Undifferentiated (Anaplastic) Thyroid Carcinoma (3)

Undifferentiated (anaplastic) thyroid carcinoma is the most aggressive and lethal form of thyroid cancer. Fortunately, it accounts for only 1% to 2% of all thyroid malignancy. If we review the term of undifferentiated (anaplastic) carcinoma, it is very interesting history. It is used to have several kind of diagnostic term. According to the time interval it is named as a sarcoma of thyroid in 1930, spindle and giant cell metaplasia in 1950, and spindle and giant cell carcinoma in 1960. Then it is renamed as anaplastic carcinoma in 1970. In this time, the immunohistochemistry was beginning to introduce, the small cell type of anaplastic carcinoma is termed as lymphoma, medullary type is termed as medullary carcinoma through the immunohistochemistry. Lastly, it is renamed undifferentiated carcinoma by WHO international classification in 2000.

Definition
Undifferentiated thyroid carcinomas (UTC) are highly malignant tumors that histologically appear wholly or partially composed of undifferentiated cells that exhibits immunohistochemical or ultrastructral features indicative of epithelial differentiation.

Etiology
Most cases of UTC show evidence of a pre-existing differentiated or poorly differentiated thyroid carcinoma.

Clinical features
Almost all patients with UTC present with rapidly expanding neck mass (Figure 1). The most frequent and important sign and symptoms are hoarseness (80%), followed by dysphagia (60%), vocal cord paralysis (50%), cervical pain (30%) and dyspenia (20%). The tumor maybe fixed or hard (75%), and may present as a single (60%) or multiple nodule (40%) with bilateral involvement in 25% of cases. Surrounding structures are frequently invaded: muscle (65%), trachea (50%), esophagus (45%), laryngeal nerve (30%) and larynx (15%). Cervical adenopathy is present in more than 40% of patients. At least 40% of patients have distant metastases at the time of diagnosis, 50% involving the lungs, 15 % the bones and 10% the brain. Cardiac metastases have also been described.

Figure 1. Undifferentiated (anaplastic) thyroid carcinoma, showing the rapidly enlarging, fixed mass. Tumor fungation is seen at the tracheostomy site.

Macroscopy
The tumors are large, fleshy, and white-tan in color, often exhibiting areas of necrosis and hemorrhage. They are typically infiltrative and in most instances replace most of the gland parenchyma with invasion into the surrounding soft tissue and adjacent structures including lymph nodes, larynx, pharynx, trachea, and esophagus.

Tumor spread and staging
Undifferentiated carcinomas typically spread beyond the thyroid by direct local extension. Metastases to regional nodes are also common but their presence is often overshadowed by the presence of extensive soft tissue. Distant metastases may be present in any sites. All undifferentiated carcinomas are considered to be T4 tumors.

Histopathology
Histologically, the majority of UTCs are widely invasive tumors composed of an admixture of spindle cells, pleomorphic giant cells and epithelioid cells. There is considerable variation in both the percentage and distribution of these cellular elements from case to case. The spindle cells can be slender pr plump, and the giant cells may contain single or multiple, bizarre nuclei. These patterns are descriptively designated squamoid, spindle cell, giant cell, paucicellular and lymphoepithelioma like (Figure 2).
The squamoid pattern is so named because of its morphologic similarity to nonkeratinizing squamous cell carcinoma of other organs, such as lung or cervix. The appearance in these areas is unmistakably epithelial because of the formation of distinct tumor nests of irregular configuration. Pleomorphism is moderate, giant cells are generally absent. The cytoplasm is abundant and acidophilic. In rare instances, squamous pearls are seen in the center of islands. In these cases, the appearance is epidermoid rather than merely squamoid. Small foci of mucin accumulation can sometimes be demonstrated in these areas by the use Mayer mucicarmine or other mucin stains.
The spindle cell pattern is best described as sarcoma-like, in the sense that, on purely morphologic grounds, it is indistinguishable from a true sarcoma. In most instances, however, the marked degree of nuclear pleomorphism scattered giant tumor cells, storiform pattern of growth, and inflammatory infiltrate give the tumor an appearance similar to that exhibited by the usual form of malignant-fibrous histiocytoma. These cellular areas alternate with extensive areas of necrosis and sclerohyaline deposition.
The giant cell pattern is characterized by a degree of pleomorphism that is substantially higher than that seen in association with the other patterns. The tumor giant cells maybe the only elements present, but more often they are seen interspersed with smaller mononuclear tumor cells that have otherwise similar morphologic features. The pattern of growth in these area is usually solid, but on occasion an artifactual separation of the cells leads to be formation of alveolar (pseudoglandular) or pseudovascular structures.
The paucicellular variant is characterized by a hypocellular proliferation of mildly atypical spindle tumor cells embedded in a dense fibrous stroma that resemble Riedel’s thyroiditis. The lymphoepithelioma-like variant histologically resembles nasopharyngeal lymphoepithelioma but is not been found to be associated with EBV infection.

Molecular genetics alteration
Multiple molecular genetic and expression studies have been performed in UTC, many involving small sample sizes. The increased replicative potential is reflected by alterations in components involved in cell cycle control such as over-expression of cyclin D1, decreased expression of p27, and inactivation of PTEN and p16. The most consistent finding is the strong association of UTC with TP53 mutations.

Figure 2. Undifferentiated (anaplastic) carcinoma. The tumor has a squamoid (A), giant cell (B) and paucicellular (C) growth patterns. D. The wall of vessel is invaded by undifferentiated carcinoma, but the lumen is still patent.

Prognosis and predictive factors
Undifferentiated thyroid carcinoma is a highly aggressive malignant neoplasm typified by rapidly progressive local disease. The overall five-year survival ranges from 0-14 % and the median survival is 2.5-6 months. Prognostic factors are related primarily to the extent of disease at presentation. Rare cases exhibiting a better prognosis usually include localized tumors less than 5 cm, particularly small foci that are only identified microscopically. Undifferentiated thyroid cancers may be associated with adjacent well-differentiated thyroid cancer, but the prognosis depends on the size of undifferentiated component and the efficacy of eradicative surgery. Those patients with tumors that are amenable to complete surgical resection combined with preoperative or postoperative adjuvant doxorubicin-based chemotherapy and irradiation may have prolonged survival. Predictor factors are associated with histomorphologic and genetic features of the tumor have not been identified.