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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.

Poorly Differentiated Thyroid Carcinoma (2)

The term of poorly differentiated carcinoma was introduced by Sakamoto et al in 1983 and their criteria were based mainly on the presence of non-glandular components with a solid, trabecular, and scirrhous growth pattern. Others have included aggressive papillary thyroid carcinoma variants such as columnar cell, tall cell, diffuse sclerosing, and solid. The fact that these papillary thyroid cancer variants tend to show a more aggressive behavior pattern that the classic type of differentiated thyroid carcinoma does not in itself justify the use of term poorly differentiated, as defined by the tumor architecture. Furthermore, these tumors do not have an invariably poor prognosis. For example, the solid variant of papillary thyroid cancer displays some aggressive features, but patients tend to be younger and with appropriate treatment, their overall prognosis is similar to that of classic papillary thyroid cancer.
The insular carcinoma is the best characterized group of poorly differentiated carcinoma. Langhans fist described it in 1907 as “wuchernde strum” (proliferating struma). He described a tumor characterized by a distinct nesting pattern, formation of small follicular lumina leading to a cribriform configuration, small size and uniformity of the tumor cells, necrosis, and a focally peritheliomatous pattern of growth. It was reinterpreted and termed poorly differentiated “insular” thyroid carcinoma by Carcangiu et al in 1984. The term insular was used to describe these tumors because the cellular appearance was similar to that seen in the insular type of carcinoid tumors.

Definition
Follicular cell neoplasm that shows limited evidence of structural follicular cell differentiation and occupy both morphologically and behaviorally an intermediate position between differentiated (follicular and papillary carcinomas) and undifferentiated (anaplastic) carcinomas (1).

Etiology
The etiology is unknown. While some of these tumors appear to arise from preexisting papillary and follicular thyroid carcinomas, others most likely arise de novo.

Clinical features
Most poorly differentiated carcinomas appear as solitary large thyroid masses, cold by scintigraphy, with or without concurrent enlarged regional lymph nodes. Frequently, there is a history of recent growth in a long-standing uninodular or multinodular thyroid. Conversely, poorly differentiated carcinomas may occasionally present as rapidly growing masses. In addition to nodal metastasis, lung and bone metastases are also relatively frequent at the time of diagnosis.

Macroscopy
Most of tumors are over 3 cm in diameter at the time of diagnosis and are solid and gray-white with frequent foci of necrosis. Most tumors have pushing borders and, rarely, a thick capsule. In many cases there is also invasive, peritumoral growth that occasionally leads to satellite nodules within the thyroid parenchyma. Extrathyroidal extension is less commonly present than in undifferentiated entiated carcinomas.

Histopathology
The histopathological appearance of poorly differentiated thyroid carcinoma is variable. Three different histologic patterns are recognized: insular, trabecular, and solid. The diagnosis relies on the identification of these patterns in the majority of the tumor together with an infiltrative pattern of growth, necrosis, and obvious vascular invasion (Figure). Discrepancies do exist with regard to the significance of a minor poorly differentiated component in an otherwise well differentiated carcinoma, but on study has shown that the presence of more than 10 % of such pattern is associated with extrathyroidal invasion, and lymph node metastasis at the diagnosis. Some tumors display clear and oncocytic cells. Rarely these tumors may contain cells with rhabdoid features.
The insular pattern is characterized by well-defined nests of tumor cells surrounded by thin fibrovascular septa, which are frequently separated from tumor cells by artefactual cleft. The nest are predominantly solid, but may contain small follicles. Tumor cells are generally small and uniform and contain round hyperchromatic or vesicular nuclei with indistinct nucleoli. Mitotic figures are common (Figure).
The trabecular pattern is characterized by cells arranged in cords or ribbons, while the solid pattern exhibits large sheets of tumor cells that occasionally may show small abortive follicles or some colloid droplets. Poorly differentiated carcinoma may contain a minor component showing features of papillary or follicular carcinoma. Also some cases show focal nuclear pleomorphism, resembling an undifferentiated carcinoma. The presence of undifferentiated component should be reported because of some of these tumors have behaved as undifferentiated carcinoma.

Figure. Poorly differentiated thyroid carcinoma. The tumor has a trabecular (A), insular (B), and solid (C) growth patterns. D. The poorly differentiated carcinomas have obvious vascular invasion.

Immunohistochemistry
Poorly differentiated carcinomas typically show immunoreactivity for thyroglobulin and TTF-1. Focal TP53 nuclear positivity and increased Ki-67 index is also common features. Most poorly differentiated carcinomas show absence of E-cadherin membranous expression in contrast to normal thyroid and well differentiated thyroid carcinomas.

