Anaplastic thyroid cancer

INTRODUCTION — Anaplastic thyroid cancers are undifferentiated tumors of the thyroid follicular epithelium. In marked contrast to differentiated thyroid cancers, anaplastic cancers are extremely aggressive, with a disease-specific mortality approaching 100 percent. Given the very rapid course of disease progression and the poor treatment outcomes, end-of-life issues and plans for comfort care measures are an integral part of initial disease management planning [1]. Early recognition of the disease is essential to allow prompt initiation of therapy.

The major clinical issues related to anaplastic thyroid cancer will be reviewed here. The molecular pathogenesis of this disorder is discussed separately. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer".)

EPIDEMIOLOGY — The age-adjusted annual incidence of anaplastic cancer is approximately one to two per million persons [2,3] and accounts for 0.9 to 9.8 percent of all thyroid cancers globally [4,5]. Patients with anaplastic cancer are older than those with differentiated cancer; the mean age at diagnosis is 65 years, and fewer than 10 percent are younger than 50 years. Sixty to 70 percent of tumors occur in women [6,7].

CLINICAL FEATURES

Antecedent thyroid disease — Approximately 20 percent of patients with anaplastic thyroid cancer have a history of differentiated thyroid cancer, and 20 to 30 percent have a coexisting differentiated cancer [8-12]; the percentage may be even higher with extensive sectioning of the thyroid gland [13]. The majority of synchronous thyroid tumors are papillary cancers, but coexisting follicular cancers have also been reported. Nearly 10 percent of patients with Hürthle cell cancers have foci of anaplastic cancer within the Hürthle cell cancer [14]. In addition, transformation from differentiated to anaplastic cancer has been described in a patient who was followed with serial biopsies [15].

These findings lend support to the hypothesis that anaplastic cancer develops from more differentiated tumors as a result of one or more dedifferentiating events [16]. Since activating mutations in BRAF and RAS are seen in both well-differentiated thyroid malignancies and anaplastic thyroid cancer, these are presumed to be early events in the progression pathway [17]. Late events that are seen more commonly in the anaplastic tumor rather than the precursor well-differentiated tumor include mutations in p53 tumor suppressor protein [18-21], 16p [22], catenin (cadherin-associated protein), beta 1, and PIK3CA [23].

Up to one-half of patients have a history of multinodular goiter, and some have a history of partial thyroidectomy for goiter.

Disease presentation — Nearly all patients with anaplastic cancer present with a thyroid mass. However, regional or distant spread is apparent at the time of initial diagnosis in 90 percent of cases [11-13,24]. Sites of regional involvement can include the perithyroidal fat and muscle, lymph nodes, larynx, trachea, esophagus, tonsil, and great vessels of the neck and mediastinum. Distant metastases are found at initial disease presentation in 15 to 50 percent of patients [8-10,12].

●The lungs are the most common site of distant metastases, being involved in up to 90 percent of patients with distant disease [9,10]. These metastases are usually intrapulmonary mass lesions, but pleural involvement can occur.

●Approximately 5 to 15 percent of patients have bone metastases.

●Five percent have brain metastases, and a few have metastases to the skin, liver, kidneys, pancreas, heart, and adrenal glands [9-11,25-29].

●Rare patients have no detectable thyroid tumor at the time of diagnosis, presenting with metastatic disease [13].

Clinical manifestations

●Symptoms – The primary symptom of anaplastic cancer is a rapidly enlarging neck mass, occurring in approximately 85 percent of patients. The enlarging thyroid tumor may cause neck pain and tenderness, and compression (or invasion) of the upper aerodigestive tract, resulting in dyspnea (approximately 35 percent of patients), dysphagia (30 percent), hoarseness (25 percent), and cough (and sometimes hemoptysis, 25 percent). Less common symptoms are chest pain, bone pain, headache, confusion, or abdominal pain from metastases [25,30].

Constitutional symptoms can occur, including anorexia, weight loss, fatigue, and fever of unknown origin [30-33]. Rarely, rapid growth of the tumor within the thyroid causes thyroiditis, with symptoms of hyperthyroidism and more severe neck pain and tenderness [25,34,35].

●Physical examination – On physical examination, most patients have bilateral but asymmetric thyroid enlargement. The goiter is typically hard and nodular and may be tender. A dominant nodule is often present. Some nodules may be softer and fluctuant, indicating focal tumor necrosis [13]. A few patients have a solitary nodule or a diffuse non-nodular goiter. The goiter is often fixed to the surrounding structures and does not move with swallowing. By the time of presentation, the primary tumor is usually greater than 5 cm in diameter, but exact measurements are often difficult because the borders of the tumor are indistinct.

