7

Fortunately enough anaplastic carcinoma of the thyroid (ACT) is not a very frequent tumor as it is one of the most deadly cancers known. With a median survival period of just a few months from diagnosis,1 and its rapidly fatal course, ACT has a grim prognosis. Case reports of long-term survivors can be found in the literature, but in every such case the diagnosis should be in doubt.² Most patients have either palpable or positive lymph nodes on imaging when diagnosed.³ Because patients are doomed to die of asphyxiation if left untreated, a tracheotomy is done in all patients along the course of the disease, which provides palliation. In a minority of patients, some form of surgery to remove the tumor can be considered if the tumor is diagnosed at a resectable stage.⁴ Radiotherapy (RT) is considered for palliation. Several chemotherapy regimens are being tested, but none has been found to drastically change the course of this fatal disease. Recent investigational and novel therapies will be reviewed.

Epidemiology

An estimated 37,200 new cases of thyroid cancer occur annually in the United States according to the Surveillance, Epidemiology, and End Results (SEER) program 2009 report.⁵ Thyroid cancers account for 2.5% of all neoplasms, and ACT accounts for 1 to 2% of all thyroid cancers.⁵ Nevertheless, the majority of the 1630 deaths from thyroid cancer expected annually in the United States are related to ACT.⁵ It seems that the incidence of thyroid cancer has been increasing while that of ACT has been declining in recent years.⁶ One possible explanation for this observed trend can be the increased use of immunohistochemistry (IHC) staining for pathology diagnosis in undifferentiated tumors.⁷ Another explanation is better control of well-differentiated thyroid cancers (WDTCs), which might dedifferentiate into ACT.⁸ Also, improvement in socioeconomic status and improvement in the content of iodine in the diet in areas where endemic goiter is common could explain this reduction in ACT incidence.⁹

Clinical Features

ACT is usually diagnosed rather late in life, during the sixth to seventh decade.^1,10 As with other thyroid cancers, women have up to a threefold higher tendency for ACT.¹¹ A rapidly growing neck mass that is firm and fixed to the surrounding tissues is the most common presenting symptom, is seen in the vast majority of patients,¹² and can even cause superior vena cava syndrome.¹³ Pain can result from intralesion hemorrhage and sudden enlargement of the neck mass. The neck mass can span from a small lesion of a few centimeters to an enormous 20-cm mass.¹ Because of its size and its tendency to penetrate and involve surrounding tissues (trachea, larynx, recurrent laryngeal nerves, pharynx, upper esophagus, and strap muscles) in the majority of patients,¹² patients often have related signs and symptoms either at presentation or later during the course of the disease (Fig. 7.1). These can be respiratory-related signs and symptoms of dyspnea, hoarseness, stridor, and tachypnea or upper digestive tract-related symptoms of progressive dysphagia, first to solids and then to liquids (Table 7.1). Airway management is the most critical issue in patients who present with anaplastic thyroid cancer and initial airway distress.¹⁴ Thirty to 60% of the patients can have metastasis to cervical lymph nodes,^1,15 and nearly half of the patients will have metastatic spread of disease when diagnosed. Furthermore, during the course of the disease, most patients will develop distant metastasis. The most frequent site for distant metastasis is the lungs, followed by the brain and bones.1 Thyrotoxicosis is a rare feature of ACT.¹⁶

Before the era of IHC, the diagnosis of ACT was done mainly with the commonly used hematoxylin-eosin stains (Fig. 7.2). Based on the patterns of cells seen, several variants of ACT were described—spindle cell, giant cell, squamoid, insular carcinoma, carcinosarcoma, paucicellular, pure squamous cell carcinoma, and small cell. The couple of latter variants carry a poorer prognosis.¹⁷ In all variants, characteristics of rapid proliferation and high grade can be found. Large areas of necrosis, hemorrhage, and invasiveness can be seen under low magnification, and a high mitotic activity, a high tumor proliferative index, and a low apoptotic rate can be seen under higher magnification.¹⁸ During the past few decades, an increased use of IHC techniques has helped more reliably differentiate these tumors from lymphoma, sarcoma, and poorly differentiated medullary thyroid carcinoma.¹⁹ Among the available IHC stains, a battery that includes neuron-specific enolase, chromogranin, calcitonin, vimentin, keratin, α-1 chemotrypsin, desmin, carcinoembryonic antigen, anticytokeratin, and thyroglobulin should be considered. Whenever a patient has a clinical course that is exceeding the expected prognosis, one should question the diagnosis and reanalyze the pathologic examination. The insular variant is thought to derive from a WDTC via a mechanism of p53 overexpression.²⁰ Morphologically, solid clusters (insulae) containing a variable number of follicles, high mitotic activity, capsular and vessel invasion, and necrosis lead to the formation of preepitheliomatous patterns, which can be found in 3% of ACT cases.²¹ ACT is characterized by markedly reduced lymphocyte/dentritic cell infiltrates, which suggests a protective role of dentritic cells and infiltrating lymphocytes against thyroid tumors.²² Thyroid cancers are infiltrated with tumor-associated macrophages that may facilitate tumor progression.²³

