12 Anaplastic Thyroid Carcinoma

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12.1 Introduction

Undifferentiated (anaplastic) thyroid carcinoma (ATC) is a highly malignant tumor that histologically appears wholly or partially composed of undifferentiated cells that exhibit immunohistochemical or ultra- structural features indicative of epithelial differentiation.

In older literature, synonyms such as “spindle and giant cell carcinoma,” “sarcomatoid carcinoma,” “pleo-

morphic carcinoma,” “dedifferentiated carcinoma,”

“metaplastic carcinoma,” or “carcinosarcoma” are used to describe this very aggressive and lethal tumor, leading to death within a few months in most of the patients.

12.2 Epidemiology

Anaplastic thyroid carcinoma is a rare disease with an incidence of approximately one or two cases per mil- lion per year [1]. It accounts for 1.6% to 13% of thyroid carcinomas [2–8] but this varies geographically with a higher incidence in Europe than in the USA. A higher incidence has been reported in endemic goiter regions.

Earlier studies from the USA indicate a percent- age of 20% [9]. A continuous decrease of ATC can be observed over recent decades [10–12]. One rea- son for this may be the introduction of iodine pro- phylaxis in endemic, iodine-deficient goiter regions [2,4,6,12–14]. However, other investigators could not find any influence of iodine supplementation on the incidence of ATC [15]. Nevertheless, the incidence of ATC in iodine-deficient areas, such as India, is still high (Table 12.1) [16,17]. On the other hand, through the introduction of immunohistochemical methods, many tumors formerly classified as ATC turned out to be lymphomas or medullary thyroid carcinomas [2,4,15,18,19]. As an additional explanation for the decrease of ATC, some authors postulate the more

12 Anaplastic Thyroid Carcinoma

Christian Passler, Reza Asari, Christian Scheuba, and Bruno Niederle

Contents

12.1 Introduction . . . 161 12.2 Epidemiology . . . 161 12.3 Etiology . . . 162

12.4 Clinical Presentation . . . 162 12.5 Macroscopy . . . 162 12.6 Cytopathology . . . 163 12.7 Fine-needle Aspiration . . . 163 12.8 Histopathology . . . 163 12.9 Pathologic Staging . . . 164

12.10 Prognostic Factors and Outcome . . . 164 12.11 Treatment . . . 164

12.11.1 Surgery . . . 165 12.11.2 Radiotherapy . . . 166 12.11.3 Chemotherapy . . . 166

12.12 Future Therapeutic Aspects . . . 167 12.13 Conclusion . . . 167

References . . . 167

Table 12.1 Incidence of ATC and iodine supplementation

Country Iodine (µg/d) Papillary (%) Follicular (%) Anaplastic (%)

Japan >240 73 17 3

USA >240 68 16 4

Switzerland 80–120 53 27 5

Germany 80–120 49 25 1

India 40–80 29 45 12

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ratio 1.5:1), as in most thyroid carcinomas [2–5, 14,18,21,23,25,26].

12.3 Etiology

There are many theories about the development of ATC, but to date, no specific etiologic agent has been identified [27]. There is clinical and pathologic evidence of ATC developing from dedifferentiation of differentiated thyroid carcinomas (DTC). The clinical evidence consists of the frequently observed long- standing history of a thyroid pathology or even for- gone thyroid surgery because of DTC [27]. Foci of ATC in DTC (incidental ATC) lead to a significantly better prognosis in comparison to pure ATC [8,11,28–

31]. This suggests that the tumor should be removed at an early stage of disease, before it undergoes complete transformation. Some authors found aggressive subtypes of papillary thyroid carcinomas, such as the tall cell variant, or insular thyroid carcinomas in association with ATC, leading them to the hypothesis that these subtypes represent an intermediate form in the anaplastic transformation process [8,27,32–34]. Since some authors did not find associated differentiated components in most ATCs, it remains controversial whether ATC may arise de novo or as consequence of transformation of DTC [23,27].

