologic Sciences, University of South Florida Morsani College of Medicine; Associate Member, Endocrinology Oncology, Program Leader, Endocrine Tumor Program, Department of Head and Neck-Encocrine Oncology, Moffitt Cancer Center
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: HRA pharma (consultant)<br/>Received income in an amount equal to or greater than $250 from: HRA Pharma.
Additional Contributors
Lodovico Balducci, MD, Professor, Oncology Fellowship Director, Department of Internal Medicine, Division of Adult Oncology, H Lee Moffitt Cancer Center and Research Institute, University of South Florida Morsani College of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Debra J Graham, MD, is gratefully acknowledged for the contributions made to this topic.
Cancer Facts & Figures 2024. American Cancer Society. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf. Accessed: April 18, 2024.
Tafinlar (dabrafenib) [package insert]. East Hanover, New Jersey 07936: Novartis Pharmaceuticals Corporation. May 2018. Available at
Mulcahy N. FDA OKs Targeted Therapy Combo for Anaplastic Thyroid Cancer. Medscape Medical News. Available at https://www.medscape.com/viewarticle/896190. May 04, 2018; Accessed: May 08, 2018.
[Guideline] NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Version 2.2024 — March 12, 2024; Accessed: April 18, 2024.
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