Table 7.1 Sign and Symptoms of Anaplastic Carcinoma of the Thyroid

Pathogenesis

As described in the previous paragraph, data exist to support a transformation pathway of a WDTC into ACT.24 Disturbances in the balance between apoptosis and proliferation, in favor of the latter, occur gradually during the progression of malignancy in thyroid tumors.²⁵ Anaplastic transformation may occur not only in primary tumors but also in metastatic lymph nodes.²⁶ Most cases, though, might have a de-novo pathogenesis. A history of a known goiter or WDTC that recently grew in an elderly patient should initiate an investigation to rule out anaplastic transformation.²⁷ There is other evidence that suggests a transformation etiology. The incidence of ACT is higher in areas endemic for goiter and in patients with previously treated WDTC.²⁸ Furthermore, synchronous diagnosis of WDTC and ACT is common.²⁹ There are studies that described small islands of WDTC in ACT specimens, and some even reported a transition spectrum of WDTC and ACT on the same slide. Insular and tall cell types of papillary thyroid cancer that are notorious for their aggressive biologic course are more frequently associated with ACT. They can be seen, therefore, as an intermediate form of cells between the well-differentiated papillary carcinoma and the poorly differentiated ACT.²¹ Poorly differentiated thyroid carcinomas represent an intermediate entity in the progression of WDTC to ACT.³⁰

Review of the literature identified potential new strategies for treating this highly lethal cancer. In studies involving anaplastic cell lines in vitro, it has been shown that the loss of p53 or the presence of abnormal p53 can be responsible for the transformation of WDTC cells to ACT.³¹ Knockdown of mutant p53 has been shown to reduce cell viability and exert antitumor activity equivalent to high doses of several chemotherapeutic agents, via the induction of apoptosis.³² Impairment of p53-mediated repression results in increased GLUT1 and p63 expression, which probably reflects the differential regulation of hypoxia-responsive pathways and basal/stem cell regulatory pathways.³³ In radiation-induced thyroid cancers, the highest frequency of RET amplification-positive cells was observed among patients with ACT with a strong p53 immunoreactivity.³⁴ FOXA1, a mammalian endodermal transcription factor, may be an important oncogene in thyroid tumorigenesis.³⁵ In recently published articles, it was shown that an analysis of distinct sets of micro-RNAs (miRNAs) was used as a tool to distinguish poorly differentiated thyroid carcinoma and suggested that a lack of deregulation of some miRNAs may select a subset of WDTC prone to dedifferentiate.³⁶ BRaf mutations, which belong to the Raf family of serine/threonine kinase, have a central role in the regulation of cell growth, cell division, and cell proliferation and appear to be involved in the tumorigenesis of a subset of ACTs and the majority of lymph node metastases.³⁷ Sorafenib, a multikinase inhibitor of the BRaf, vascular endothelial growth factor receptor-2, and platelet-derived growth factor receptor-β kinase have been shown to decrease tumor growth and angiogenesis in an orthotopic model of ACT.³⁸ Anaplastic transformation of thyroid cells is accompanied by the overexpression of a cell proliferation/genetic instability-related gene cluster that includes pololike kinase 1.³⁹ Apolipoprotein E, known to play a role in cholesterol transport and metabolism, was found to be one of the typical biological characteristics of anaplastic thyroid carcinoma.⁴⁰ Results of a recent study demonstrated that gain of chromosome 20 is important in the pathogenesis of ACT and/or progression of differentiated thyroid cancers to ACT in both primary tumors and cell lines.⁴¹ It has been suggested that derangement of the E-cadherin/catenin complex is associated with the transformation of differentiated into anaplastic thyroid carcinoma,⁴² as well as ANXA1 expression.⁴³ An altered expression of serum response factor, a transcription factor of the MADS box family in papillary carcinoma cells, may play an important role in WDTC carcinogenesis and progression.⁴⁴ Aberrant tumor suppressor activity and increased proliferative activity were found to be most prevalent in ACT, followed by poorly differentiated thyroid carcinomas and WDTC.⁴⁵ Loss of CBX7 gene expression correlates with a highly malignant phenotype in patients with thyroid cancer.⁴⁶ Annexin II and S100A10, a member of the S100 family that forms a heterotetramer with annexin IIH, promote carcinoma invasion and metastasis by plasminogen activation and contribute to the aggressive characteristics of anaplastic carcinoma.⁴⁷