On the molecular level, tumor suppressor genes are thought to play an essential role in the development of ATC. The most investigated tumor suppressor gene is p53. Lack or production of abnormal p53 protein causes higher susceptibility to malignant transformation. Mutations or overexpression of p53 are frequently detected in ATC [34–38]. Other on- cogenes that are believed to play a role in anaplastic transformation are bcl-2, cyclin D1, β-catenin, Met, c-myc, Nm23, and ras [27].

12.5 Macroscopy

Most of the ATCs replace the majority of the gland parenchyma. Up to 90% of patients show invasion of the tumor into adjacent structures and organs, mostly

Fig. 12.1 Anaplastic (undifferentiated) thyroid cancer (ATC) in magnetic resonance imaging: partly cystic inhomogeneous 9 × 7 × 9-cm mass in the right thyroid lobe without gross infil- tration of neighboring organs. a Axial view. b Coronal view

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in fatty tissue and muscles (Fig. 12.2), but also into the larynx, trachea, pharynx, esophagus, jugular vein, and carotid artery [4,12,14,42].

Macroscopically they are fleshy and white-tan col- ored tumors exhibiting areas of necrosis and hemorrhage (Fig. 12.3).

Nearly 50% of the patients present with distant metastases at diagnosis, and they may be present at any site. The most commonly involved organ is the lung (80%), followed by bone (6–15%) and brain (5–13%).

Up to 75% of the patients develop distant metastases during follow-up [4,7,14,21,23,30,31,39–41].

12.6 Cytopathology

The diagnosis is often suspected through the typi- cal clinical presentation, but nevertheless has to be ascertained by fine-needle aspiration (FNA) or core needle biopsy. Accurate diagnosis should be possible in 90% of patients [1,14,43], even though some authors report an accurate diagnosis by FNA in only 30% of cases [8]. Open biopsy should be reserved for ambiguous situations in order not to delay treatment by prolonged wound healing [44].

12.7 Fine-needle Aspiration

Aspirates are typically highly cellular [45]. The cells are presented singly or in clusters and there is a marked nuclear pleomorphism. The cell types include squamoid, giant cell and spindle cell. The nuclei are

bizarre and single or multiple. They reveal coarsely clumped chromatin and single or multiple prominent nucleoli. Mitotic figures may be numerous. Occasional osteoclast-like giant cells can be seen [45]. The back- ground smear reveals necrotic debris often with ac- companying polymorphonuclear leukocytes. Because of the presence of the latter cells care must be taken to distinguish these tumors from acute thyroiditis [45].

12.8 Histopathology

When an ATC is well sampled, it is possible to find well-differentiated or poorly differentiated thyroid carcinoma in many tumors. This finding supports the belief that ATC arises from the transformation (dedifferentiation) of a pre-existing, better differentiated carcinoma. Some cases may arise de novo [45].

The majority of ATCs are composed of an admix- ture of spindle cells, pleomorphic giant cells, and epithelioid cells (Fig. 12.4). The spindle cells can be slen- der or plump, and the giant cells may contain single or multiple, bizarre nuclei. About 20–30% of the tumors can present frankly epithelioid areas, sometimes exhibiting squamoid features. Mitotic figures are a very frequent finding [45].

Some tumors may be highly vascularized and the neoplastic cells can be arranged in a hemangioperi- cytic-like pattern or may form irregular anastomos- ing tumor cell-lined clefts mimicking an angiosar- coma [45].

It is of the utmost importance to rule out lymphomas and medullary thyroid carcinomas. This can be done by immunohistochemical staining for calcito- nin, carcinoembryonic antigen, and chromogranin A

Fig. 12.2 Macroscopically radical en bloc thyroidectomy with adjacent strap muscles; the ATC is localized in the right thyroid lobe. The patients presented with a local recurrence (12 cm) and distant metastases (lung, pleura) 8 weeks later, and suc- cumbed 10 weeks after primary surgery

Fig. 12.3 Macroscopic view of the opened specimen. The large tumor is fleshy, white-tan in color, and exhibits areas of necrosis and hemorrhage

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in the case of medullary thyroid carcinoma, and for leukocyte common antigen (LCA), CD 79a, and CD 3 in the case of lymphoma. In addition, the diagnosis of ATC can immunohistochemically be confirmed by coexpression of mesenchymal (vimentin) and epithelial (CAM 5.2) markers [12].

