The Optically Clear Nucleus 289 Clinical Research 289 Address correspondence to Dr. Z. Baloch, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 6 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104. E-mail: baloch@mail.med. upenn.edu Endocrine Pathology, vol. 13, no. 4, 289–299, Winter 2002 © Copyright 2002 by Humana Press Inc. All rights of any nature whatsoever reserved. 1046–3976/02/13:289–299/ $20.00 Etiology and Significance of the “Optically Clear Nucleus” Zubair W. Baloch, MD, PHD and Virginia A. LiVolsi, MD Abstract Papillary thyroid carcinoma (PTC) is diagnosed in both cytology and surgical pathology specimens on the basis of distinct nuclear morphology, characterized by nuclear elonga- tion, chromatin clearing, intranuclear grooves, and inclusions. Although these nuclear features are specific to papillary carcinoma, they can be mimicked in some benign condi- tions. The majority of PTC cases do not pose diagnostic problems. However, a distinct subset of cases has generated controversy among experts. These cases are follicular pat- terned tumors that show minimal nuclear changes in PTC. Several investigators have explored the role of immunohistochemical markers in the histologic diagnosis of PTC. Somatic rearrangements of the RET protooncogene are the most frequent genetic abnormality found in PTC. The frequency of these rearrangements has varied according to the geographic region, radiation exposure, and methodologies used and histologic variant of PTC. Recent studies have suggested that RET/PTC may be the cause of this specific nuclear change in PTC; however, the role of RET/PTC in tumor progression still needs to be defined. Key Words: Papillary carcinoma; immunohistochemistry; diagnosis; RET/PTC. have had thyroid cancer, and some of these still survive 40 yr after diagnosis [1,2]. At present, thyroid carcinoma in general is classified pathologically as well-differen- tiated, poorly differentiated, and anaplastic carcinoma [3–5]. Well-differentiated carci- nomas comprise a major portion of thyroid cancers [3,5,6]. They are more common in young adults, whereas, less differentiated and anaplastic tumors of the thyroid are prevalent in old age. Well-differentiated thy- roid tumors are known for their indolent biologic behavior and excellent prognosis, with the reported 5-yr survival rates of 90% for males and 94% for females [7]. On the other hand, anaplastic carcinoma is an extremely aggressive tumor and can lead to death within 6-mo of diagnosis. The prog- nosis of poorly differentiated carcinoma falls between that of well-differentiated and anaplastic carcinoma [4–6]. Introduction Primary malignant tumors of the thy- roid constitute <1% of all human cancers and are a rare cause of death. The annual incidence of thyroid cancer in different parts of the world ranges from 0.5 to 10 cases per 100,000 population. Thyroid cancer is the most common type of endo- crine malignancy (90% of all endocrine malignancies) and accounts for the major- ity of deaths from endocrine cancers. According to the American Cancer Soci- ety, approx 17,000 new cases of thyroid cancer are diagnosed annually and 1200 deaths are related to thyroid cancers, accounting for 60% of total deaths from endocrine malignancies. Despite these statistics, the majority of thyroid cancers are treat- able and carry an excellent prognosis. In the United States, approx 190,000 patients