There is evidence to support the observation that estrogen is an important factor in the development of thyroid cancer. The subcellular localization of estrogen receptor α and β may account for the different pathogenesis of thyroid papillary and anaplastic cancers.48

The exact mechanisms that are involved in the transformation of WDTC to ACT are not fully understood and need further elucidation. With the recent increased knowledge of the many critical genes and proteins affected in ACT, and the extensive array of targeted therapies being developed for patients with cancer, there are new opportunities to design clinical trials based on tumor molecular profiling and preclinical studies of potentially synergistic combinatorial novel therapies.

Diagnosis

As with other thyroid masses, clinical examination and cytologic specimen acquired through fine-needle aspiration (FNA) are usually the first steps taken and are usually sufficient for diagnosis. A typical clinical presentation, as described above, warrants FNA examination, which can be reliable in nearly 90% of the patients.⁴⁹ As mentioned previously, IHC staining must be done to confirm the diagnosis and to suggest other tumors with a curable option.⁵⁰ MIB-1 is an antibody against K_i-67, which is a protein expressed in proliferating cells, and is a molecular marker already used in cytological evaluation. MIB-1 index was significantly higher in ACT than in other thyroid cancer types.⁵¹ There is a rare report of implantation of anaplastic thyroid carcinoma along the track of FNA.⁵² A large-bore needle biopsy or an open incisional biopsy might be indicated as further IHC staining is needed. In patients with a history of WDTC who develop a rapidly growing mass elsewhere, a possibility of metastatic WDTC with anaplastic transformation must be considered, which can also be diagnosed by FNA biopsy.⁵³ A preoperative imaging method such as computed tomography scan with intravenous contrast media can be considered to better understand the sometimes difficult anatomy and lack of anatomic and surgical landmarks due to the compressive and invasiveness characteristics of the tumor. In an elderly patient presenting with a large necrotic thyroid mass of low attenuation, anaplastic carcinoma should be included in differential diagnosis.⁵⁴ Riedel thyroiditis, a rare thyroid disease characterized by dense fibrous tissues that replace the thyroid gland and invade the adjacent structures, can mimic ACT.⁵⁵ In a recently published article, it was reported that ACT demonstrates intense uptake on ¹⁸F-fluorodeoxyglucose positron emission tomography (PET) images. In 50% of the patients, the medical records reported a direct impact of PET findings on the management of the patient, relative to other imaging modalities.⁵⁶

A panel of internationally recognized thyroid pathologists held a consensus meeting in Turin, Italy, in 2007. They developed the following consensus diagnostic criteria for poorly differentiated thyroid carcinomas: (1) presence of a solid/trabecular/insular pattern of growth; (2) absence of the conventional nuclear features of papillary carcinoma; and (3) presence of at least one of the following features: convoluted nuclei, mitotic activity ≥3 × 10 high power field, and tumor necrosis.⁵⁷