In order to determine the extent of local tumor growth and the presence of distant metastases, it is helpful to perform pretherapeutic computed tomog- raphy or magnetic resonance imaging of the neck and chest [41].

12.9 Pathologic Staging

All ATC are considered to be T4 tumors (T4a: ATC within the thyroid gland; T4b: ATC infiltrating be- yond the thyroid gland). All are staged as “stage 4”

(stage IVA: T4a, N0 or N1, M0; stage IVB: T4b, N0 or N1, M0; stage IVC: every T, No or N1, M1) [46].

death within a short time period is distant metastases at time of presentation [5,19,21,40,42,49]. Other inconsistently found favorable prognostic factors are young age [21,24,40], small tumor size (<5 cm) [2,4,30,40,47,49], focal anaplastic transformation in DTC [8,30,32,40,50], and completeness of tumor resection [4,12,22,29,47,51]—all predict improved survival. Other series reported the same fatal outcome in patients with or without associated DTC (Fig. 12.5) [12,20,21,25,51].

Sugitani et al. [30] developed a prognostic index (PI) for patients with ATC based on four independent prognostic factors identified by multivariate analysis.

The factors were acute onset of symptoms (within 1 month), tumor diameter >5 cm, white blood cell (WBC) count ≥10,000/mm3, and distant metastases at presentation. For every present factor one point was given resulting in five different patient groups from P0 to P4. The difference in survival between the different groups was statistically significant. They resolved to perform multimodal therapy with a combination of surgery, radiotherapy, and chemotherapy in patients with a low PI, and palliative therapy in patients with a high PI.

12.11 Treatment

In many patients is it impossible to radically remove the primary tumor because of its early invasive growth. Thus the main goal of therapy is control of local disease in order to avoid death from suffocation. Surgery, radiotherapy, or chemotherapy alone is seldom sufficient to control the disease [21,52,53].

At the present time there is no known curative treatment in case of distant metastases. Multimodal treatment using hyperfractionated radiotherapy, chemotherapy, and surgery seems to be the best way to achieve this goal and is thus the treatment of choice [7,21,51,54,55].

Fig. 12.4 The thyroid mass, classified as undifferentiated thy- roid cancer, shows two cell populations histologically, giant cells (a) and spindle cells (b)

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12.11.1 Surgery

The role of surgery is controversial. On the one hand, surgery seems indicated only for open biopsy when needle biopsy fails to obtain enough tissue to differ- entiate ATC from thyroid lymphoma. Surgery seems ineffective in achieving local tumor control, but it is indicated for securing the airway, via tracheostomy when necessary, in individual patients [39]. On the other hand, extended surgery, including partial resection of vital organs, has been recommended, since long-term survival has been reported with low morbidity through the use of this procedure [56,57].

Other authors described a high rate of complications in extended surgery for ATC [20,21,58]. The main role of surgery concerns debulking of tumor masses that facilitates radiotherapy and chemotherapy for local tumor control [4,21,59,60]. It seems to be useful to do primary, preoperative hyperfractionated radiotherapy in combination with chemotherapy in order to enhance resectability [7,55]. Whereas Tennvall et al. [55] reported local tumor control in 60% of the patients but no impact on survival using this treatment protocol including surgery, Sugino et al. [31]

have observed a significantly better survival rate in patients undergoing debulking surgery followed by radiation in comparison to patients who did not undergo surgery (1-year survival 60% versus 20%, respectively). Other authors also reported prolonged survival in patients in whom complete surgical resection in combination with radiotherapy and/

or chemotherapy was performed [22,30,40,51]. A recent report showed no impact on survival, either by the extent or the achieved completeness of resection [23]. Our own experience shows a statistically

significant higher survival rate in patients where complete microscopic tumor resection (R0) can be achieved. R0-resected patients had a median survival of 6.1 months compared to 2.2 months in patients with micro- or macroscopic (R1/R2) tumor residues (P<0.001) (Fig. 12.6) [12].