Approximately 50 percent of patients have enlarged cervical lymph nodes. Other findings of local extension of the disease include stridor, tracheal deviation, vocal cord paralysis due to compression or invasion of the trachea, and venous dilatation and superior vena cava syndrome due to retrosternal tumor growth.

The skin overlying the tumor may be erythematous or even ulcerated, and there may be metastases in the skin of the chest and abdomen [13,36]. Focal neurologic symptoms or signs suggesting brain metastases may also be present.

●Laboratory – Most patients have normal serum thyroid hormone and thyroid-stimulating hormone (TSH) concentrations, except for those few patients with tumor-related thyroiditis and hyperthyroidism from presumed rapid tumor growth and concomitant tissue destruction [25,34,35]. Serum thyroglobulin concentrations may be high, most often due to secretion from a coexisting differentiated cancer, rather than the anaplastic cancer. Rare patients have leukocytosis due to tumor secretion of lymphokines [37,38].

●Ultrasound – The findings on thyroid ultrasound are not specific for anaplastic thyroid cancer. Ultrasonography cannot distinguish benign from malignant intrathyroidal tumors (both tend to be hypoechoic). However, detection of extrathyroidal invasion can provide support for the diagnosis of cancer. Ultrasonography of the neck also can accurately identify involvement of local and regional nodes. (See "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Criteria for identifying cancer'.)

DIAGNOSIS — We agree with the American Thyroid Association (ATA) guidelines that note while fine-needle aspiration (FNA) cytology can yield important diagnostic information, a core biopsy may be necessary to firmly establish the diagnosis and to obtain adequate material for molecular testing and immunostaining [39]. Evaluation of the biopsy material should include routine light microscopy and analysis with immunohistochemistry (table 1). (See 'Molecular testing' below and "Diagnostic approach to and treatment of thyroid nodules" and "Thyroid biopsy".)

The diagnosis of anaplastic cancer is usually established by cytologic examination of cells obtained by FNA biopsy [40,41] and/or of tissue obtained by large-needle or surgical biopsy [42]. Sometimes the diagnosis is made only after surgery is done for what was thought to be a poorly differentiated or occasionally a well-differentiated tumor. Differentiation of anaplastic and poorly differentiated thyroid cancer may be difficult in some patients. (See 'Differential diagnosis' below.)

On cytopathology, morphologic patterns of anaplastic thyroid cancer include spindle cell, pleomorphic giant cell, and/or squamoid [9]. Many anaplastic thyroid cancers have a mixed morphology of two or all three patterns. One common mixed morphologic type is biphasic spindle and giant cell tumor (picture 1). Numerous mitotic figures and atypical mitoses are present (picture 2). There is typically extensive necrosis. Unlike differentiated thyroid cancer, anaplastic thyroid cancer cells are much less likely to stain positive for thyroid transcription factor 1 (TTF1) or PAX-8 and do not stain positive for thyroglobulin in the anaplastic component of the tumor (may see thyroglobulin staining in the associated more well-differentiated component of the tumor) (table 1). (See "Atlas of thyroid cytopathology", section on 'Anaplastic'.)

DIFFERENTIAL DIAGNOSIS — Other malignancies that may look histologically similar to anaplastic thyroid cancer but have significantly different treatment and prognosis include:

●Poorly differentiated thyroid cancer. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer", section on 'Anaplastic and poorly differentiated thyroid cancer'.)

●Medullary thyroid cancer. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Diagnosis'.)

●Lymphoma. (See "Atlas of thyroid cytopathology", section on 'Lymphoma'.)

●Melanoma. (See "Pathologic characteristics of melanoma", section on 'Histopathologic diagnosis'.)

●Sarcoma. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Histopathology'.)

Differentiation of anaplastic and poorly differentiated thyroid cancer may be difficult in some patients with anaplastic thyroid cancer who have coexisting poorly differentiated (or well-differentiated) thyroid cancer. Careful attention to morphology and immunohistochemical studies (table 1) is required to distinguish anaplastic thyroid cancer from poorly differentiated thyroid cancer and other malignancies.

The differential diagnosis in a patient presenting with a neck mass is extensive and varies with the age of the patient at presentation. Although the majority of these masses represent benign thyroid nodules and cysts or differentiated thyroid cancer, a rapidly growing neck mass is concerning for anaplastic thyroid cancer or primary lymphoma of the thyroid (see "Diagnostic approach to and treatment of thyroid nodules"). Neck masses that are not of thyroidal origin may be congenital (ie, vascular anomaly), inflammatory (lymph node enlargement), or other neoplastic (primary or metastatic disease) disorders. The differential diagnosis of a neck mass is reviewed separately. (See "Differential diagnosis of a neck mass".)