Prognostic Factors and Clinical Course

All ACTs are considered T4 tumors, stratified to T4a, which is intrathyroidal anaplastic carcinoma, and T4b, which is anaplastic carcinoma with gross extrathyroid extension. Therefore, all anaplastic carcinomas are considered Stage IV, in which Stage IVA describes intrathyroidal anaplastic carcinoma, any N, M0; Stage IVB includes anaplastic carcinoma with extrathyroid extension, any N, M0; and stage IVC includes patients with distant metastasis (M1).⁵⁸ Although ACT is staged according to the American Joint Committee on Cancer as stage IV, regardless of other prognostic features, several risk factors have been described. Among the favorable prognostic factors are younger age (< 60 or 75 years), female sex (although in several studies it was found to carry an unfavorable prognosis),⁵⁹ smaller tumors, no capsular invasion, lack of metastatic disease, and lesser extent of disease.^1,60 The latter defines the tumor as either stage IVA, when the tumor is resectable, or stage IVB, unresectable ACTs. Incidentally detected ACTs are rare, and it is unclear whether they confer a better prognosis.⁶¹ Extensive surgical treatment is recommended for patients with stage IVA tumors, and palliative care is appropriate for patients with stage IVC tumors.⁴ For patients with stage IVB, surgical treatment as a primary therapy is appropriate only when curative resection of the tumor is expected.⁴ Aneuploidy and high S-phase fraction were shown to be biomarkers of poor clinical outcome in poorly differentiated thyroid carcinoma and ACT.⁶² Leukocytosis, hypoalbuminemia, and hypothyroxinemia were reported as poor prognostic indicators.

Management of Anaplastic Carcinoma of the Thyroid

Despite aggressive multimodalty therapy including surgery, radiation, and chemotherapy, there is no effective systemic treatment for ACT. Because of the rarity of the disease, its aggressiveness, and lack of prospective clinical trials, the evidence in the literature emerges from retrospective studies. Treatment options include surgery, RT (external beam), chemotherapy, combined therapy, and investigational clinical trials. Often, a single modality is not effective for ACT. Unfortunately, there are no data to support the efficacy of combined modality treatment to prolong survival or improve the quality of life of patients with ACT, and the outcome is still very poor.

Surgery

Surgical treatment of local disease offers the best opportunity for prolonged survival if the tumor is intrathyroidal.¹² However, the role of surgery in ACT is controversial. A selected subset of patients with small ACT that is confined to the thyroid gland may benefit from surgical intervention and complete resection of gross disease.63 When used alone, surgery is seldom adequate to achieve overall control of the disease, but surgery combined with RT or chemotherapy may improve local control. Junor el al⁶⁴ found that total or partial thyroidectomy was associated with increased survival. This association was most marked for patients presenting without dyspnea. Betka et al⁶⁵ noted that there was no difference in the survival of patients who were treated with primary surgery or primary chemotherapy and/or RT. However, the best results were obtained in patients in whom the tumor was surgically removed after primary chemotherapy and RT. Brignardello et al⁴ reported the outcome of 30 patients with ACT. Patients were treated by surgery either before or followed by chemoradiotherapy or chemotherapy alone. Multivariate analysis showed that maximal debulking followed by adjuvant chemoradiotherapy was the only treatment that modified the survival of patients with ACT. Chen et al⁶⁰ found that treatment with surgery plus or minus RT was statistically significant as prognostic for survival on multivariate analysis. Swaak-Kragten et al¹⁰ reported that locoregional control was significantly higher in patients who had undergone resection or chemoradiation, with best results for patients who underwent both. However, the survival benefit of patients who had complete response (CR) remained borderline. Three patients survived for more than 5 years; all had undergone surgical resection and chemoradiation. Unfortunately, more than 70% of the patients present with locally aggressive disease in which the tumor infiltrates surrounding tissues such as trachea, esophagus, and larynx and encases major blood vessels,¹² or presents with metastatic disease. The consensus on the surgical treatment of ACT recommends complete surgical resection whenever possible in selected patients,⁶⁶ and only if postoperative morbidity is low. Resection of vital structures such as the larynx or the esophagus should be avoided. In this case, there is a high rate of local recurrence despite extensive surgical resection due to the aggressive nature of the tumor,⁶³ and neither the extent of surgery nor the completeness of resection has a significant effect on survival.²⁹

Lateral neck dissection is indicated whenever a complete resection is possible and all gross tumor is removed.