Complete tumor resection can be achieved mainly in incidental ATCs limited to the thyroid [40], and therefore only in a small number of patients and at the expense of a higher morbidity, especially vocal cord paralysis [12]. Because of the high incidence of complications and the questionable impact on survival we do not see any justification for an ultraradical surgical approach involving segmental resections of esophagus, larynx, and trachea, except in very special cases (young patient with limited infiltration without distant metastases). However, we are consistent in re- moving infiltrated neck muscles and in performing (partial) sleeve resections of the laryngeal, tracheal, and esophageal wall, if macroscopic tumor resection seems possible (restricted radical approach) [12]. This aggressive surgical management with organ preserva- tion (without ultraradical en bloc resections of esophagus, trachea, or larynx) is considered the preferred surgical approach, as is the case in other centers [51].

According to a recently published consensus on the treatment of ATC, total thyroidectomy is justified if cervical and mediastinal disease can be resected with limited morbidity [41].

Apart from emergency situations (intratracheal hemorrhage, acute dyspnea, bilateral vocal cord paralysis) a primary tracheostomy should be avoided [61]. Nevertheless in our own experience a tracheostomy became inevitable in 9% of R0 resections and in 23% of R1/R2 resections [12].

Fig. 12.5 Estimated survival according to Kaplan-Meier in 120 patients with ATC comparing pure ATCs and ATCs with differenti- ated parts; P = 0.334 [12]

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12.11.2 Radiotherapy

Radiotherapy plays an important role in achieving local tumor control. A minimum radiation dose of

>30 Gy seems necessary [19]. Pierie et al. [40] showed a better outcome in patients who received a total dose of >45 Gy than in those who received ≤45 Gy. In order to reduce toxicity and allow a high total radiation dose, hyperfractionation is useful [59]. Additionally, acceleration of radiotherapy seems to improve local tumor control [55]. Tennvall et al. [55] report on three protocols combining doxorubicin, hyperfractionated radiotherapy, and surgery in 55 patients with ATC. In protocol A a target dose of 30 Gy was administered preoperatively for a period of 3 weeks and an additional 16 Gy postoperatively for 1.5 weeks. The radiation dose was administered twice daily with a target dose of 1 Gy per fraction. In protocol B radiotherapy was accelerated by administering 1.3 Gy per fraction twice daily to the same total doses pre- and postoperatively. The total treatment time was short- ened from 70 to 50 days by acceleration. In protocol C radiotherapy was further accelerated by increasing the target dose to 1.6 Gy per fraction twice daily and administering the radiation only preoperatively to a total dose of 46 Gy in 29 fractions within 3 weeks.

Radiation therapy was combined with weekly admin- istration of doxorubicin at 20 mg i.v., and was con- tinued after the completion of local treatment for a maximum of 3 months. A strong correlation between local tumor control and acceleration of radiotherapy could be found. Additional surgery was, however, a prerequisite for eradication of local disease. Among patients undergoing surgery, 83% showed no signs of local recurrence. No significant improvement of sur-

vival could be reached, since there was no observed response in distant metastases. Nevertheless 5 patients (9%) survived for longer than 2 years and seem to be cured.

Other investigators also find improved local control using a combination of radiotherapy and chemotherapy, but no or only little improvement of survival [54,59].

12.11.3 Chemotherapy

According to Ain [14] successful systemic chemotherapy is of major importance for survival because of the high incidence of patients with distant metastases at presentation. Unfortunately, no chemotherapeutic agent has yet been found that leads to improved survival or that has an effect on present distant metastases [40,41,55,62].

Doxorubicin is the most commonly used drug, showing no evidence of complete response when used as monotherapy [53,63]. Addition of other chemotherapeutic agents such as cisplatin and/or bleo- mycin did not show an improvement in survival [53,62,64,65]. The main limitation is high drug toxicity. Chemotherapy has its role for local tumor control in combination with radiotherapy, since doxorubicin is successfully used as a radiosensitizer [40,55].