EVALUATION — For patients diagnosed with anaplastic thyroid cancer on the basis of the findings on cytopathology, further evaluation should include laboratory evaluation, imaging studies, and testing for BRAF V600E mutation [39].

History and physical examination — All patients with anaplastic thyroid cancer should undergo evaluation of the airway and vocal cords. Some patients may require emergency intervention to secure the airway or avert impending neurovascular compromise.

Laboratory evaluation — We typically measure:

●Thyroid function tests (TSH, free thyroxine [T4]), if not previously measured

●Complete blood count

●Electrolytes, blood urea nitrogen (BUN), creatinine, glucose, and liver function tests

●Serum calcium and phosphorus (to assess for hypercalcemia of malignancy or hypocalcemia due to compromise of the parathyroid glands secondary to invading anaplastic thyroid cancer)

●Serum thyroglobulin

We measure serum thyroglobulin as part of the initial evaluation to assess for the possibility of metastatic well-differentiated thyroid cancer (20 to 30 percent of patients with anaplastic thyroid cancer have coexisting differentiated thyroid cancer) and to assist in determining if the metastatic lesions are from the well-differentiated component of the tumor (rather than anaplastic metastatic sites). In patients with metastatic differentiated thyroid cancer, the thyroglobulin level is markedly elevated, whereas it should be normal in patients with anaplastic thyroid cancer. Elevated serum thyroglobulin can also be seen in nodular thyroid disease and goiter. (See "Differentiated thyroid cancer: Role of serum thyroglobulin".)

Imaging — Appropriate imaging is critical for defining the extent of disease, planning therapy, and monitoring the response to treatment. We typically obtain the following:

●Ultrasound of the neck (if not already performed)

●Positron emission tomography (PET)/computed tomography (CT) using 18F-fluorodeoxyglucose (18FDG; neck to pelvis)

●Brain magnetic resonance imaging (MRI) or CT

●Skeletal radiographs if bony metastases are present (radiographs typically show lytic lesions)

If PET/CT scanning is not readily available, cross-sectional imaging of the brain, neck, chest, abdomen, and pelvis with CT or MRI provides adequate initial staging information.

PET/CT scan is being used with increasing frequency to evaluate and monitor patients with anaplastic thyroid cancer [43]. Compared with differentiated thyroid cancer, anaplastic cancer is very hypermetabolic with intense uptake of 18FDG in the primary thyroid tumor, cervical and mediastinal lymph nodes, and in distant metastases [44-47].

CT of the neck and mediastinum can accurately delineate the extent of the thyroid tumor and identify tumor invasion of the great vessels and upper aerodigestive tract [48]. Typical findings include masses that are isodense or slightly hyperdense relative to skeletal muscle, dense calcifications, and areas of necrosis (image 1). MRI is similarly useful for defining the local extent of disease and for identifying distant metastases [49,50].

Molecular testing — We perform a rapid test for BRAF V600E mutations as quickly as possible (using immunohistochemical staining on FNA or core biopsy samples with an antibody specific for the BRAF V600E-mutated protein) so as not to delay treatment [51]. In addition, next-generation molecular sequencing (if available) should be performed to evaluate for the presence of other targetable mutations that might be able to be treated in the context of a clinical trial (preferred), through standard of care, or through a compassionate use program. Promising targets that are seen in anaplastic thyroid cancer and should be included in the evaluation include, at the minimum, BRAF, TSC1, TSC2, ALK fusion genes, NTRK fusion genes, and RET fusion genes. (See 'Our approach to treatment' below.)

Other — Rarely, fine-needle biopsy of distant metastatic sites is required to differentiate anaplastic from differentiated thyroid cancer. In patients with surgically resectable disease, biopsy of distant metastases can be performed after completion of primary surgery [39].

Patients with anaplastic thyroid cancer who present with a rapidly growing neck mass and voice hoarseness require evaluation by an otolaryngologist/head and neck surgeon to assess for vocal cord function, airway invasion, and resectability.

STAGING — The Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) have adopted the eighth (2017) TNM (tumor, node, metastasis) classification system (table 2) [52]. In the updated staging system, the T category follows the same definitions as those used for differentiated thyroid cancers, rather than classifying all anaplastic thyroid cancer as T4 disease. (See "Differentiated thyroid cancer: Clinicopathologic staging", section on 'TNM system'.)