Palliative surgical intervention may be required for patients with ACT who present with airway distress. Usually, resection is not possible and tracheotomy is required to avoid asphyxia. Sometimes, immediate airway control may require debulking of tumor. Cricothyrotomy may be helpful in avoiding acute airway catastrophe.²⁹ Prophylactic tracheotomy is not indicated because data exist to support that it decreases the survival of patients with ACT because postoperative external RT often could not be administered or was delayed because of local complications of the tracheotomy.⁶⁷

Radiotherapy

RT can be given with a curative or palliative intent, as neoadjuvant or adjuvant therapy to surgery, or in combination with chemotherapeutic drugs. Several studies were able to show statistically significant differences in local control and even in survival between groups who were treated with different radiation protocols, yet the clinical significance of those studies is debatable because no major breakthrough was achieved and median survival improved by only a few months. Nevertheless, because most patients present with a nonresectable disease, due to its tendency to invade neighboring critical structures, RT remains a cornerstone treatment modality in ACT. Because for most patients survival is not altered, when considering RT as a treatment modality in this region and in reviewing studies one should always keep in mind the potential toxicity of radiation, including mucositis of the pharynx, esophagus, trachea, and myelopathy.

Studies examining the timing of RT, the total dose given, the number of fractionation, and modern radiation delivery methods such as three-dimensionally guided radiation therapy (3DRT) and intensity-modulated radiation therapy (IMRT) are described.

Adjuvant RT might be more effective if surgical debulking is achieved.⁶⁴ A total radiation dose greater than 30 Gy or even 45 Gy was shown to improve survival.^10,68,69 RT can be given in hyperfractionated doses to address the aggressive doubling time nature of this tumor, yet a recent study described little benefit with the use of this strategy.^70,71 Another study was able to demonstrate improved local control and reduce treatment time.⁷² Modern radiation delivery methods try to overcome the limitations caused by the tumor’s challenging anatomic location.⁷³ In an article published by the MD Anderson group in Texas,⁷⁴ 53 patients were treated with either 3DRT or IMRT with a median radiation dose of 55 Gy; 74% received concomitant chemotherapy, yet no difference in outcome was achieved compared with historical results.

Chemotherapy

Distant metastasis is very common among patients with ACT at the time of presentation. Kebebew et al⁷⁵ reported distant metastasis at the time of presentation in 43% of 516 patients with ACT from SEER analysis. Therefore, systemic chemotherapy was given to patients with ACT; however, it was found that none of the systemic chemotherapy regimens prevented the poor outcome and death of the patients, although the survival period was prolonged for those who responded to treatment, usually by several months.

Doxorubicin has been the most common chemotherapy agent used, either alone or in combination with other antineoplastic agents including cisplatin, bleomycin, vincristine, and melphalan. Doxorubicin, as a single agent, has the most effect on ACT, with 5 to 22% partial response (PR) in several studies.^76–79 Other single agents, such as cisplatin, bleomycin, and etoposide (VP-16), were less effective.^77,80

Combined chemotherapy showed a slightly improved response. Doxorubicin, 60 mg/m2 intravenously every 3 weeks, given as a single agent to 21 patients with ACT-induced 5% (1 patient) PR compared with 34% overall response (6 patients, 3 with CR and 3 with PR) for 18 patients treated with a combination of doxorubicin (60 mg/m² intravenously every 3 weeks) and cisplatin (40 mg/m² every 3 weeks). Two of these patients survived for 41 and 34 months.⁷⁹ Combining other antineoplastic agents such as bleomycin⁸¹ to this protocol, protocols including doxorubicin, vincristine, and bleomycin, or other combined chemotherapy regimens did not improve the overall response rate.¹³

Newer protocols with promising results used paclitaxel, given as a single agent either as the only treatment or as induction chemotherapy before surgery and RT. Ain et al⁸² reported a total response rate of 53% in 19 patients treated with a 96-hour infusion of paclitaxel every 3 weeks for one to six cycles. However, only one patient had a CR, whereas nine patients had a PR. The median survival for the responder was 32 weeks and for nonresponders was only 7 weeks. Higashiyama et al⁸³ performed induction chemotherapy by giving paclitaxel on a weekly basis to patients with IVB (nine patients) and IVC (four patients) disease. The response rate was 33% for patients with stage IVB disease and 25% for patients with stage IVC disease. Curative surgery and adjuvant therapy were performed in four of the patients with stage IVB disease, and all four were alive and free of disease 32 months after treatment. Survival of patients with stage IVB disease treated with induction paclitaxel was significantly better compared with historical data of similar patients’ group.