Differential diagnosis
This includes medullary carcinoma, follicular carcinoma, metastatic carcinoma and solid variant of papillary carcinoma. Demonstration of positive immunostaining for thyroglobulin is useful in the distinction of these tumors from medullary and metastatic carcinomas. Rarely, poorly differentiated carcinomas may coexpress calcitonin and other neuroendocrine markers in scattered cells. Thyroid papillary carcinoma with solid areas usually occurs in young patients and exhibits typical nuclear features of ground-glass appearance and grooves.

Prognosis and predictive factors
The means survival ratio is about 50% in most series. The majority of patients die in the first three years after diagnosis and few patients survive >5 years. Death is usually caused by regional and distant metastases rather than by local invasion. The prognosis of patients with poorly differentiated carcinoma depends on primarily on the TNM staging, completeness of surgery and responsiveness to radiation iodine therapy. The prognostic significance of the prominence of necrotic foci, histologic pattern, extent of vascular invasion and degree of aneuploidy remains controversial. There is no sufficient evidence that any molecular genetic alteration plays a significant role in prognosis.

Thyroid carcinoma (1)

Malignant tumors of thyroid follicular cell origin have been classified into well differentiated thyroid carcinoma, which is composed of papillary and follicular carcinoma, poorly differentiated carcinoma and undifferentiated (anaplastic) carcinoma The vast majority of patients with well differentiated thyroid carcinoma have an excellent prognosis regardless of the types of treatment used, whereas patients with undifferentiated carcinoma uniformly have a poor prognosis.

There is a growing evidence for the existence of a group of tumors that fall between well differentiated thyroid carcinoma and undifferentiated thyroid carcinoma in terms of both morphologic appearance and biologic behavior. These tumors, classified as poorly differentiated, may represent intermediate entities in the progression of well differentiated to undifferentiated thyroid carcinoma.

Бамбай булчирхайн эсийн шинжилгээний дүгнэлт өгөх нь

The Bethesda System for Reporting Thyroid Cytopathology (2009):
Recommended Diagnostic Categories*

I. Nondiagnostic or Unsatisfactory
Cyst fluid only
Virtually acellular specimen
Other (obscuring blood, clotting artifact, etc)

II. Benign
Consistent with a benign follicular nodule (includes adenomatoid nodule, colloid nodule, etc)
Consistent with lymphocytic (Hashimoto) thyroiditis in the proper clinical context
Consistent with granulomatous (subacute) thyroiditis
Other

III. Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance

IV. Follicular Neoplasm or Suspicious for a Follicular Neoplasm
Specify if Hürthle cell (oncocytic) type

V. Suspicious for Malignancy
Suspicious for papillary carcinoma
Suspicious for medullary carcinoma
Suspicious for metastatic carcinoma
Suspicious for lymphoma
Other

VI. Malignant
Papillary thyroid carcinoma
Poorly differentiated carcinoma
Medullary thyroid carcinoma
Undifferentiated (anaplastic) carcinoma
Squamous cell carcinoma
Carcinoma with mixed features (specify)
Metastatic carcinoma
Non-Hodgkin lymphoma
Other
* Adapted with permission from Ali and Cibas.3

Malignant teratoid medulloepithelioma

Case No.1
This patient was 11 years old boy who diagnosed a protruding mass in right eye on CT findings. He received enucleation as a treatment. On gross examination, the lesion was brown colored mass with cystic change and hemorrhage, measuring 1.2 x 1.0 x 0.8 cm. The following photos are from the this mass. What do you think about the pathological diagnosis?

Final pathological diagnosis was malignant teratoid medulloepithelioma.

Information. Medulloepithelioma is a rare, malignant embryonal tumour of the central nervous system of young children, typically occurring between 6 months and 5 years of age, with about half of the cases occurring during the first 2 years. Histologically, it is characterised by papillary, tubular or trabecular arrangements of neoplastic neuroepithelium mimicking the embryonic neural tube. It may arise along nerve trunks or in the eye. Medulloepithelioma of the central nervous system is a highly malignant neoplasm with a high propensity of dissemination, while ocular medulloepithelioma usually has a benign course. Ocular medulloepithelioma most commonly affects one eye and arises from the nonpigmented epithelium of the ciliarybody. It is a slow-growing tumour, with two pathologic variants, i.e. non-teratoid and teratoid when heterologous elements, such as brain, cartilage or skeletal muscle, can be found in the tumour tissue. Both variants can be either benign or malignant. Medulloepithelioma is the second most common intraocular tumor in children, after retinoblastoma. It is usually diagnosed in the first decade of life, mostly in early childhood at a mean age of 2–4 years, although rarely it has been reported in adults. J Neurooncol (2010) 96: 443-448

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