All anaplastic cancers are considered stage IV cancers [53]. Intrathyroidal anaplastic cancers are designated IVA, whereas anaplastic cancers with gross extrathyroidal extension or cervical lymph node metastases are IVB and with distant metastases IVC.

OUR APPROACH TO TREATMENT — Selection of initial therapy is guided by stage of disease and results of molecular testing (if available) (algorithm 1). (See 'Molecular testing' above.)

The following approach, which is largely consistent with the American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) guidelines for management of patients with anaplastic thyroid cancer [39,54], is based upon case series and clinical experience. Because this is a rare tumor and many of the patients may be elderly and/or have significant symptoms related to the disease that may affect their performance status, accruing patients to large clinical studies is very difficult but should be a priority.

BRAF V600E mutation identified

Stage IVA — For patients who present with resectable tumors, we suggest complete resection followed by combined chemotherapy and radiation (algorithm 1).

Extent of surgery — For most patients with an intrathyroidal anaplastic cancer, we suggest total thyroidectomy (if it can be done with complete gross resection of tumor and minimal morbidity) rather than lobectomy. The rationale for this is that differentiated thyroid cancer and anaplastic thyroid cancer often coexist, and total thyroidectomy offers a greater chance of complete resection, which facilitates subsequent treatment with radioiodine of the accompanying differentiated thyroid cancer. For the rare patients with intrathyroidal anaplastic thyroid cancer, without a coexistent well-differentiated thyroid cancer component, thyroid lobectomy with wide margins of adjacent soft tissue on the side of the tumor is an appropriately aggressive alternative surgical approach.

In a systematic review of surgery in anaplastic thyroid cancer (stage IVA 10 percent, IVB 48 percent, and IVC 36 percent), median survival was 6.6 months in patients undergoing primary surgery and 2.1 months for nonsurgical patients [55].

Chemoradiation — At Memorial Sloan Kettering Cancer Center (MSKCC) and other centers, intensity-modulated radiation therapy (IMRT) is given in combination with chemotherapy [56,57]. A randomized phase II study through the Radiation Therapy Oncology Group for anaplastic thyroid cancer was completed using IMRT with a total dose of 66 Gy in 33 daily fractions [58].

At MSKCC, a total dose of 70 Gy to gross tumor is used, 60 to 66 Gy to the postoperative bed, and 50 to 54 Gy to potential microscopic residual disease regions with standard daily fractionation. The dose of radiation can change if clinically indicated. Doxorubicin 20 mg/m² weekly or paclitaxel 50 mg/m² weekly is used throughout the radiation course but there are other reasonable regimens described in the literature [59-62].

There are very little data about the optimal chemotherapy to be used with radiation therapy for anaplastic thyroid cancer. The majority of the data includes either anthracyclines [56,63], taxanes [61,64,65], or even the combination of both [57,66].

As examples:

●In one study, 37 patients were treated with weekly doxorubicin (10 mg/m²) with hyperfractionated radiation therapy (given three days per week) for a median total dose of 5760 cGy [56]. Median survival was six months with 28 percent alive at one year. The median locoregional, progression-free survival was 10.1 months. Older patients (≥70 years) had worse outcomes than younger patients, with 60 percent dying in the first three months.

●Another study evaluated a more intensive regimen combining surgery (if possible) with cisplatin (120 mg/m²) and doxorubicin (60 mg/m²), both before and after hyperfractionated radiation therapy [59]. For 30 patients, median survival was 10 months and three-year survival was 27 percent.

Although these reports support a possible survival advantage for combined modality therapy (combining radiation and chemotherapy), selection bias is a major confounding factor in determining the effect of treatment on outcome. Patients who undergo resection followed by adjuvant therapy often have less extensive disease. The optimal timing of the individual components and the selection of chemotherapy regimen are uncertain.

Randomized controlled trials are not available to definitively prove benefit for combined modality therapy. Thus, there are no standard regimens. However, the use of weekly doxorubicin (10 mg/m²) concurrently with radiation therapy is both reasonable and commonly applied [56], while more aggressive regimens have combined docetaxel and doxorubicin [62] or cisplatin and doxorubicin [59] with radiation. Given the overall poor prognosis of current treatment modalities, consideration should always be given to referring a patient with anaplastic cancer for participation in a clinical trial.