Combined Therapy

The lack of effective chemotherapy as well as the failure of each single modality in the management of ACT has led to the application of multimodality regimens, combining surgery, RT, and chemotherapy. Multimodal treatment varied between protocols that applied surgery (when feasible) followed by adjuvant chemoradiotherapy or regimens that consist of neoadjuvant RT combined with chemotherapy (as radiosensitizing agent), followed by surgery (when possible), or chemoradiotherapy for unresectable disease (Table 7.2). The most common chemotherapy agent used was doxorubicin, mainly as a radiosensitizer. However, there was no standardized protocol in selecting patients for chemotherapy or RT, and conflicting data exist regarding the results of these protocols.

A 50-year experience of the Mayo Clinic with 134 patients with ACT was reported by McIver et al,⁸⁴ in which neither the extent of resection nor postoperative RT or multimodal therapy including surgery, chemotherapy (doxorubicin used for radiosensitization), and RT improved survival.

On the other hand, De Crevoisier et al⁸⁵ reported that CR was achieved in 19 of the 30 patients treated with surgery either before or after chemoradiotherapy including twice daily RT 1.25 Gy for a total dose of 40 Gy and six cycles of doxorubicin. In a median follow-up of 45 months, 7 patients were alive, with 6 of them having complete tumor resection.

Several studies have reported increased survival of patients treated by surgery followed by chemoradiotherapy. Haigh et al⁶³ found that complete resection of ACT with adjuvant chemotherapy and irradiation was associated with prolonged survival. Agents used for chemotherapy usually were based on doxorubicin, but paclitaxel, cisplatin, carboplatinum, etoposide (VP-16), cyclophosphamide, melphalan, and bleomycin were also used. External beam radiation was administered to the neck or the mediastinum, with the total doses ranging from 45 to 75 Gy. Brignardello et al⁴ showed that maximal debulking of ATC followed by adjuvant chemoradiotherapy was the only treatment that improved the survival of patients with ACT compared with chemoradiotherapy followed by surgery or chemotherapy alone. Chang et al⁸⁶ found that there was a small improvement in the survival of patients who had complete excision of ACT followed by aggressive multimodality therapy. Heron et al⁸⁷ showed in a retrospective study that patients who were treated with surgery and hyperfractionated RT in conjunction with chemotherapy had long-term survival (> 2 years).

On the other hand, there are few studies showing that treatment with chemoradiotherapy before surgery has improved survival. Besic et al⁸⁸ reported the treatment results of 79 patients with ACT treated either by primary surgery (26 patients) or by primary chemotherapy and/or RT (53 patients) including 12 patients in whom surgery was performed after chemotherapy or RT. Although the patients in the second group had larger tumors, the best results were obtained in patients whose tumor was surgically removed after primary chemotherapy and RT. Busnardo et al⁸⁹ found that only a few patients respond to chemotherapy; however, combined therapy may provide some benefit in patients with ACT, and preoperative chemotherapy and RT may enhance surgical resectability of the primary tumor.

Promising data emerge from newer protocols, including hyperfractionation RT as well as using docetaxel combined with doxorubicin. In the only prospective study using multimodality treatment for ACT, Tennvall et al⁷² reported on 55 patients treated with a multimodality regimen consisting of hyperfractionation RT combined with doxorubicin, followed by surgery when feasible. The RT dose varied during the years, from 1 Gy × 2/d until 1988 to 1.3 Gy × 2/d between 1989 and 1992 and 1.6 Gy × 2/d thereafter, to a total dose of 46 Gy. Surgery was possible in 40 patients. Only 13 patients died of local failure. Five patients (9%) survived more than 2 years, and 60% of the patients had no sign of local recurrence, with favorable results in the third group. Foote et al⁹⁰ reported enhanced survival in 10 patients with locoregionally confined ACT treated with surgery (where feasible), IMRT, and radiosensitizing + adjuvant chemotherapy including docetaxel and doxorubicin. Five patients (50%) were alive and cancer free at a median follow-up of 44 months (range, 32 to 89 months). Although the protocol improved survival in patients with stage IVA and IVB disease, the benefit in patients with metastatic disease remains uncertain. Troch et al⁹¹ treated six patients with ACT with standard external beam radiation of 60 Gy in 30 fractions along with docetaxel 100 mg every 3 weeks for a total of six cycles. With a median follow-up of 21 months, five patients were alive.