Application of Immunohistochemistry to Thyroid Neoplasms

Archives of Pathology & Laboratory Medicine,  Mar 2008  by Fischer, Sandra,  Asa, Sylvia L

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Context.-Thyroid lesions with nodular architecture and follicular pattern of growth often pose difficulties in accurate diagnosis during the assessment of cytologic and histologic specimens. The diagnosis of follicular neoplasm on cytology or of follicular tumor of uncertain malignant potential on histology is likely to cause confusion among clinicians and delay effective management of these lesions. Occasionally, thyroid tumors represent unusual or meta-static lesions and their accurate diagnosis requires immu-nohistochemical confirmation.

Objective.-To review the literature on the applications of immunohistochemistry in the differential diagnosis of thyroid tumors.

Data Sources.-Relevant articles indexed in PubMed (National Library of Medicine) between 1976 and 2006.

Conclusions.-Our review supports the use of ancillary techniques involving a panel of antibodies suitable for im-munohistochemistry and molecular analysis in the assessment of thyroid nodules. These tools can improve diagnostic accuracy when combined with standard morphologic criteria.

(Arch Pathol Lab Med. 2008;132:359-372)

Thyroid cancer is the most common endocrine malignancy, and more than 95% of thyroid carcinomas originate from follicular epithelial cells.1 The incidence of thyroid carcinomas derived from follicular cells varies worldwide depending on dietary iodine intake, but in most countries it has increased during the past few decades and in North America it is one of the most rapidly increasing cancers, representing a major cause of morbidity in premenopausal women.2,3 Medullary carcinomas that originate from parafollicular C cells, which are involved in the production of calcitonin, are rare, representing only about 3% of thyroid tumors. Most follicular cell-derived carcinomas are well-differentiated malignancies that can be effectively treated by surgical resection with or without radioactive iodine ablation. They tend to occur more often in females and in patients at a younger age. A subset comprising undifferentiated carcinomas that usually affect older patients behave very aggressively, and for these tumors there is no effective management at the present time. In addition, there is a third category of poorly differentiated carcinomas with an intermediate biology between well-differentiated and undifferentiated thyroid carcinomas.

Papillary thyroid carcinoma (PTC) is the most common of the well-differentiated carcinomas (85%) and is characterized by distinctive nuclear features.1,4 Metastasis to regional lymph nodes may occur in up to 50% of cases of PTC. Variants of papillary carcinoma include the classical subtypes with papillary architecture; the follicular variant PTC that lacks papillae but retains classical nuclear atypia; oncocytic tumors that can have either papillary or follicular architecture associated with the nuclear features of PTC and oncocytic cytoplasm; and tall-cell, solid, and crib-riform types. Follicular thyroid carcinoma (FTC) is less frequent (10%) and is composed of follicles with variable size lined by well-differentiated epithelial cells lacking the characteristic nuclear features of papillary carcinoma. Because follicular carcinomas are able to disseminate he-matogenously, distant metastasis occurs in up to 20% of cases. Variants of FTC include oncocytic and clear cell subtypes.4

Most thyroid tumors can be readily diagnosed using histopathologic criteria, which allow the pathologist to differentiate benign from malignant lesions and guarantee an accurate classification for the majority of the variants of carcinomas derived from follicular epithelial cells. However, in most cases, the pathologist is confronted with thyroid lesions in which the distinction between benign and malignant can be quite subtle. The decision favoring one or another has clinical consequences and implies different modalities of treatment. On one hand, there is the need to avoid excessive treatment and psychological discomfort to the patient. On the other hand, patients with potentially aggressive disease need to be guaranteed effective management at the initial stages of disease when it is still curable. For this reason, the approach to these challenging tumors should include ancillary techniques, immunohistochemistry and molecular profiling, that can improve the standard morphologic assessment both in surgical specimens and in cytology samples obtained by fine-needle aspiration.5-8

Genetic studies have identified a process of cumulative molecular events involved in thyroid tumor initiation and progression, resulting in genomic instability and the capacity for independent cellular growth, invasion, and metastasis. 9 It seems unrealistic to expect a single tool, in the form of a magic biomarker, to be able to effectively resolve the diagnostic dilemmas in thyroid pathology. Each marker differentially expressed in tumorous and nontumorous tissues represents a snapshot of the molecular events succeeding in the tissue environment. The amount of information a single marker offers is often insufficient to understand tumor biology or to render accurate diagnosis. The use of combined immunohistochemical markers as a panel seems to be an alternative to aid some of the diagnostic challenges in surgical pathology and cytopathology of thyroid specimens.7,10,11 Most important, genomic and proteomic technologic approaches are being developed to introduce molecular signatures capable of separating benign from malignant thyroid tumors and, in the last group, to distinguish tumors with indolent and aggressive behavior.12-14