The addition of pazopanib to combined modality therapy (eg, concurrent paclitaxel and IMRT) did not improve survival outcomes compared with the addition of placebo in 89 patients with anaplastic thyroid cancer (stage IVA to IVC) [58]. However, in an unplanned, post hoc analysis, the one-year overall survival favored the pazopanib arm (37.1 versus 29 percent), with the strongest benefit in patients without metastatic disease at presentation.

Stage IVB — If a BRAF V600E mutation is present, we initiate neoadjuvant dabrafenib (150 mg twice daily) plus trametinib (2 mg daily) to improve the chance of complete tumor resection (algorithm 1) [67,68]. If initial surgery is going to be attempted without neoadjuvant dabrafenib plus trametinib in a patient whose scans suggest resectable disease, it should be performed by an experienced thyroid cancer surgeon with the understanding that surgery should be stopped early if the chance for morbidity is high.

●Resectable – If the response to dabrafenib plus trametinib is favorable and disease is considered resectable, complete resection should be attempted, as long as gross tumor resection can be achieved with minimal morbidity. For patients with locally advanced disease, the extent of surgery depends upon the degree of soft tissue involvement. Options include total thyroidectomy, lobectomy with wide margins of adjacent soft tissue, or en bloc resection.

In patients with resectable disease, surgery is followed with chemoradiation as described for stage IVA (see 'Stage IVA' above). Some patients have prolonged survival (>2 years) with surgery combined with postoperative adjuvant chemoradiation [6,11,69,70].

●Unresectable – If disease remains unresectable, dabrafenib plus trametinib can be continued if associated with disease stability or improvement. If the response is not favorable, alternative management options include chemoradiation (see 'Chemoradiation' above), clinical trials, or best supportive care.

In nonrandomized small studies, improvements in outcomes with dabrafenib plus trametinib have been reported in a few cases [67,71-73]. In a study of dabrafenib and trametinib in rare BRAF mutant tumors, 36 patients had unresectable or metastatic anaplastic thyroid cancer with the BRAF V600E mutation [74]. The complete and partial response rates were 6 and 47 percent, respectively, with a 12- and 24-month progression-free survival rate of 43.2 and 27.0 percent, respectively [74].

In another small study in patients with BRAF-mutated anaplastic thyroid cancer who were treated with the BRAF inhibitor, vemurafenib, there was a 29 percent response rate [75].

Stage IVC — There is no curative therapy for metastatic anaplastic thyroid cancer, and the disease is uniformly fatal. In one case series, the median survival in patients with anaplastic thyroid cancer with distant metastases at the time of initial diagnosis was 4.2 months, compared with 6 months in those without metastases [76].

Active therapy preferred — For patients who present with metastatic disease who desire active therapy (rather than palliative care), enrollment in clinical trials of BRAF-targeted therapy (based on molecular testing) is strongly encouraged (algorithm 1). (See 'Molecular testing' above.)

If clinical trials are not available, we suggest dabrafenib plus trametinib in tumors with a BRAF mutation. Surgical resection for residual tumor can be considered if the disease is responsive [59,69]. If resectable, surgery should then be followed by re-initiation of dabrafenib plus trametinib if the distant metastases are stable or improved during prior therapy [71,73]. If not resectable, we continue dabrafenib plus trametinib if we are seeing an otherwise favorable response to therapy. If the response to dabrafenib plus trametinib is not favorable, options include chemoradiation, clinical trials, or best supportive care. If a patient's performance status is adequate, participation in a clinical study is strongly recommended. If a clinical study is not available, and a patient seems to be a good candidate to receive systemic therapy after progression on dabrafenib and trametinib, we would follow a similar approach as noted below when there is no targetable mutation. (See 'Another targetable mutation absent or unknown' below.)

End-of-life care — Given the very rapid course of disease progression and the poor treatment outcomes, end-of-life issues and plans for comfort care measures are an integral part of disease management planning for all patients with anaplastic thyroid cancer, especially for patients with stage IVB or IVC disease [39]. Palliative and end-of-life care issues are reviewed in detail separately. (See "Approach to symptom assessment in palliative care" and "Assessment and management of dyspnea in palliative care" and "Overview of managing common non-pain symptoms in palliative care".)

BRAF V600E mutation not identified or unknown

Stage IVA or resectable IVB disease — For patients with tumor localized to the thyroid or if locoregional disease is resectable, complete resection should be attempted, as long as gross tumor resection can be achieved with minimal morbidity (algorithm 1). After complete resection, some patients have prolonged survival (>2 years), often in conjunction with postoperative adjuvant chemoradiation [6,11,55,69,70]. (See 'Stage IVA' above.)