Schlumberger et al. [54] reported on 20 patients who had been treated with radiotherapy and, age-dependent, received chemotherapy with a combination of doxorubicin and cisplatin (<65 years) or mitoxantrone. Although local tumor control was achieved, occurrence and continuing existence of distant metastases could not be influenced.

Fig. 12.6 Estimated survival according to Kaplan-Meier of 120 patients with ATC, comparing R0 and R1/R2 resections;

P<0.001 [12]

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Kober et al. [66] reported on the results of combination chemotherapy using cisplatin, vincristine, and mitoxantrone. Out of 15 patients, 10 who responded, completely (4 patients) or partially (6 patients), were compared with non-responders, and these patients demonstrated a markedly prolonged median survival (20.8 months versus 4.5 months, respectively).

Ain et al. [67] reported on the good results with reduced cell counts of all ATC cell lines in vivo and on diminishing size of xenograft tumors using paclitaxel.

A subsequent phase II study showed a 53% response rate using paclitaxel. Patients who demonstrated a therapeutic response showed a significantly improved survival of 32 weeks, compared to 7 weeks in non-re- sponding patients [68]. Further studies are necessary to eventually confirm an impact on survival by using paclitaxel.

Controversies remain about the optimal sequence of treatment modalities in ATC. Some centers use surgery as the first-line therapy in ATC with postoperative chemo- and radiotherapy [40,54], whereas others prefer primary chemo- and radiotherapy, followed by surgery, if feasible [7,55]. Potential disadvantages of the latter approach may be a delay in securing the airway and a possible delay in surgery because of the toxicity of combined radiotherapy/chemotherapy [69]. The decision about the sequence must finally be an individual one, based on patients’ conditions and tumor characteristics.

12.12 Future Therapeutic Aspects

Tumor suppressor gene therapy is a promising future directive. In vitro analysis showed inhibition of growth and dedifferentiation of ATC cell lines by re- introduction of p53 wild-type [70–72]. In vivo studies followed. After subcutaneous injection of anaplastic tumor cells in nude mice adenovirus-mediated tumor suppressor p53 gene therapy led to near complete inhibition of tumor growth, and tumor regression was observed with the addition of doxorubicin [73]. His- tone deacetylase (HDAC) inhibitors promote apoptosis and differential cell cycle arrest in anaplastic cancer cell lines [74]. Clinical trials using HDAC inhibitors to treat ATC have not yet been carried out [27]. Angio- genesis inhibitors are additional substances showing some effect against human ATC xenografts in nude mice [75]. A further therapeutic directive is to use bone morphogenic proteins as negative regulators to thyroid carcinoma growth. Franzen and Heldin [76]

showed cell cycle arrest of anaplastic carcinoma cells in the G1-phase by using bone morphogenic protein

(BMP-7). Injection of bovine seminal ribonuclease resulted in complete regression of in vivo established anaplastic thyroid cancer in nude mice by inducing apoptosis [77].

As shown recently [78], lovastatin, a 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitor, induces a dose-dependent apoptosis and differentiation in ATC cells.

12.13 Conclusion

Multimodal treatment using hyperfractionated radiotherapy, chemotherapy, and surgery may be the treatment of choice for ATC. Surgery plays an important role because local tumor control cannot be achieved without debulking of large tumor masses.

Current evidence indicates that undifferentiated thyroid carcinoma originates from follicular cells.

Therefore prognostic factors are related primarily to the extent of the disease at presentation. A small number of patients with completely resectable tumors (mainly as incidental ATC in the form of small foci of ATC in differentiated carcinomas) may be cured by aggressive surgery in combination with radiotherapy and chemotherapy. Nevertheless, in most patients death from ATC cannot be avoided, since multimodal treatment does not have much influence on distant metastases and thus on the survival rate.

However, quality of life can be improved. It is prob- ably less severe to die from distant metastases, than from suffocation due to failure of local tumor control.

Although future therapeutic aspects are promising, clinical trials showing their impact on survival are still lacking.

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