Stage IVB (unresectable) or IVC disease — For patients with unresectable locoregional or metastatic disease, options include systemic therapy, chemoradiation (see 'Chemoradiation' above), or supportive care depending on the clinical setting.

Another targetable mutation present — If another targetable mutation is present, enrollment in a clinical trial of mutation-directed therapy is preferred. Specific inhibitors of oncogenic ALK, NTRK, or RET fusion mutations can be considered for unresectable stage IVB or IVC disease, preferably within the context of a clinical trial, although the use of NTRK or RET inhibitors are US Food and Drug Administration (FDA) approved for this indication.

Significant activity in metastatic disease has been shown in anaplastic thyroid cancer with NTRK fusion genes [77,78] and RET fusion genes [79] (although all studies have been small and, in some cases, equivalent to case reports). Other potential targets include TSC1/TSC2 mutations [80] and ALK fusion genes [81].

Mutation-specific kinase inhibitor regimens include:

●Larotrectinib or entrectinib (NTRK gene fusion) – Larotrectinib and entrectinib, highly selective inhibitors of TRK kinases, have been FDA approved for treatment of any solid tumor bearing an NTRK1-3 fusion mutation, including anaplastic thyroid cancer [82,83].

●Selpercatinib or pralsetinib (RET fusion) – Selpercatinib and pralsetinib are oral kinase inhibitors that selectively target RET kinase. They have been approved by the FDA for the treatment of advanced or metastatic RET fusion-positive thyroid cancer, RET-mutant medullary thyroid cancer, and other types of cancers which have an alteration (mutation or fusion) in the RET gene [79,84]. In the clinical study, activity was seen in anaplastic thyroid cancer with a RET fusion gene [79].

●Other – A prolonged response was reported in a phase II study with everolimus in a patient with anaplastic thyroid cancer containing a TSC2 mutation [80]. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer", section on 'Anaplastic and poorly differentiated thyroid cancer'.)

Considering that high expression of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) in anaplastic thyroid cancer [85], immunotherapy may be a promising approach. There have been several promising small studies of immunotherapy alone or in combination with other agents [86-89], but these still need to be better evaluated. Many studies are in progress, evaluating if there is activity with immunotherapy in metastatic anaplastic thyroid cancer. However, there are concerns about the safety of using immunotherapy with radiation therapy in anaplastic thyroid cancer [66].

Another targetable mutation absent or unknown — If a targetable mutation is absent or testing is unavailable, options include chemoradiation (see 'Chemoradiation' above) followed by observation or clinical trials.

In patients who would otherwise be eligible for systemic therapy but do not have a clinical trial available, there are other reasonable options, but they are all based on fairly small, single studies and the lack of extensive data needs to be considered in discussion with the patient.

●Cytotoxic chemotherapy – There are some data to support the use of cytotoxic chemotherapy. As an example, in a randomized trial comparing combination cisplatin and doxorubicin versus doxorubicin alone, the complete response rate was higher in the combination group (3 of 18 patients [17 percent] compared with none of 21 patients in the doxorubicin group) [90]. Paclitaxel as a single agent has been reported to have a response rate of 53 percent [91]. We have not seen such responses to either of these approaches; however, both of these regimens are reasonable to consider.

●Immunotherapy – The Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab (ATLEP) study evaluated the combination of lenvatinib and pembrolizumab in both anaplastic and poorly differentiated thyroid cancer [92]. In 27 patients with anaplastic thyroid cancer, 51.9 percent of patients had a partial response. The median progression-free survival was reported to be 9.5 months and median overall survival was 10.25 months. A single institution study of ipilimumab and nivolumab in anaplastic thyroid cancer reported partial responses in 3 of 10 patients [88].

In patients with advanced disease who do not desire or who are not eligible for systemic therapy, palliation of symptoms is a high priority [39]. Treatment should be directed toward securing the airway and ensuring access for nutritional support. Locoregional resection may be necessary for palliation of airway or esophageal obstruction. However, death is usually attributable to upper airway obstruction and suffocation (often despite tracheostomy) in 50 to 60 percent of patients and to a combination of complications of local and distant disease in the remainder [11,93]. For patients with bone metastases, palliative radiotherapy may be beneficial in improving pain. (See 'End-of-life care' above.)

MONITORING — Patients who respond to initial management (M0 disease) require surveillance for recurrence. There is no known role for adjuvant therapy.

●Imaging – We typically obtain chest CT at four weeks and a single positron emission tomography (PET)/CT scan at three months after the completion of chemoradiation therapy [45]. Thereafter, we monitor with CT scans (with contrast) of the neck, chest, and abdomen (including adrenal glands) every one to three months for the first 24 months and then less frequently (every 4 to 12 months) thereafter. Brain imaging during the first three months after treatment is recommended with a low threshold of repeating if concerning symptoms develop. Other imaging studies should be based upon clinical symptoms that develop during follow-up. The benefit of continued imaging after four years is questionable, although annual imaging of the neck and chest are reasonable.

Radioactive iodine has no role in the primary treatment of anaplastic thyroid cancer. However, radioactive iodine scanning/ablation/therapy should be considered in survivors, one to two years after initial therapy, if a significant component of the original tumor was well differentiated or if the serum thyroglobulin level remains inappropriately elevated during follow-up. (See "Differentiated thyroid cancer: Radioiodine treatment".)

●Thyroid hormone replacement – Patients who have total thyroidectomy require thyroid hormone therapy to replace normal thyroid hormone production. T4 (approximately 1.6 mcg/kg of body weight) should be started immediately after surgery. The adequacy of therapy should be evaluated clinically and by measurement of serum TSH in one month. The goal of T4 therapy should be to restore and maintain euthyroidism; suppression of serum TSH concentrations to less than normal is not indicated, unless for treatment of coexisting differentiated thyroid cancer. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Postoperative thyroid hormone therapy'.)

PROGNOSIS — Anaplastic thyroid cancers are extremely aggressive, with a disease-specific mortality approaching 100 percent. The median survival from diagnosis ranges from three to seven months, and the one- and five-year survival rates are 20 to 35 percent and 5 to 14 percent, respectively [11,12,24,69,94-96], although many feel that these estimates are overly optimistic. In a review of published case series (1771 patients treated between 1949 and 2007), the median survival was five months, and the one-year survival was 20 percent [4]. Several important prognostic characteristics have been identified. Patients with disease either confined to the thyroid or with only local and regional metastases survive longer than those with distant metastases [6,8,10,97]. Tumor size also appears to be important. In one study, as an example, the two-year survival was 25 versus 3 to 15 percent in patients with tumors less than 6 cm versus larger than 6 cm in maximum dimension [8,11].

Other variables that may predict a worse prognosis include older age at diagnosis, male sex, and dyspnea as a presenting symptom [6,8-11,94,97,98]. Patients who were previously treated for differentiated cancer and subsequently developed anaplastic cancer have outcomes similar to those without an antecedent cancer [9,10].

Relatively favorable prognostic factors include unilateral tumor, diameter of less than 5 cm, and the absence of extrathyroidal invasion or cervical lymph node involvement.

The use of targeted therapy will likely change the overall median survival rates. (See 'BRAF V600E mutation identified' above and 'Another targetable mutation present' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thyroid nodules and cancer".)

SUMMARY AND RECOMMENDATIONS

●Clinical features – The primary symptom of anaplastic cancer is a rapidly enlarging neck mass, occurring in approximately 85 percent of patients. Approximately 20 percent of patients have a history of differentiated thyroid cancer, and 20 to 30 percent have a coexisting differentiated cancer. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of anaplastic cancer is usually established by cytologic examination of cells obtained by fine-needle aspiration (FNA) biopsy and/or of tissue obtained by large-needle or surgical biopsy. Evaluation of the biopsy material should include routine light microscopy and analysis with immunohistochemistry (table 1). On cytopathology, morphologic patterns of anaplastic thyroid cancer include spindle cell, pleomorphic giant cell, and/or squamoid (picture 1). Many anaplastic thyroid cancers have a mixed morphology of two or all three patterns. (See 'Diagnosis' above.)

●Differential diagnosis – Other malignancies that may look histologically similar to anaplastic thyroid cancer but have significantly different treatment and prognosis include poorly differentiated thyroid cancer, medullary thyroid cancer, lymphoma, melanoma, and sarcoma. Careful attention to morphology and immunohistochemical studies (table 1) are required to distinguish anaplastic thyroid cancer from poorly differentiated thyroid cancer and other malignancies. (See 'Differential diagnosis' above.)

●Evaluation

•Laboratory testing – For patients diagnosed with anaplastic thyroid cancer on the basis of the findings on cytopathology, we obtain the following laboratory tests: thyroid-stimulating hormone [TSH], free thyroxine [T4], thyroglobulin, complete blood count, electrolytes, blood urea nitrogen [BUN], creatinine, glucose, liver function tests, calcium, and phosphorus. (See 'Laboratory evaluation' above.)

•Imaging – Initial imaging to determine extent of disease should include ultrasound of the neck (if not already performed), positron emission tomography (PET)/CT using 18 F-fluorodeoxyglucose (18FDG; neck to pelvis), and brain MRI or CT. If PET/CT scanning is not readily available, cross-sectional imaging of the brain, neck, chest, abdomen, and pelvis with CT or MRI provides adequate initial staging information. (See 'Imaging' above.)

•Molecular testing – All tumors should be evaluated for the presence of a BRAF mutation as quickly as possible after the diagnosis (using immunohistochemical staining on FNA or core biopsy samples with an antibody specific for the BRAF V600E-mutated protein) (algorithm 1). If available, next-generation molecular sequencing of the cancer should be performed to evaluate for the presence of other targetable mutations that might be able to be treated. Promising and approved targets that are seen in anaplastic thyroid cancer and should be included in the evaluation include BRAF, TSC1, TSC2, ALK fusion genes, RET fusion genes, and NTRK fusion genes. (See 'Molecular testing' above.)

●Treatment

•BRAF V600E mutation identified

-Stage IVA – For patients who present with resectable tumors (algorithm 1), we suggest complete resection followed by combined modality therapy with chemotherapy and radiation (Grade 2C). (See 'Stage IVA' above.)

For most patients, we suggest total thyroidectomy (if it can be done with complete gross resection of tumor and minimal morbidity) rather than lobectomy (Grade 2C). Differentiated thyroid cancer and anaplastic thyroid cancer often coexist, and total thyroidectomy will facilitate subsequent treatment of the differentiated thyroid cancer. However, for the rare patients with intrathyroidal anaplastic thyroid cancer, without a coexistent well-differentiated thyroid cancer component, thyroid lobectomy with wide margins of adjacent soft tissue on the side of the tumor is an appropriately aggressive alternative surgical approach. (See 'Extent of surgery' above.)

Chemotherapy options include doxorubicin, docetaxel, or cisplatin and doxorubicin. (See 'Chemoradiation' above.)

-Stage IVB or IVC – For patients with stage IVB or IVC disease with a BRAF V600E mutation (algorithm 1), we suggest dabrafenib plus trametinib (Grade 2C), followed by evaluation for resectability. If the response to dabrafenib plus trametinib is favorable and disease is resectable, resection is followed by chemoradiation for stage IVB disease and re-initiation of dabrafenib plus trametinib for stage IVC disease. If disease remains unresectable, dabrafenib plus trametinib can be continued if associated with disease stability or improvement. If the response is not favorable, alternative management options include chemoradiation, clinical trials, or best supportive care. (See 'Stage IVB' above and 'Stage IVC' above.)

•BRAF V600E not identified or unknown

-Stage IVA – For patients who present with resectable tumors (algorithm 1), we suggest complete resection followed by combined chemotherapy and radiation (Grade 2C). (See 'Stage IVA or resectable IVB disease' above.)

The extent of thyroid surgery and chemoradiation therapy are the same as for patients with Stage IVA disease with a BRAF V600E mutation. (See 'Extent of surgery' above and 'Chemoradiation' above.)

-Stage IVB resectable – For patients with locally advanced (stage IVB) resectable disease without a BRAF V600E mutation (algorithm 1), we suggest surgery (Grade 2C). The extent of surgery depends upon the degree of soft tissue involvement. Options include total thyroidectomy, lobectomy with wide margins of adjacent soft tissue, or en bloc resection. Patients whose tumors are resected completely are treated with chemoradiation. (See 'Stage IVA or resectable IVB disease' above.)

-Stage IVB unresectable or stage IVC – For patients with unresectable stage IVB or IVC disease without a BRAF V600E mutation, options include targeted therapy (if another targetable mutation is present), chemoradiation, clinical trials, or supportive care, depending on the clinical setting. (See 'Stage IVB (unresectable) or IVC disease' above.)

In patients with advanced disease without a targetable mutation, palliation of symptoms is a high priority. Treatment should be directed toward securing the airway and ensuring access for nutritional support. If the patient has a good performance status, enrollment in clinical trials of targeted therapy is strongly encouraged. (See 'Another targetable mutation absent or unknown' above.)

●Prognosis – Anaplastic thyroid cancer is almost always rapidly fatal, the few exceptions being patients whose tumors are small and who are treated very aggressively. Palliative/comfort care should be an integral part treatment planning for all patients with anaplastic thyroid cancer, especially for patients with stage IVB or IVC disease. (See 'Prognosis' above and 'End-of-life care' above.)